Patricia Van Arnum
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Seeking ways to improve or achieve the synthesis of an active pharmaceutical ingredient (API) or intermediate used in the
synthesis of an API is an ongoing task for contract manufacturers, pharmaceutical companies, research centers, and universities.
Some recent advances in asymmetric synthesis, natural product synthesis, and green chemistry are improving select synthethic
routes.
Asymmetric synthesis
(PHOTO: MIRIAM MASLO/SPL, SCIENCE PHOTO LIBRARY, GETTY IMAGES)
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Synthesizing enantiomerically pure compounds is an important area of process research and development. Researchers at Ohio
State University in Columbus, Ohio, reported on the use of parallel kinetic synthesis, whereby a single catalyst transformed
a racemic mixture of aziridines to a pair of regioisomeric products with good yield and high enantioselectivity (1). The researchers
used a dimeric yttrium salen catalyst to accelerate the ring opening of aliphatic aziridines by trimethylsilylazide, thereby
inducing nucleophilic attack at the primary position of one enantiomer and the secondary position of the other (1).
In another development, researchers at Rutgers University in New Brunswick, New Jersey, advanced an approach for enantioselective
amine acylation. The researchers reported on the use of a small-molecule catalyst to acylate amines enantioselectively. Specifically,
the researchers described that acyl pyridinium salts derived from 4-(dimethylamino)pyridine and benzoic anhydride are made
chiral from the interaction with a chiral thiourea anion receptor (2).
Natural products
Natural products provide potential drug candidates, but the synthetic route to a natural product can be difficult to achieve.
A recent breakthrough was reported by researchers at the Scripps Research Institute in La Jolla, California, who successfully
synthesized palua'amine, a complex alkaloid that has shown potential as a possible anticancer, antibacterial, and antifungal
agent. The compound is derived from a sponge off Palau, an island nation in the Pacific Ocean. The compound was discovered
in 1993, but the complexity of the molecule has made its synthesis very challenging, according to a Jan. 7, 2010, Scripps
Research Institute press release.
The compound has eight contiguous stereogenic centers, several reactive nitrogen-containing moieties, and a highly strained
core that forms a junction between two five- membered rings (3). Scripps Research chemist Phil Baran, who led the team that
made the breakthrough, has been working on the synthesis since he arrived as a faculty member at Scripps Research more than
six years ago, according to the release.
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The key breakthrough was a cyclization strategy to make the strained core (3). The synthesis of palau'amine was achieved via highly chemoselective transformations, cascade reactions, and a transannular cyclization to secure the trans-5,5 ring junction
(4). One of the more significant later advances was applying silver-mediated oxidation, which stabilized an intermediate to
permit the five final steps to a macro-paula'amine, according to the release.
Another group of researchers at Scripps Research Institute reported on a strategy for aryl carbon–hydrogen olefination, an
approach that may be useful for synthesizing natural products and other drugs. The palladium-catalyzed Mizoroki–Heck reaction,
which couples aryl halides with olefins, is widely used to forge carbon–carbon bonds (5). But this approach has certain disadvantages,
namely installing the halide of interest is not always easy, according to a Dec. 3, 2009 Scripps Research Institute release.
An alternative method, palladium-catalyzed carbon–hydrogenation olefination, has been limited to specific cases that generally
include electron-rich heterocyles and/or stoichiometric palladium (5). The researchers instead used a carboxylate-directed
palladium (II)-catalyzed carbon–hydrogen olefination reaction using phenylacetic acid and 3-phenylpropionic acid substrates
with oxygen at atmospheric pressure as the oxidant and amino-acid derivatives as the ligands. This approach was used to produce
commercial drug scaffolds and to synthesize 2-tetralone and naphtholic acid natural product cores (5).
