Woodward, Robert B. (1917-1979)

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Woodward, Robert B. (1917-1979)

American biochemist

Robert B. Woodward was arguably the greatest organic synthesis chemist of the twentieth century. He accomplished the total synthesis of several important natural products and pharmaceuticals. Total synthesis means that the molecule of interestno matter how complexis built directly from the smallest, most common compounds and is not just a derivation of a related larger molecule. In order to accomplish his work, Woodward combined physical chemistry principles, including quantum mechanics, with traditional reaction methods to design elaborate synthetic schemes. With Nobel Laureate Roald Hoffmann, he designed a set of rules for predicting reaction outcomes based on stereochemistry, the study of the spatial arrangements of molecules. Woodward won the Nobel Prize in chemistry in 1965.

Robert Burns Woodward was born in Boston on April 10, 1917, to Arthur and Margaret (Burns) Woodward. His father died when he was very young. Woodward obtained his first chemistry set while still a child and taught himself most of the basic principles of the science by doing experiments at home. By the time he graduated at the age of 16 from Quincy High School in Quincy, Massachusetts, in 1933, his knowledge of chemistry exceeded that of many of his instructors. He entered the Massachusetts Institute of Technology (MIT) the same year but nearly failed a few months later, apparently impatient with the rules and required courses.

The MIT chemistry faculty, however, recognized Woodward's unusual talent and rescued him. They obtained funding and a laboratory for his work and allowed him complete freedom to design his own curriculum, which he made far more rigorous than the required one. Woodward obtained his doctorate degree from MIT only four years later, at the age of 20, and then joined the faculty of Harvard University after a year of postdoctoral work there.

Woodward spent virtually all of his career at Harvard but also did a significant amount of consulting work with various corporations and institutes around the world. As is true in most modern scientific endeavors, Woodward's working style was characterized by collaboration with many other researchers. He also insisted on utilizing the most up-to-date instrumentation, theories.

The design of a synthesis, the crux of Woodward's work, involves much more than a simple list of chemicals or procedures. Biochemical molecules exhibit not only a particular bonding pattern of atoms, but also a certain arrangement of those atoms in space. The study of the spatial arrangements of molecules is called stereochemistry, and the individual configurations of a molecule are called its stereoisomers. Sometimes the same molecule may have many different stereoisomers; only one of those, however, will be biologically relevant. Consequently, a synthesis scheme must consider the basic reaction conditions that will bond two atoms together as well as determine how to ensure that the reaction orients the atoms properly to obtain the correct stereoisomer.

Physical chemists postulate that certain areas around an atom or molecule are more likely to contain electrons than other areas. These areas of probability, called orbitals, are described mathematically but are usually visualized as having specific shapes and orientations relative to the rest of the atom or molecule. Chemists visualize bonding as an overlap of two partially full orbitals to make one completely full molecular orbital with two electrons. Woodward and Roald Hoffmann of Cornell University established the Woodward-Hoffmann rules based on quantum mechanics, which explain whether a particular overlap is likely or even possible for the orbitals of two reacting species. By carefully choosing the shape of the reactant species and reaction conditions, the chemist can make certain that the atoms are oriented to obtain exactly the correct stereochemical configuration. In 1970, Woodward and Hoffmann published their classic work on the subject, The Conservation of Orbital Symmetry; Woodward by that time had demonstrated repeatedly by his own startling successes at synthesis that the rules worked.

Woodward and his colleagues synthesized a lengthy list of difficult molecules over the years. In 1944 their research, motivated by wartime shortages of the material and funded by the Polaroid Corporation, prompted Woodwardonly 27 years old at the timeand William E. Doering to announce the first total synthesis of quinine, important in the treatment of malaria . Chemists had been trying unsuccessfully to synthesize quinine for more than a century.

In 1947, Woodward and C. H. Schramm, another organic chemist, reported that they had created an artificial protein by bonding amino acids into a long chain molecule, knowledge that proved useful to both researchers and workers in the plastics industry. In 1951, Woodward and his colleagues (funded partly by Merck and the Monsanto Corporation) announced the first total synthesis of cholesterol and cortisone, both biochemical steroids. Cortisone had only recently been identified as an effective drug in the treatment of rheumatoid arthritis, so its synthesis was of great importance.

Woodward's other accomplishments in synthesis include strychnine (1954), a poison isolated from Strychnosspecies and often used to kill rats; colchicine (1963), a toxic natural product found in autumn crocus; and lysergic acid (1954) and reserpine (1956), both psychoactive substances. Reserpine, a tranquilizer found naturally in the Indian snake root plant Rauwolfia, was widely used to treat mental illness and was one of the first genuinely effective psychiatric medicines. In 1960, after four years of work, Woodward synthesized chlorophyll , the light energy capturing pigment in green plants, and in 1962 he accomplished the total synthesis of a tetracycline antibiotic.

Total synthesis requires the design and then precise implementation of elaborate procedures composed of many steps. Each step in a synthetic procedure either adds or subtracts chemical groups from a starting molecule or rearranges the orientation or order of the atoms in the molecule. Since it is impossible, even with the utmost care, to achieve one hundred percent conversion of starting compound to product at any given step, the greater the number of steps, the less product is obtained.

Woodward and Doering produced approximately a half a gram of quinine from about five pounds of starting materials; they began with benzaldehyde, a simple, inexpensive chemical obtained from coal tar, and designed a 17-step synthetic procedure. The 20-step synthesis that led to the first steroid nucleus required 22 lb (10 kg) of starting material and yielded less than a twentieth of an ounce of product. The best synthesis schemes thus have the fewest number of steps, although for some very complicated molecules, "few" may mean several dozen. When Woodward successfully synthesized chlorophyll (which has an elaborate interconnected ring structure), for example, he required 55 steps for the synthesis.

Woodward's close friend, Nobel Laureate Vladimir Prelog, helped establish the CIBA-Geigy Corporation-funded Woodward Institute in Zurich, Switzerland, in the early 1960s. There, Woodward could work on whatever project he chose, without the intrusion of teaching or administrative duties. Initially, the Swiss Federal Institute of Technology had tried to hire Woodward away from Harvard; when it failed, the Woodward Institute provided an alternative way of ensuring that Woodward visited and worked frequently in Switzerland. In 1965, Woodward and his Swiss collaborators synthesized Cephalosporin C, an important antibiotic. In 1971 he succeeded in synthesizing vitamin B12, a molecule bearing some chemical similarity to chlorophyll, but with cobalt instead of magnesium as the central metal atom. Until the end of his life, Woodward worked on the synthesis of the antibiotic erythromycin.

Woodward, who received a Nobel Prize in 1965, helped start two organic chemistry journals, Tetrahedron Letters and Tetrahedron, served on the boards of several science organizations, and received awards and honorary degrees from many countries. Some of his many honors include the Davy Medal (1959) and the Copley Medal (1978), both from the Royal Society of Britain, and the United States' National Medal of Science (1964). He reached full professor status at Harvard in 1950 and in 1960 became the Donner Professor of Science. Woodward supervised more than three hundred graduate students and postdoctoral students throughout his career.

Woodward married Irji Pullman in 1938 and had two daughters. He was married for the second time in 1946 to Eudoxia Muller, who had also been a consultant at the Polaroid Corporation. The couple had two children. Woodward died at his home of a heart attack on July 8, 1979, at the age of 62.

See also Biochemical analysis techniques; Biochemistry; History of the development of antibiotics

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