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ASYMMETRIC CATALYSIS WINS
Chemistry Nobel honors Knowles, Noyori, Sharpless for chiral syntheses
The 2001 Nobel Prize in Chemistry will be shared by three scientists who devised techniques for catalytic asymmetric synthesis--the use of chiral catalysts to accelerate the production of single-enantiomer compounds for pharmaceutical use and a wide range of other applications.
One-half of the approximately $950,000 prize will be split by Monsanto retiree William S. Knowles and chemistry professor Ryoji Noyori of Nagoya University, in Japan, for their work on catalytic asymmetric hydrogenation reactions. The other half goes to chemistry professor K. Barry Sharpless of Scripps Research Institute for research on catalytic asymmetric oxidations.
According to the Royal Swedish Academy of Sciences, Stockholm, the discoveries made by the three men "have had a very great impact on academic research and the development of new drugs and materials and are used in many industrial syntheses of drugs and other biologically active compounds." Sharpless and Noyori also shared--along with emeritus professor of chemistry Henri B. Kagan of the University of Paris-South--this year's $100,000 Wolf Foundation Prize in Chemistry for "pioneering, creative, and crucial work in developing asymmetric catalysis" (C&EN, Jan. 22, page 15).
The Nobel Prize announcement is "very sudden," Knowles tells C&EN. His contributions have not been widely acknowledged, but synthetic organic chemists recognize him as the person who jump-started the field of asymmetric catalysis. In 1968, he showed that a chiral transition-metal-based catalyst could transfer chirality to a nonchiral substrate, resulting in a chiral product. He took a rhodium-based hydrogenation catalyst discovered by John A. Osborn, Sir Geoffrey Wilkinson, and coworkers at Imperial College, London, and demonstrated that a chiral version of the complex could catalyze the reduction of achiral styrenes to asymmetric products such as (+)-hydatropic acid.
Knowles's group later developed a chiral diphosphine-rhodium complex that hydrogenates an enamide to a precursor of l-DOPA, a treatment for Parkinson's disease. This led to the first commercial use of a chiral transition-metal complex for catalytic asymmetric synthesis and to a number of similar commercial processes.
In the early 1950s, "it became my dream to contribute to society by becoming a good chemist," Noyori told C&EN earlier this year (July 23, page 33). He helped fulfill that dream in part by improving the enantiomeric efficiency of chiral catalysis. His group designed and synthesized the chiral disphosphine-binaphthyl compound BINAP, whose complexes with transition metals are remarkably effective asymmetric hydrogenation catalysts. BINAP-ruthenium(II) complexes catalyze the hydrogenation of functionalized olefins to form chiral products of high enantiomeric purity. For example, a BINAP-ruthenium(II) catalyst converts an unsaturated carboxylic acid to the anti-inflammatory agent naproxen with a yield of 92% and an enantiomeric purity of 97%.
Noyori and coworkers later found that ketone substrates are susceptible to conversion as well, if a base such as 1,2-diamine is added to the catalytic complex. BINAP-catalyzed hydrogenation reactions are currently used for the industrial- and lab-scale synthesis of pharmaceuticals, agrochemicals, flavors, and fragrances.
In 1980, Sharpless' group developed transition-metal and tartrate catalysts for the asymmetric epoxidation of allylic alcohols to epoxy alcohols. "I was very excited" by that discovery, Sharpless says. "That was a moment that only comes once or twice in a lifetime." Later on, he and his coworkers discovered that molecular sieves could be used to further improve the efficiency of asymmetric epoxidation--a process that led to the ton-scale industrial production of chiral glycidols, which are used to synthesize beta-blocker heart medicines, among other products. More recently, the researchers devised osmium-based catalysts for the catalytic dihydroxylation of olefins to chiral diols.
"The prize is long overdue," says chemistry professor Eric N. Jacobsen of Harvard University, who specializes in asymmetric catalysis. The Nobel committee "selected brilliantly," he says. "The choice of Knowles might have caught some by surprise, but it's extremely well deserved. By showing that you could get enzymelike selectivity with a synthetic catalyst and helping develop a commercial process, Knowles set the bar very, very high."
Of Noyori's work, Jacobsen says: "You can't open a journal today without seeing some new application of BINAP. And his most recent results--on the selective hydrogenation of carbonyl compounds in the presence of alkenes--are arguably his best, because they could lead to the next stage of what might be possible: doing selective reactions in a complicated context, sort of the way enzymes do."
Sharpless' epoxidation and dihydroxylation showed that synthetic catalysts could combine enzymelike selectivity with sufficient generality for a wide range of substrates, Jacobsen adds. "I just can't overstate how useful his work has been and how fundamentally it changed the way people thought about what you could do."
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