Synthesis of natural products . Researchers at the University of California in Berkeley recently reported on the synthesis of the alkaloid complanadine
A, a dimer of another natural product called lycodine. The pseudo-symmetry of this molecule adds to the challenge of its synthesis.
Medicinally, complanadine A is thought to aid in the production of nerve growth factors, something of interest for regenerative
medicine and Alzheimer's disease research. Complanadine A is isolated from club moss, which grows naturally in the wild. However,
the difficulty of isolating significant quantities of complanadine A from this natural source has limited further biological
research on the molecule. The Berkeley researchers synthesized complanadine A using a common tetracyclic precursor to the
two halves of the dimer. A crucial part of the synthesis was developing an iridium-catalyzed carbon–hydrogen functionalization
to produce a boronic ester, which was followed by a Suzuki coupling (10, 11).
Silver-catalyzed coupling. Fluorine-based compounds are important building blocks in pharmaceutical synthesis. Researchers led by Tobias Ritter, associate
professor in the Department of Biology and Chemistry at Harvard University, recently reported on a new cross-coupling reaction
that attached fluorine atoms onto aromatic substituents. The reaction uses silver oxide to catalyze the fluorination of aryl
tin compounds with the electrophilic fluorinating reagent
N-chloromethyl-N-fluorotriethylenediammonium hexafluorophosphate. The researchers asserted that the reaction is the first example of silver
catalysis being applied for carbon–heteroatom bond formation by cross-coupling chemistry. Carbon-fluorine bond formation by
transition-metal catalysis is difficult, and only a few methods for the synthesis of aryl fluorides have been developed, according
to the researchers. Typically, transition metal-catalyzed fluorination reactions for synthesizing functionalized arenes use
palladium in the catalyst (12).
An advantage of the silver-catalyzed fluorination reaction is its versatility in terms of the variety of functional groups
that can be tolerated and the breadth of the substrate scope. The researchers showed that the cross-coupling reaction can
be used to fluorinate polypeptides, polyketides, and alkaloids and can be tolerated by various functional groups, including
vinyl ethers, dienones, alcohols, allylic alcohols, ethers, esters, and oxetanes (12).
New approaches to fluorination are useful for not only producing fluorinated molecules for use in pharmaceuticals, but such
approaches also can be applied in imaging techniques. A long-term goal of the research by Ritter and his team is the development
of new methods for the synthesis of small-molecule-tracers for positron emission tomography (PET), an imaging technique to
study biological processes in vivo. PET with the isotope 18F is currently limited by the absence of general chemistry that can introduce fluorine into molecules at a late stage. The
approach to carbon–fluorine bond formation using high-valent transition metal fluorides via oxidation of aryl transition metal complexes with electrophilic fluorination reagents is one approach to resolve that challenge
(12).
Patricia Van Arnum is a senior editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, pvanarnum@advanstar.com
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