RESEARCH
Syntheses, General Approach Bring Nobel Prize R. B. Woodward of Harvard named for his skill in "art" of organic chemistry
Dr. R. B. Woodward Plan in detail, then carry it out
38
C&EN
NOV. 1, 1965
The significance of the Swedish Royal Academy of Sciences' award of the 1965 Nobel Prize in Chemistry to Dr. R. B. Woodward is in the citation: for his meritorious contributions to the "art" of organic synthesis. The honor thus acknowledges not only Dr. Woodward's syntheses of natural products as major achievements in themselves, but recognizes also the distinctive way in which he accomplished them. The results of the new Nobel laureate's methods give other synthetic organic chemists a standard to apply to their own work. But perhaps equally important, others of his calling have been given the incentive to attack problems that seem insurmountable. Beginning with the total synthesis of quinine in 1944, Dr. Woodward has developed a succession of highly original, elegant syntheses—an impressive list of organic chemical landmarks. He helped unravel the structure of strychnine in 1947. This was followed in 1949 by the synthesis of sempervirine, the synthesis of patulin a year later, and the first total synthesis of steroids (including cholesterol and cortisone) in 1951. He carried out the first synthesis of lanostenol (a triterpenoid), and the total syntheses of strychnine, lysergic acid, and ergonovine in 1954. His total synthesis of reserpine was disclosed in 1956, and that of chlorophyll in 1960. Vitamin B12. Dr. Woodward and his co-workers at Harvard are now working on the total synthesis of vitamin B 12 . Although it's too early to predict how soon this synthesis will be complete, he is pleased with progress so far. He and his group have recently prepared one of the key intermediates. Synthetic organic chemistry provides an excellent opportunity, the Harvard scientist believes, to meet the main objective of pure science—increase man's understanding of his environment. To successfully reach this goal, a scientist must plan his research in detail. Once this detailed plan is made, all the available tools (intellectual and physical) must be brought to bear on the problem.
It is this detailed planning and application of theory that sets Dr. Woodward apart from most other organic chemists. In a sense, he has achieved another synthesis—joining syntheticand physical-organic chemists. He has convinced others of the relevance and importance of theoretical organic chemistry to synthesis. Stereochemistry. In the course of his syntheses, Dr. Woodward intensively uses physical organic chemistry, particularly stereochemistry. Most of the compounds he has synthesized have large numbers of asymmetric centers. Reserpine, for example, has six asymmetric carbons. The vitamin B 12 intermediate recently synthesized also contains six asymmetric carbons. Thus, in reactions such as those involving ring closure, detailed consideration of all stereochemical consequences is extremely important. Synthetic organic chemistry also offers an opportunity to discover new principles. Chemists in this area of research continually test principles and try to make them more precise. But sometimes no existing principles seem to apply. The chemistry of natural products has generally led to great contributions to theories of organic chemistry, Dr. Woodward says. And it's consistent with his strong theoretical bent that he has made several contributions to theory. For example, he was the first to conceive of ferrocene's sandwich structure. He has also made basic contributions to the mechanism of reactions, such as the Diels-Alder condensation. More recently, he has proposed the so-called conservation of orbital symmetry, a principle unrecognized in the field of molecular orbital theory until then. The principle, which came as an outgrowth of his vitamin B 12 efforts, deals with the stereochemistry of electrocyclic reactions. The Nobel laureate was the first to make full use of modern theory in structure determinations and syntheses. His work makes it clear that the modern electronic theory of reaction mechanisms is a powerful, indispens-
able weapon for organic chemists if they would only master and apply it. The development of the electronic theory of organic chemistry (based on quantum mechanics and supported by the work of many physical organic chemists) began about 1925. Al though the scheme was potentially valuable to organic chemists, many felt that the new body of theory could be of only little help to practitioners of classical organic chemistry. In addition to applying the latest theories, Dr. Woodward urges use of the most appropriate instruments. As early as 1941, he discovered general izations relating the environment of «,β-unsaturated ketones and conjugated dienes to the position of their maxi mum ultraviolet absorption. From this beginning, he has gone on to make the most refined use of UV, infrared, and nuclear magnetic resonance spec troscopy. True to his thesis of using the best available tools, he finds it obvious that the most effective way to get at a structure now is with x-ray crystallog raphy. As this technique becomes routine in organic chemistry, there will be less need for older chemical meth ods for determining structures. The Nobel laureate and his Harvard co workers are successfully using x-ray crystallography in their vitamin B 1 2 work, for example. The use of all available tools has speeded the syntheses of complex molecules and structure determina tions. Quinine's structure, for in stance, was determined in 1908, al most a century after it was first iso lated as a pure substance. And the problem of determining strychnine's structure could hardly even begin for a century after the pure substance was available. It wasn't completed until 1947, capping almost 50 years of in tensive effort. Easier. However, with advances in the science of organic chemistry, the task has become easier. With greater understanding of chemical principles, with advances in experimental meth ods, and with increasing use of ancil lary physical disciplines, structures may now be determined in a small fraction of the time once required. Reserpine is a case in point: It was isolated in 1952, and its structure was fully elucidated by 1955. While Dr. Woodward views syn thetic organic chemistry primarily as a pure science, he doesn't exclude the possibility of practical applications of
his work. Practical aspects are going to be more important, he feels. For example, industrial synthesis of ster oids may become practical. And syn thetic reserpine is now produced com petitively with reserpine from the nat ural source, he notes. Thiamine, ribo flavin, ascorbic acid, and vitamin A, for example, have been synthesized. In almost every case, the enormous demand for many of these substances is met by industrial synthesis on a large scale. The degree of synthetic complexity which has been mastered on the indus trial scale in recent years is astonishing by earlier standards, Dr. Woodward says. This provides a basis for con fidently expecting ever-increasing ac tivity in this area. The steroid hor mones and their analogs are remark able examples. Should demand be come very large, larger than could be supplied by methods based on natural steroidal raw materials, total synthesis would form a basis for production. Continue. Contrary to the utilitar ian spirit of the day, however, syn thesis for its own sake will continue. There is excitement, adventure, and challenge in organic synthesis; and there can also be great art, Dr. Wood ward says. But while it is art, he points out, successful synthetic work is precise. The ability to predict, then complete the 55 steps in the total synthesis of chlorophyll requires precision. He expects to continue his work in synthetic organic chemistry. Part of his work will also be to continue to teach others. As Donner Professor of Science at Harvard (since 1960), he isn't required to lecture formally. But he feels that all he actually does is teach. Directing the research of about 25 graduate students and postdoctorates each year is teaching, but at a high level. H e points out that about two thirds of his students and postdoctoral fellows (he has trained about 250) go into academic work. He thus feels that he is contributing to chemical education. Dr. Woodward comments that it is the skill and devotion of the many people working with him who have made it possible for him to win the Nobel Prize. But he provided the leadership, associates note. In addi tion to possessing unusual intelligence (he had his Ph.D. from MIT in 1937 at age 20) he is a perceptive man, a perfectionist, and a hard worker, put ting in 10 to 12 hours most days.
Bacterial B12 Compound Is Cobalt-Free Corrinoid lacks cobalt found in other Bi2 vitamins Metabolic studies of a primitive bacterium have led to the discovery of a cobalt-free vitamin B 1 2 compound at the University of California, Berke ley. Corrin-aminopropanolphosphoribose has been identified in extracts from Chromatium strain D by Dr. J. I. Toohey of Berkeley's department of cell physiology [Proc. Natl. Acad. Set. U.S., 54, 934 (1965)]. The mol ecules of all previously known vitamin Bi2 compounds contain cobalt complexed in the center of a planar struc ture containing three pyrroline rings and a pyrrolidine ring. The corrinoid compound from Chro matium also lacks the heterocyclic base found in the B 1 2 compounds. But it does contain phosphate, ribose, and the methyl and aminoalkyl side chains present in the other B 1 2 com pound. Its physiological activity hasn't yet been determined. Chromatium's ability to fix atmos pheric carbon dioxide and nitrogen into organic compounds makes it an interesting organism for metabolic studies. Dr. Toohey sought to class ify the corrinoid compound in the cells' metabolic products by identify ing the heterocyclic base which, like the corrin ring, is coordinated with the central cobalt atom in vitamin B 1 2 . This heterocyclic base varies with the bacterial strain that produces the vita min. Dr. Toohey found no heterocyclic base at all in the corrinoid extract from Chromatium. The same hydrolysis technique that yielded more than 0.8 micromole of dimethylbenzimidazole per micromole of one B 1 2 compound, for example, produced no base from the new substance. Further work re vealed that cobalt, too, is absent—xray fluorescence analysis detected none of the metal in 0.5-micromole samples. Under the same conditions, 0.05 micromole of cobalt was detect able in vitamin B 1 2 samples. The medium used to grow Chro matium cultures at Berkeley contained 10 micrograms of cobalt per liter. A fivefold increase in cobalt concentra tion had no effect; about 1.1 mg. of the cobalt-free corrinoid compound was recovered per gram of cells grown in such enriched media; none of the NOV. 1, 1965 C & E N
39
