Optimizing Small-Molecule Synthesis

Catalysis for olefin metathesis and aldol reactions and synthetic routes to natural products are some recent gains.
Jan 02, 2009
Volume 33, Issue 1

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.

Olefin metathesis

Figure 1: Double ring-closing metathesis in the synthesis of Mercks NK-1 inflammation drug candidate.

Figure 2: Ring-closing metathesis (RCM) and cross-metathesis (CM) in the synthesis of Eisais pladienolide 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).

Patricia Van Arnum
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).

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).

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