K. Barry Sharpless Steps into the Spotlight
By Mika Ono
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.
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