Producing pharmaceutical compounds in a cost-effective and operationally efficient way is an ongoing challenge for process
R&D chemists. Improving product yield, purity, and enantioselectivity requires a myriad of approaches and tools to enhance
process understanding and analysis. Some recent advances involve strategies for accelerating reaction discovery, approaches
for inducing chirality and stereochemical analysis, and applications in nanotechnology for protein elucidation.
Accelerated serendipity
Patricia Van Arnum
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Researchers at Princeton University recently reported on the use of "accelerated serendipity," a process involving robotics
and high-throughput and automated workflow as a tool in process R&D. The researchers wanted to see whether serendipity could
be forced or simulated to occur on a predictable basis in the realm of reaction discovery to provide a reliable platform to
access valuable transformations or unexpected reaction pathways (1). The researchers used a high-throughput, automated workflow
and evaluated a large number of random reactions and discovered a photoredox-catalyzed carbon–hydrogen arylation reaction
for constructing benzylic amines, an important structural component within pharmaceutical compounds that is not readily accessed
by means of simple substrates. The mechanism directly coupled tertiary amines with cyanoaromatics by using mild and operationally
manageable reaction conditions. The researchers asserted that this carbon–carbon bond-forming protocol can be widely used
in the synthesis of benzylic and heterobenzylic amines (1).
"This is a very different way of approaching how we come up with valuable chemical reactions," said David MacMillan, professor
of chemistry at Princeton University and co-author of the recent study, in a Nov. 28, 2011, Princeton University release.
"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."
MacMillan conceived of accelerated serendipity following his doctoral work at the University of California–Irvine during the
1990s, according to the Princeton University release. When envisioning his team's recently reported project, MacMillan calculated
that if, in a single day, he ran the equivalent of one reaction per day for three years—nearly 1100 reactions—the odds favored
a new discovery, according to the release. The Princeton University researchers began running reactions once a day using a
high-throughput, automated reaction accelerator in Princeton's Merck Center for Catalysis.
A key part of the process was applying photoredox catalysis, an approach to synthesize chemical reactions using a low-power
light source, according to the university release. MacMillan had earlier reported on the use of photoredox catalysis with
organocatalysis in the direct asymmetric alkylation of aldehydes (2). The use of photoredox catalysts in organic-compound
synthesis is relatively new comparative to other chemocatalytic approaches and broadened the compounds and reactions under
study. For their latest work, MacMillan and his team carried out this process on the molecules before each reaction cycle.
In the case of the researchers' recent work, the focus was on benzylic amines, important in many pharmaceutical compounds.
"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 in the
university release. "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," he said.
