Discovery may lower drug costs

Organocatalysis, a term coined by MacMillan, circumvents the use of large quantities of dangerous, sensitive and costly metals in a catalytic reaction by replacing them with simple organic molecules.

Many organocatalytic reactions are photolytic, which means that they make use of high-energy light to initiate the reaction. The problem, MacMillan explained, was that the reactions required such a high-energy input that they were impractical for use on a large scale.

Sixteen months ago, Nicewicz thought to merge organocatalysis with classical inorganic catalysis, and the result was that the same transformations could be performed using little more than the reactants, a pair of organic and inorganic catalysts, and a 15-watt fluorescent light bulb as a photon source.

“[Nicewicz’] brilliance was that he went off and put together ideas completely in inorganic chemistry, and did photoredox catalysis and merged it with organocatalysis to allow the whole thing to happen,” MacMillan explained.

Though the article, published in the journal Science earlier this month, outlines an alkylation reaction, a particularly sensitive, expensive and common reaction in catalytic chemistry, the method is applicable to a wide variety of reactions.

Part of what makes organocatalytics appealing is its high enantioselectivity. An enantiomer is essentially one of a pair of molecules that are mirror images of each other (think of your left and right hands). The human body usually produces, and makes use of, only one enantiomer of a given molecule.

The functional difference was thought to be trivial until, in the late 1950s and early 1960s, the administration of the sedative Thalidomide to pregnant women to combat morning sickness was correlated with severe birth defects in their children. It was later discovered that, while one enantiomer acts as a sedative, the other causes limb deformities.

After thousands of children were born with birth defects, the Food and Drug Administration enacted strict guidelines for the enantiomeric specificity of drugs, necessitating costly and often environmentally unfriendly methods of purification. As a result, there has since been a need for enantioselective reactions that produce only one mirror image of a molecule.

MacMillan and Nicewicz’ reaction fits the bill, with high levels of selectivity resulting from the asymmetric nature of the molecules involved in the reaction.

“This method has the ultimate potential of streamlining the synthesis of particular pharmaceuticals,” Nicewicz said in an e-mail. “In essence, it could provide a small but hopefully significant role in reducing the cost of drug production.”

MacMillan cited the example of Merck Pharmaceuticals, which employs an organocatalytic reaction to produce the single enantiomer of the molecule in Januvia, a medication for type 2 diabetes. The characteristics of the reaction allow the company to avoid a purification step and, over the course of 12 years, will save $1.5 billion in production costs, MacMillan explained.

MacMillan came to Princeton during a renewed effort by the University to revamp the chemistry department. He said he saw an opportunity to build a department from the ground up and explained that his move coincided with a $500 million initiative that includes construction of the new chemistry building slated for completion in fall 2010.

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In collaboration with Merck, Princeton has also built the Merck Center for Catalysis, which possesses several high-throughput robots that accelerate the research process tremendously. “A good grad student can run five reactions in a day,” said MacMillan, who is also the director of the center. “A robot can run 1,000.” This takes a lot of the grunt work out of research, allowing graduate students more time to think about and plan their experiments, he explained.

MacMillan said that, in addition to further research into organocatalysis, his group is currently making use of its robotics facility to carry out a method of research called accelerated serendipity, whereby thousands of random reactions are run each day in the hope of stumbling upon something useful. The process has already produced some exciting results, MacMillan said, adding that he looks forward to developing the process as the project matures.