Heterocyclic compounds play an important role in medicinal chemistry and drug synthesis. Like any important functional class
of compounds, developments that facilitate their production or elucidate their reaction mechanisms are significant for process
chemists in the pharmaceutical industry. In two separate developments, researchers at The Scripps Research Institute (TSRI)
in La Jolla, California recently reported on the use of zinc sulfinates as reagents for the direct chemical functionalization
of nitrogen-based heterocycles and on reaction-tracking tools to better elucidate copper-catalyzed reactions in making triazoles.
Patricia Van Arnum
A toolkit for synthesizing heterocycles
In the first development, scientists at TSRI developed a set of chemical tools to simplify the synthesis of nitrogen-based
heterocycles through more time- and cost-efficient chemical modifications of these compounds. In their work, the researchers
pointed out that although advances in transition-metal-mediated cross-coupling have simplified the synthesis of such heterocycles,
the carbon–hydrogen functionalization of medicinally important heterocycles that does not rely on prefunctionalized starting
materials was an area requiring further research (1). Although the properties of heterocycles, such as their aqueous solubility
and their ability to act as ligands, are desirable for biological applications, these properties also make such heterocycles
challenging as substrates for direct chemical functionalization (1). To address that problem, the researchers used zinc sulfinate
salts to transfer alkyl radicals to heterocycles, thereby allowing for the mild (i.e., moderate temperature, 50 °C or less),
direct, and simple formation of carbon–carbon bonds while reacting in a complementary fashion to other carbon–hydrogen functionalization
methods (i.e., Minisci, borono-Minisci, electrophilic aromatic substitution, transition-metal-mediated carbon–hydrogen insertion,
and carbon–hydrogen deprotonation) (1). The researchers prepared a toolkit of these reagents and studied their reactivity
across a range of heterocycles (natural products, drugs, and building blocks) without recourse to protecting-group chemistry.
The reagents could be used in tandem in a single pot in the presence of water and air (1).
"Feedback from companies that have started to use this toolkit indicates that it solves a real problem for them by boosting
their chemists' productivity and by expanding the realm of compounds that they can feasibly generate," said Phil S. Baran,
PhD, a professor in the Department of Chemistry and a member of the Skaggs Institute for Chemical Biology at TSRI who led
the study, in a Nov. 28, 2012 TSRI press release. The resistance of nitrogen heterocycles to modification by traditional techniques
has slowed drug discovery and has put potential modifications out of reach, notes TSRI.
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The genesis behind the toolkit began with the goal for a more a simplified approach. "The ideal for discovery chemists would
be a method that works in water, in an open flask, [and] with procedures that are simple enough to be automated," said Baran.
His group's previous work in synthesizing a natural product heterocycle, palau'amine, a toxin made by sea sponges in the Western
Pacific that has shown anticancer, antibacterial and antifungal pharmaceutical promise, was a helpful beginning.
"As we developed an understanding of how that compound reacts, we recognized that it might help us solve this larger problem
that discovery chemists face," said Baran in the release. In that synthesis, palau'amine was made by a route featuring highly
chemoselective transformations, cascade reactions, and a transannular cyclization to produce the trans-5,5 ring junction (2) and led the researchers to examine reagents that would modify heterocycles directly.
Although direct methods exist, they often require extreme temperatures as well as expensive and hazardous reagents. During
2010 and 2011, Baran's laboratory experimented with several comparatively safe chemical reagents that work in mild conditions
to make commonly desired heterocycle modifications, such as the addition of a difluoromethyl group, according to the TSRI
2012 release. One of these new reagents, a zinc dialkylsulfinate salt (DFMS), which was designed to transfer the difluoromethyl
group, turned out to work particularly well. "We quickly realized that we might be able to make related zinc sulfinate salts
that would attach other functional groups to heterocycles," Baran said.
In their recent work, Baran and his team developed an initial toolkit consisting of 10 of these zinc-based salts, each of
which attaches a different functional group to a heterocycle framework. "We selected these groups because they are commonly
used by medicinal chemists," said Fionn O'Hara, PhD, a postdoctoral researcher in the Baran laboratory and a co-author of
the recent study (1). In many cases, these reagents can be used to sequentially make more than one modification to a starting
compound. The groups that can be attached with the new reagents include trifluoromethyl, difluoromethyl, trifluoroethyl, monofluoromethyl,
isopropyl and triethylene glycol monomethyl ether.
To show the ability of the reagents to work in biological media, Baran's team used the reagents to difluoromethylate or trifluoromethylate
heterocycles in a solution of cell lysate as well as to serve as a buffer medium (i.e., tris), which is commonly used in laboratory-dish
Baran's laboratory collaborated with scientists from Pfizer. "They provided insight into the types of compounds that would
be valuable, assistance with optimization, and, most importantly, testing of the chemistry in their drug-discovery laboratories,
where it is meant to be used," Baran said.
The first of the zinc sulfinate salts, DFMS, also known as Baran difluoromethylation reagent, is being manufactured in bulk
and marketed by chemical suppliers, according to the TSRI release. Baran is working to expand his initial toolkit to provide
more heterocycle-modifying choices.