Optimizing Small-Molecule Synthesis

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.)

Olefin metathesis

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 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.

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).

Aldol reactions

Researchers at the University of California at Berkeley developed an enzyme-like polymer catalyst consisting of a hyperbranched polyethyleneimine derivative and proline that eliminates self-aldol reactions by suppressing an irreversible aldol pathway. Self-aldol reactions with enolizable aldehydes in reactions such as cross-aldol processes represent a challenge to achieving desired chemoselectivity (4).

The research team, led by Jean M.J. Frecht, professor of chemistry and chemical engineering in the Department of Chemistry at the University of California at Berkeley, points out that the usual approach for suppressing self-aldol reactions is to use large excesses of one reaction component. Initial research suggests that using the polymer catalyst allows the aldol reaction to proceed selectively in water. The polymer catalyst system or a modified version has the potential, for example, to prepare a, -unsaturated ketones using cross ketone/aldehyde reactions without the need for excess substrate (4).

Biomimetic synthesis

Natural products can offer a pool of potential drug candidates, but the lack of a synthetic or semisynthetic route to making a compound of interest can limit the applications in drug development. Researchers at the University of California at Berkeley, the University of British Columbia, and the Ludwig-Maximilians-Universitaet (LMU) in Munich, recently reported using biomimetic synthesis to make exiguamine A and B. Exiguamine A and B are natural products derived from a marine sponge found in the waters of Papua New Guinea. They inhibit the action of indoleamine-2,3-dioxygenase (IDO), an enzyme that protects the fetus during pregnancy against an immune response of the mother, and are being explored in cancer research.

"Ultimately, IDO lends the cancer cells immunotolerance," said Dirk Trauner, professor for chemical biology and genetics at LMU, in an Aug. 4, 2008 LMU press release. "This enzyme [IDO] can do so by breaking down the amino acid tryptophan, which is essential for T-cells. But these immune cells are required by the body's immune response for destroying tumors. As such, IDO inhibitors, and our substances [exiguamine A and B] are only two of many such agents [that] could be employed in cancer therapy in [the] future for a large number tumors."

As the name implies, biomimetic synthesis parallels a synthetic or chemical route of a biological process. The approach is considered most successful when biosynthetic intermediates are set up to undergo reaction cascades. An example is pericyclic cascades or cationic polyene cyclizations that mimic the assembly of terpenoids (5).

Trauner and his team focused on the catecholamine cascade for synthesizing exiguamine A and later isolating exiguamine B. Catecholamines are intermediates that have potential in synthetic reactions because they may be readily oxidized to highly reactive electrophilic ortho-quinone and have a nucleophilic amine as an additional source of reactivity. The biosynthesis of exiguamine A involved a tautomerization of an ortho-quinone to a vinyl ortho-quinone methide, which was the key step of the synthesis, followed by oxa-6p electrocyclization (5).

Trauner is exploring other organic reactions that can be used in natural product research. "We have achieved the first asymmetrical Nazarov cyclizations and the first catalytic 6p electrocyclizations," he said in the LMU release. "These are important methods for synthesizing five and six-member rings that play a central role in the chemistry of natural products. I am convinced that the large majority of natural products are still unknown and that a multitude of interesting discoveries regarding their chemistry and biology are awaiting us."

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

References

1. X. Bei, D.P. Allen, and R. Pederson, "Highly Efficient Olefin Metathesis," Pharm.Technol.32 (9), Pharmaceutical Ingredients Suppl., s18–s23 (2008).

2. A.H. Hoveyda et al., "Highly Efficient Molybdenum-Based Catalysts for Enantioselective Alkene Metathesis," Nature 456 (7224), 933–937 (2008).

3. B. Halford, " A Catalyst With Fluxionality," Chem. Eng. News. 86 (47), 11 (2008).

4. J. Frecht, "Control of Aldol Reaction Pathways of Enolizable Aldehydes in an Aqueous Environment with a Hyperbranched Polymeric Catalyst," J. Amer. Chem. Soc. 130 (51), 17287–17289 (2008).

5. D. Trauner et al., "Biomimetic Synthesis of the IDO Inhibitors Exiguamine A and B," Nature Chem. Bio, online, DOI:10.1038/nchembio.107, Aug. 1, 2008.