K. Barry Sharpless Steps into the Spotlight

By Mika Ono and Jason Bardi

It was 1980 and the experiments were going suspiciously well.

"Most of us in research know that almost all of those things that seem much better than they should be are, indeed, not correct," says K. Barry Sharpless, W.M. Keck Professor of Chemistry, The Skaggs Institute for Chemical Biology at The Scripps Research Institute (TSRI). "[In these cases] it's important to kill it as fast as you can. That, in fact, is my special talent."

What he and his colleague Tsutomu Katsuki, now at Kyushu University in Japan, were working on was developing a process by which molecules of one "handedness"—or chirality—could be produced. Many molecules, natural or synthetic, come in two "mirror-image" forms—one left-handed, one right. While in nature molecules of only one "handedness" occur, no one had yet figured out how to make them easily in the laboratory.

Sharpless kept trying new ways to challenge the all-too-perfect results, but none succeeded in derailing the findings.

"We kept trying to kill it, and it kept getting better," he recalls. "I was very excited. That was a moment that only comes once or twice in a lifetime."

Sharpless and Katsuki had, in fact, made an enormous breakthrough. They had developed what would come to be known as "the Sharpless asymmetric epoxidation," a simple process by which molecules of a single handedness could be selectively produced.

Some two decades later—on Wednesday, October 10, 2001, at 3 AM to be precise—the telephone rang at the Sharpless house. Groggily, as he had only gone to bed an hour earlier, Sharpless received the news that he had won the 2001 Nobel Prize in Chemistry with two other scientists working in the field of chirality, St. Louis's William S. Knowles and Nagoya University's Ryoji Noyori.

The Importance of Handedness

Chiral molecules were one of the great discoveries of Louis Pasteur, who observed in the mid-1800s that two distinct crystal forms of tartaric acid would rotate polarized light in opposite directions. Pasteur correctly postulated that the two crystal forms were enantiomers, or right and left handed mirror images of each other. Chirality is central to life, as many of important molecules come in two mirror-image forms that have very different properties. The fundamental molecules of life—DNA and proteins—are, in fact, composed respectively of right- and left-handed subunits only. Nature often discriminates between chiral forms of small molecules, too, and what is a medicine on the one hand can be a poison on the other.

One example of this is thalidomide. Thalidomide, which was given to pregnant women as a sedative and anti-nausea drug in the 1950s in Europe, turned out to produce debilitating birth defects such as missing limbs. But, in fact, only one enantiomer of the molecule is responsible for these effects.

"Because they didn't in those days test [left and right handed molecules] separately, they didn't find out that [one form of] the drug was good for causing women to relax, to help them sleep, while the other one was a teratogen, [causing birth defects]," explained Sharpless. "That would have been a case where, if this were available, it might have been less tragic." Sharpless is careful to point out that even this case is not simple, as the two forms of the molecule are interconverted slightly in the body.

This Dr. Jekyll-Mr. Hyde persona of different handedness of the same molecule is true of other substances as well. For example, a left-handed molecule makes up the active ingredient in the drug Ethambutol, used to treat tuberculosis. Its right-handed counterpart can cause blindness. The left-handed form of Penicillamine has anti-arthritic properties, while its right-handed form is extremely toxic.

Even when one hand of a molecule appears to be neutral, it is often prudent to leave it out of a drug. Not only can the dosage be halved in this manner, but long-term safety risks, some that may not appear for generations, can be reduced. Sharpless notes, "You've got to keep the chemicals down as much as possible… More targeted drugs is what it is all about."

When Sharpless and Katsuki developed the Sharpless expoxidation in 1980, they solved a long-standing dilemma. Chemical synthesis of a useful compound would most often result in a racemic mixture—one composed of equal amounts of right- and left-handed forms. However, chemists knew for years that nature often gets around this problem by selectively synthesizing only one chiral form or the other. With their method, Katsuki and Sharpless found a way to do the same thing in the laboratory.

One aspect of this method that makes it useful in the real world is its simplicity. It uses two inexpensive, readily available commercial agents—a titanium compound and either the right or left hand of the chemical tartrate—a close relative of the same substance that enabled Pasteur to discover the property of chirality over 150 years before.

Julius Rebek, director of The Skaggs Institute where Sharpless conducts his research, describes the ease of the process metaphorically, "The original Sharpless epoxidation reagent was made from white wine, white paint, rubbing alcohol, and peroxide—go figure."

Accolades

By 11 AM on October 10, the news that Sharpless had won the Nobel Prize had spread. Sharpless stood in the W. M. Keck Foundation Amphitheater of TSRI's Beckman Center for Chemical Sciences Building surrounded by television cameras, photographers, and journalists, who peppered him with questions.

How did he feel? "Discombobulated."

How did he hear the news? Ehud "Udi" Keinan, a TSRI colleague colleague, called.

What next? "I want to make structures that work almost instantly." In other words, nothing short of revolutionizing the process by which drugs are developed.

Sharpless was generous in his thanks to his family, his friends, his supporters—who include philanthropists Sam Skaggs and Arnold Beckman, the W. M. Keck Foundation, and the National Institutes of Health—and his many colleagues and fellow employees at TSRI.

"There are so many excellent people here who make this place happen," he said.

 

 

 

 



TSRI's new Nobel laureate K. Barry Sharpless fields questions from reporters. Photos by Jason S. Bardi.