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ASYMMETRIC CATALYSIS WINS
[C&EN, Oct. 15, 2001]

CHIRAL CATALYSIS RIDING HIGH
[C&EN, Oct. 29, 2001]

CHIRAL PHARMACEUTICALS
[C&EN, Oct. 1, 2001]

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SCIENCE & TECHNOLOGY
November 5, 2001
Volume 79, Number 45
CENEAR 79 45 p. 37-39
ISSN 0009-2347
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WILLIAM WHO?
Chemists in industry don't earn many Nobel Prizes, so when one does, it's a moment to savor

STU BORMAN, C&EN WASHINGTON

"William Who?" Some chemists might be forgiven for asking that question several weeks ago when the Royal Swedish Academy of Sciences awarded the 2001 Nobel Prize in Chemistry to Monsanto retiree William S. Knowles; chemistry professor Ryoji Noyori of Nagoya University, in Japan; and chemistry professor K. Barry Sharpless of Scripps Research Institute.

MONSANTO TEAM Vineyard (from left), Knowles, and Sabacky worked on the development of chiral catalysis. PHOTO BY CHRISTINE NOONAN
Noyori and Sharpless are well known in the chemistry community. Their work on catalytic asymmetric synthesis has been reported in dozens of recent journal papers and has been covered widely in publications like C&EN. But Knowles's research has not been covered as extensively, and Knowles himself has not been as well known.

The Nobel Prize has now put an end to that. The essential contribution for which Knowles earned the prize is that he was the first to develop a transition-metal-based chiral catalyst that could transfer chirality to a prochiral substrate with high enantiomeric efficiency--showing that asymmetric catalysis can be the best way to make optically active products.

"One of the charms of research is that you never know where it's going or who the leader is going to be," writes David Gutsche in a congratulatory letter to Knowles, a longtime friend. Gutsche is a professor of chemistry emeritus at Washington University, St. Louis, and is now a chemistry professor at Texas Christian University, Fort Worth.

"Bill Knowles's monumental contributions cannot be overstated," says chemistry professor emeritus Jack Halpern of the University of Chicago. "The recognition and praise, albeit belated, are richly deserved and highly gratifying."

The Nobel committee "selected brilliantly," says chemistry professor Eric N. Jacobsen of Harvard University, who specializes in asymmetric catalysis. "The choice of Knowles might have caught some by surprise, but it's extremely well deserved, and he definitely set the stage for the whole field with his work. So I was especially happy to see him be recognized. The award going to Sharpless and Noyori, everyone expected at this point."

Knowles has been less well known than the other two new chemistry laureates, Jacobsen explains, "partly because he worked in industry and partly because the work that he did is now 30 years old. So a lot of people just aren't aware of it. But when I was a postdoc with Sharpless, I asked him what was the event or who was the person who gave him the inspiration and the confidence to work in the field of asymmetric catalysis. He didn't even think for a second. He immediately said, 'It was Knowles.' "

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 for the field from day one," Jacobsen adds. "That has served the field very well, obviously."

Knowles, now 84, earned a bachelor's degree in chemistry at Harvard in 1939 and a Ph.D. in steroid chemistry at Columbia University in 1942. He accepted a position at Monsanto, in St. Louis, immediately after graduating from Columbia. In 1951, he studied the total synthesis of steroids while on a company-sponsored postdoctoral fellowship in the laboratory of Harvard chemistry professor and Nobel Laureate Robert B. Woodward. The postdoc represented "a turning point in my career," Knowles says, because it gave him an appreciation for a type of synthesis that was much more complex than the industrial process development projects he had been involved in up to that point.

At Monsanto, Knowles had specialized in exploratory process development on organic chemicals and intermediates, including fine chemicals and plasticizers, but after the postdoc with Woodward, he began a program on the total synthesis of steroids. In the late 1960s, Knowles headed a three-man team that set out to develop a catalyst that could be used to synthesize individual enantiomers of chiral compounds directly.

RHODIUM CATALYSIS Knowles and coworkers developed a chiral rhodium catalyst for asymmetric hydrogenation of substituted styrenes.
HIS TEAMMATES
on the project were Monsanto organic chemists Billy D. Vineyard and M. Jerry Sabacky. Actually, "the early phosphines and hydrogenations were all done solo by Sabacky," Knowles says. "I saw the potential of the project and abandoned all the other things I was doing to join it, and Vineyard, who was looking for challenging work, also joined us at about the same time." The group aimed to synthesize enantiomers without having to separate them from racemic mixtures (which was difficult and expensive) and without having to produce them in microorganisms (which generally produced only small amounts of natural products that were hard to isolate).

"Two developments that occurred in the mid-'60s offered a very attractive approach toward making such a catalyst," Knowles explained in a review article [Acc. Chem. Res., 16, 106 (1983)].

One was a rhodium-based homogeneous catalyst for hydrogenation of unhindered olefins, which had been discovered by John A. Osborn, Sir Geoffrey Wilkinson, and coworkers at Imperial College, London. "Homogeneous catalysts had been reported before," wrote Knowles, "but this was the first one that compared in rates with the well-known heterogeneous counterparts." Wilkinson later won a Nobel Prize in Chemistry for his work on organometallic compounds, and he was also the coauthor of the popular textbook "Advanced Inorganic Chemistry," better known as "Cotton & Wilkinson."

THE SECOND PRECEDENT was the discovery of methods for preparing optically active phosphines. These techniques were developed independently by groups led by chemistry professors Kurt M. Mislow of Princeton University and Leopold Horner of the University of Mainz, Germany.

To create chiral catalysts, Knowles, Vineyard, and Sabacky replaced the achiral ligand in Wilkinson's catalyst with a chiral ligand--either a known chiral ligand or one synthesized by the Mislow method. Knowles and coworkers verified the validity of this approach by creating a rhodium catalyst containing the known chiral ligand methylpropylphenylphosphine and using it to hydrogenate substituted styrenes, forming enantiomeric products such as (+)-hydratropic acid. Several academic research groups obtained similar results shortly thereafter.

Initially, the enantiomeric yields of the Monsanto group's catalytic chiral syntheses were poor. So after the principle had been demonstrated, the problem "became one of finding a proper match between ligand and substrate to get synthetically useful efficiencies," Knowles continued.

Eventually, the researchers were successful at solving this problem. For example, one catalyst they developed--a rhodium complex of a chiral monophosphine ligand called CAMP--was capable of catalyzing the asymmetric synthesis of desired products with enantiomeric excesses ranging from 80 to 88%.

In 1971, chemistry professor Henri B. Kagan of University of Paris South, Orsay, France, reported another important development in asymmetric catalysis--the synthesis of DIOP, a tartrate-derived ligand that was the first example of a chiral bis(phosphine). "His chiral diphosphine was the first of a long series showing there were many other ways to make an efficient chiral catalyst," Knowles says.

The Monsanto group soon developed its own diphosphine catalysts. One such catalyst was a rhodium complex of a diphosphine ligand called DiPAMP. DiPAMP, which could be easily synthesized using Mislow-type chemistry, was capable of catalyzing hydrogenation reactions with an enantiomeric efficiency of 95%.

Rhodium catalysts like the DiPAMP complex were expensive. However, they were so efficient that it was easily possible to use them to "make thousands of moles of product per mole of chiral agent," Knowles wrote, and "this enormous multiplier effect easily [offset] the high cost." Indeed, Monsanto used DiPAMP for a number of years in a commercial process--the catalytic hydrogenation of an enamide substrate to form a precursor of L-DOPA (3,4-dihydroxyphenylalanine), a treatment for Parkinson's disease.

AROUND 1980, the detailed atomic-level mechanism of the Monsanto team's rhodium-catalyzed asymmetric syntheses was worked out by Halpern's group and that of chemistry professor John M. Brown at the Dyson Perrins Laboratory of the University of Oxford. "The catalytic cycle proved very attractive for mechanistic study, and several key intermediates were revealed," Brown notes.

In 1981, Knowles, Vineyard, and Sabacky shared Monsanto's $25,000 Charles A. Thomas & Carroll A. Hochwalt Award for their collaboration in the invention of the asymmetric phosphine-rhodium catalysts used in the synthesis of L-DOPA and related products. At the time, Howard A. Schneiderman, then-senior vice president of R&D at Monsanto, said, "This achievement capped a century-long effort by organic chemists to control in a practical way the introduction of asymmetry in a molecule."

L-DOPA ROUTE This reaction, developed by Knowles, Vineyard, and Sabacky, was used at Monsanto as a commercial route to the Parkinson's drug L-DOPA.

AND NOW, Knowles has received one of those coveted early-morning phone calls from Sweden. He then helped spread the good news quickly to his group. "He called me at five o'clock in the morning and said, 'We won the Nobel Prize,' " Vineyard says.

"On behalf of everyone who works for Monsanto, we want to congratulate Dr. Knowles for his extraordinary accomplishments," says Hendrik A. Verfaillie, president and chief executive officer of Monsanto, now the agricultural products subsidiary of Pharmacia Corp. "The work that he undertook has changed the face of part of modern medicine, and we're proud to see this recognition for Dr. Knowles's personal achievements."

From time to time "we are fortunate enough that the science we pursue makes a profound difference for the world around us," adds Monsanto Chief Technology Officer Robert T. Fraley. "This is one of those times. Dr. Knowles has once again fulfilled a tradition of great science."

Now that the "William who?" question has been answered and Knowles has a bit more of the world's attention than he had before, he tells C&EN that the key message he would like to deliver is that, in his opinion, "industry does too little exploratory research." His group's Nobel Prize-winning project on asymmetric catalysis is "an excellent example of how a modest and inexpensive exploratory effort in industry can produce significant results," he says.

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100 YEARS AGO
Dutch Chemist Van't Hoff Won First Nobel Prize In Chemistry

In October 1901, Jacobus Henricus van't Hoff, then a professor at the University of Berlin, was named winner of the first Nobel Prize in Chemistry. He was recognized, according to the citation, for "the extraordinary services he has rendered by the discovery of the laws of chemical dynamics and osmotic pressure in solutions."

7945sci-hoff
Van't Hoff
COURTESY OF EDGAR FEHS SMITH COLLECTION
Van't Hoff's pioneering work, in the then-new discipline of physical chemistry, has had a significant impact on chemistry, biology, physics, and geology. He established the mathematical relationship between temperature, solute concentration, and osmotic pressure of dilute solutions. He investigated the dynamic nature of chemical equilibria and the velocity of chemical reactions, deducing, for example, the famous reaction isochore named after him that expresses the variation of equilibrium constant of a reversible reaction with temperature.

The third child in a family of seven children, van't Hoff was born in Rotterdam, the Netherlands, in 1852. He obtained a technology diploma at the Polytechnic School at Delft in 1871 and, three years later, a doctor's degree at the University of Utrecht.

His Ph.D. thesis was titled "Contribution to the Knowledge of Cyanoacetic Acids and Malonic Acid." However, a pamphlet that van't Hoff had published several months earlier proved to be far more influential--and controversial. In the pamphlet, which consisted of 12 pages of text and one page of diagrams, he postulated that the carbon atom in organic compounds has a three-dimensional tetrahedral structure.

His ideas on the stereochemistry of organic compounds were ridiculed by organic chemists in Germany such as Hermann Kolbe, who edited Journal für praktische Chemie (Journal for Practical Chemistry). Kolbe suggested that the pamphlet should be ignored because "the fancy trifles in it are totally devoid of any factual reality and are completely incomprehensible to any clear-minded researcher."

Van't Hoff's revolutionary ideas on stereochemistry found acceptance, however, with publication in 1875 of a paper on "chemistry in space." The following year, he was appointed lecturer at the University of Amsterdam, and two years later he became professor of chemistry, mineralogy, and geology at the university.

In 1895 he moved to Berlin, where he studied the origin and formation of oceanic salt deposits. By then, van't Hoff was highly respected within the chemical community for bringing physics and chemistry together, according to E. W. (Bert) Meijer, professor of macromolecular and organic chemistry at Eindhoven University of Technology, the Netherlands.

"Without doubt every modern chemist agrees that van't Hoff fully deserved the Nobel Prize, although many of them will connect van't Hoff's name more to stereochemistry than to the award science on chemical kinetics or osmotic pressure," Meijer writes in an essay on van't Hoff's 100 years of impact on stereochemistry in the Netherlands [Angew. Chem. Int. Ed., 40, 3783 (2001)].

Van't Hoff died of tuberculosis at Steglitz, near Berlin, in 1911.--MICHAEL FREEMANTLE



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