Underlying the networking between pharmaceutical companies and custom manufacturers gathering at InformexUSA in San Francisco
later this month will be the exchange of sound chemistry needed to optimize the synthesis of intermediates or small-molecule
active pharmaceutical ingredients (APIs). The success of route selection, process development, and commercial manufacture
is specific to a particular compound, but equally important is building scientific critical mass for current and future projects.
Some recent approaches include next-generation catalysts for olefin metathesis, polymeric catalysis for aldol reactions, and
biomimetic synthesis of natural product-based APIs.
(TOP: GLOWIMAGES/GETTY IMAGES FIGURES ARE COURTESY OF MATERIA.)
Figure 1: Double ring-closing metathesis in the synthesis of Mercks NK-1 inflammation drug candidate.
Olefin metathesis is an efficient method for constructing carbon–carbon double bonds. Recent pharmaceutical applications include
work by K.C. Nicolaou, professor of chemistry at the Scripps Research Institute, and his group for the syntheses of a variety
of complex biologically active molecules using olefin metathesis as the key step (1). Merck & Co. (Whitehouse Station, NJ)
reported the synthesis of an NK-1 inflammation drug candidate in which double ring-closing metathesis was used to build a
key spirocyclic intermediate (see Figure 1) (1). Researchers at Eisai (Tokyo) reported the use of both ring-closing metathesis
and cross metathesis in the synthesis of pladienolide (see Figure 2). Eisai showed that cross-metathesis was successful when
traditional Julia–Kocienski coupling failed to produce the desired product (1).
Figure 2: Ring-closing metathesis (RCM) and cross-metathesis (CM) in the synthesis of Eisais pladienolide drug candidate.
Researchers from Boston College and the Massachusetts Institute of Technology (MIT) recently developed a new catalyst for
olefin metathesis that provides selectivity for a broad range of reactions. The researchers, Amir H. Hoveyda, professor of
chemistry at Boston College, and Richard R. Schrock, professor of chemistry at MIT and the 2005 Nobel Laureate in chemistry,
developed a new chiral catalyst consisting of an enantiomerically pure monodentate aryloxide group bonded to a stereogeneic
molybdenum center for alkene metathesis reactions. Enantiomerically pure aryloxide is not commonly used as a ligand in enantioselective
catalysis, according to the researchers (2).
Patricia Van Arnum
The structural flexibility of the catalyst is an important part of its design. "We expect this highly flexible palette of
catalysts to be useful for a wide variety of catalytic reactions that are catalyzed by a high-oxidation-state alkydiene species,
and to be able to design catalytic metathesis reactions with a control that has been rarely, if ever, observed before," said
Schrock in an Nov. 16, 2008 MIT press release.
The researchers applied the catalyst to the enantioselective synthesis of quebrachamine, a natural product alkaloid from the
Aspidosperma plant. The quebrachamine was made through an alkene-metathesis reaction using the aryloxide–molybdenum catalyst and achieved
an 84% yield with 96% enantiomeric excess (2, 3). The researchers said these results were not able to be achieved with previously
reported chiral catalysts (2).