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November 28, 2011

Accelerated Serendipity with robotically assisted 1000 new chemical reactions per day

Scientists can now take that "a-ha" moment to go with a method Princeton University researchers developed — and successfully tested — to speed up the chances of an unexpected yet groundbreaking chemical discovery.

The new technique tries to accomplish "accelerated serendipity" by using robotics to perform more than 1,000 chemical reactions a day with molecules never before combined. In a single day of trials, the Princeton researchers discovered a shortcut for producing pharmaceutical-like compounds that shaves weeks off the traditional process, the researchers report.

Science - Discovery of an α-Amino C–H Arylation Reaction Using the Strategy of Accelerated Serendipity



"Our process is designed specifically for serendipity to occur. The molecules that should be combined are those for which the result is unknown," he said. "In our lab, we used this technique to make new findings in a much more routine and rapid fashion, and we show that if you have enough events involved, serendipity won't be rare. In fact, you can enable it to happen on almost a daily basis."

The MacMillan lab's technique does more than just expedite the discovery process — the researchers actually developed a unique framework for creating new materials or finding better ways of producing existing ones, said Stephen Buchwald, a professor of chemistry at the Massachusetts Institute of Technology.

"This is a particularly brilliant approach," said Buchwald, who is familiar with the work but had no role in it.

"Usually, one takes molecules that one thinks will react and tries to figure out the best way to achieve that reaction," he said. "This team took molecules for which there was no obvious reaction between them and looked for 'accidental' reactivity. This approach could be useful for any field that requires new types of matter or a more efficient means of synthesizing known compounds."

Illustrating that principle, the Princeton researchers combined two molecules with no history of reacting to generate the type of chemical functionality found in eight of the world's top 100 pharmaceuticals, MacMillan said. The reaction involved a nitrogen-based molecule known as an amine that has a hydrogen and carbon pair, and a circle of atoms stabilized by their bonds known as an aromatic ring.

The result was a carbon-nitrogen molecule with an aromatic ring, a building block of many amine-based pharmaceuticals, explained MacMillan. This class of drugs mimics natural amine molecules in the body and includes medications such as antihistamines, decongestants and antidepressants. In drug development, chemists "tweak" organic molecules to enhance their ability to bind with and disrupt enzymes in a biological system, which is how pharmaceuticals basically operate, MacMillan said. A molecule with an aromatic ring has increased reactivity and makes the tweaking process much easier, he said, but attaching the aromatic ring is a process in itself that typically involves two to three weeks of successive chemical reactions.

The reaction MacMillan and his team found provides a quick way around that.

"We quickly realized that any pharmaceutical research chemist could immediately take these very simple components and, via a reaction no one had known about, start assembling molecules with an adjacent aromatic ring rapidly," MacMillan said.

"Instead of having to construct these important molecules circuitously using lots of different chemistry over a period of days if not weeks, we can now do it immediately in the space of one chemical reaction in one day."

Buchwald said that the rapid production of this molecule is as surprising as it is significant.

"The way these types of molecules — alpha aryl amines — were produced in this project is highly efficient, and no person could truthfully say that they would have predicted this reaction," Buchwald said. "This group was able to take a reaction that no one knew was possible and make it practical and useful in a very short time. This really speaks to the power of their overall method."

An important feature of the Princeton researchers' molecule — like any important discovery — is that its application extends beyond the material itself, MacMillan said. He and his colleagues have begun mining the very process that created the molecule for indications that other novel reactions can be brought about.

"If we found this was one really valuable reaction, we wondered what others exist that we just don't know about," MacMillan said.

"Another very valuable aspect of the molecule we created is that once we understood how it happened, it set us up to design other completely new reactions based upon our understanding of what happened initially," he said. "Now, we're applying similar techniques broadly, finding new reactions continually and determining which ones are important.
Serendipity has long been a welcome yet elusive phenomenon in the advancement of chemistry. We sought to exploit serendipity as a means of rapidly identifying unanticipated chemical transformations. By using a high-throughput, automated workflow and evaluating a large number of random reactions, we have discovered a photoredox-catalyzed C–H arylation reaction for the construction of benzylic amines, an important structural motif within pharmaceutical compounds that is not readily accessed via simple substrates. The mechanism directly couples tertiary amines with cyanoaromatics by using mild and operationally trivial conditions.

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