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October 27, 2003
Volume 81, Number 43
CENEAR 81 43 p. 42
ISSN 0009-2347


JACS AT 125

A PRACTICAL REACTION
Titanium-catalyzed asymmetric epoxidation paved the way to a Nobel Prize in Chemistry

MAUREEN ROUHI

The paper titled "The First Practical Method for Asymmetric Epoxidation," which reports the discovery of titanium-catalyzed asymmetric epoxidation [J. Am. Chem. Soc., 102, 5974 (1980)] evokes vivid memories for K. Barry Sharpless. Also called the Sharpless asymmetric epoxidation (AE), the reaction uses inexpensive reagents--(+)- or (–)-diethyl tartrate, titanium tetraisopropoxide, and tert-butyl hydroperoxide--to convert allylic alcohols into epoxides with high enantioselectivity and high predictability. The (+)-tartrate always adds the oxygen atom from one side of the plane of the double bond, and the (–)-tartrate adds the oxygen from the opposite side.

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CHEERS Katsuki (left) and Sharpless, in 1980, celebrate the discovery of titanium-catalyzed asymmetric epoxidation. COURTESY OF THE SHARPLESS LAB

The paper is one of the 125 most cited papers in the history of the Journal of the American Chemical Society, but it might never have been published there. Sharpless, a chemistry professor at Scripps Research Institute and winner of the Nobel Prize in Chemistry in 2001 for his work on asymmetric oxidations, says one reviewer rejected the paper on the grounds that it was merely an incremental improvement over previous work. The paper was published only after Barry M. Trost--then a member of the JACS Board of Editors and now a Stanford University chemistry professor--intervened, Sharpless says. "I wish I had kept the referee's report, because this was literally a Nobel Prize-winning paper," he adds.

Sharpless began exploring asymmetric transition-metal-catalyzed epoxidations of allylic alcohols in 1974. Among metals known to be active, he focused on vanadium and molybdenum because the rest--titanium, zirconium, niobium, and tantalum--were less effective. A practical reaction remained elusive, and by 1979, "my faith in the project was at its lowest," he wrote in a personal account of the discovery (CHEMTECH, November 1985, page 692).

In September 1979, however, Tsutomu Katsuki joined the Sharpless lab as a postdoc. His first task was to reevaluate titanium as an epoxidation catalyst. Influenced by discussions with the late Stanford chemistry professor Harry S. Mosher about the importance of C2-symmetric ligands, as advocated by Henri B. Kagan, Katsuki selected (+)-diethyl tartrate as a ligand for a titanium system to epoxidize a racemic mixture of isopropylvinylcarbinol, a chiral alcohol.

At this point, Sharpless says, he would have been satisfied with a diastereoselective system. "But the reaction was massively diastereoselective," Sharpless recalls. "It only reacted halfway, too, and I had a eureka moment. A 50% conversion looked like the reaction had eaten one enantiomer and not the other." When tested with prochiral allylic alcohols such as geraniol and nerol, the new AE system worked all the time. "I hadn't expected an asymmetric reaction to be so promiscuous," Sharpless says.

Sharpless credits Katsuki for making a key contribution to the discovery of titanium-catalyzed AE. Katsuki is now a chemistry professor at Kyushu University, in Japan, where the reaction is called the Katsuki-Sharpless epoxidation, as Sharpless himself always cites it. Sharpless says that after calling his father first about the news of the Nobel Prize, he called Katsuki next.

After further fine-tuning the reaction, Sharpless and coworkers wrote the how-to manual of titanium-catalyzed AE in a full paper titled "Catalytic Asymmetric Epoxidation and Kinetic Resolution: Modified Procedures Including In Situ Derivatization" [J. Am. Chem. Soc., 109, 5765 (1987)]. "If anybody has any questions about this reaction, I hope I answered them in this paper," Sharpless says. This paper also ranks among the top 125 most highly cited JACS papers.

M. G. Finn was a Sharpless graduate student in the early 1980s. He helped elucidate the mechanism of titanium-catalyzed AE for his Ph.D. thesis. He and Sharpless are now colleagues at Scripps. He says the reaction is important for two reasons. First, enantiomerically pure epoxides lead to a variety of interesting enantiomerically pure compounds. And second, the reaction established that human control of asymmetry could be much more general than what had been achieved up to that time.

"This was the early 1980s," Finn tells C&EN. "Asymmetric hydrogenation of olefins was the only practical catalytic asymmetric reaction then, but it does not give access to many compounds people wanted to make. Asymmetric epoxidation is tremendously useful because it makes a unit--the epoxide--that's easy to manipulate." Along with Sharpless' later catalytic reactions--asymmetric dihydroxylation and asymmetric aminohydroxylation--AE is a key synthetic organic chemistry tool. "What distinguishes Sharpless is that he focuses on reactions that are highly useful at a practical level," Finn adds.

Sharpless says he was inspired by enzymes to discover reactions that allow absolute control in the synthesis of stereocenters. He has come full circle, declaring that "catalysts made by humans just can't compare with enzymes" for making functional compounds. What most excites him these days is a new "philosophy" for organic synthesis--called click chemistry--that he believes will accelerate discovery of compounds with useful properties. "Function is what we really need, not discrete compounds," he says. And in click chemistry, he and others are using enzymes as reaction vessels for the last step in a synthetic sequence as a way to discover potent new inhibitors and modes of action (C&EN, Feb. 11, 2002, page 29).

In a commemorative issue of Chirality [15, 114 (2003)], Finn and Katsuki write, "Even a brief examination of this work [click chemistry] should convince the reader that it is all a piece with the rest of [Sharpless'] career and that curiosity ... and an appreciation for the practical can take a scientist very far indeed."


C&EN is celebrating the 125th volume of the Journal of the American Chemical Society by featuring selected papers from among its 125 most highly cited. Sharpless' papers are ranked 54th and 62nd.



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IN SITU CLICK CHEMISTRY
[C&EN, February 11, 2002]

ASYMMETRIC CATALYSIS WINS
[C&EN, October 15, 2001]

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