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Patricia Van Arnum was executive editor of Pharmaceutical Technology.
Advances in micellar catalysis, solid-state chemistry, catalytic asymmetric synthesis, and function-oriented synthesis for natural products represent noteworthy developments in green chemistry that can be applied to the synthesis of active pharmaceutical ingredients.
Approaches to improve the environmental profile of manufacturing processes and end products is an important goal in many industries, including pharmaceuticals. In the case of pharmaceutical manufacturing, these approaches can involve ways to increase reaction efficiency and yield in order to reduce waste, reduce solvents and reagents, or to improve reaction conditions when synthesizing active pharmaceutical ingredients, intermediates, or lead compounds. Several entries considered in the 2009 Presidential Green Chemistry Challenge Awards, an annual recognition by the US Environmental Protection Agency, provide approaches in green chemistry with applications to the pharmaceutical industry (1).
Bruce H. Lipshutz, professor in the chemistry and biochemistry department of the University of California at Santa Barbara, California, developed an approach to increase reaction efficiency and enhance catalytic activity and thereby reduce the use of organic solvents used in certain chemical reactions (1).
Lipshutz and his team found that a mono-PEGylated, alpha-tocopherylated sebacid acid derivative (PTS) allows several common organic reactions catalyzed by transition metals, particularly palladium and ruthenium, to use water as the only solvent, to be run at room temperature, and produce product in high isolated yield. PTS may be used under mild aqueous conditions for olefin metathesis reactions, palladium-catalyzed Suzuki, Heck, and Sonogashira cross-couplings (2–4). By permitting the catalysis under aqueous conditions, PTS eliminates the use of organic solvents in these reactions (1).
PTS functions as a surfactant. It is a nanomicelle-foaming amphiphile that features vitamin E or tocopheral as the inner lipophilic solvent with a 10-carbon linker and PEG-600 hydrophilic portion. Under aqueous conditions, the micelles formed in the PTS function as nanoreactors that allow for high concentration of reactants and catalysts within these micelles to increase reaction rates. The increased activity allows the reaction to be run at ambient temperatures.
PTS is covered by patents owned by the National Research Council in Canada, a research and development organization of the Canadian government, and is under exclusive license to the bioscience company Zymes (Hasbrouck Heights, NJ).
Leonard R. MacGillivray, professor in the chemistry department at the University of Iowa, developed a method to control chemical reactivity in the organic solid state. The approach involves using small-molecule templates to assemble olefins (which undergo intermolecular [2+2] photodimerization) in discrete assemblies for solid-state reactions. The solid-state arrangements of the olefins are controlled by the template rather than by the long-range crystal packing. MacGillivray used this method for the solid-state synthesis of ladderanes, building blocks for natural products, and reported regiospecificity, no byproducts, and a 100% yield. Such an approach allows molecules to react in geometries and orientations that are typically inaccessible in solution. In 2008, he demonstrated a solvent-free method using mortar-and pestle grinding for cocrystal formation, thereby offering a green approach for synthesizing the ligands that may be used as self-assembled metal-organic structures and porous materials (1, 5, 6).
Catalytic asymmetric synthesis
T.V. RajanBabu, professor in the chemistry department at Ohio State University, and his team discovered a new codimerization of ethylene and various functionalized vinylarenes, 1,3-dienes, and strained alkenes (i.e., asymmetric hydrovinylation). This chemistry has applications in the enantioselective synthesis of nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, fluriprofen, and fenoprofen from the corresponding styrenes and ethylene (1). Specifically, the group developed highly catalytic protocols to allow for the codimerization of ethylene and various functionalized vinylarenes, 1,3-dienes, and strained alkenes under mild reactions conditions to product 3-arylbutenes. Such chemistry can be applied to the synthesis of select NSAIDs (1).
His work has further application in the synthesis of steroid derivatives. Cyclic and acylic 1,3-dienes can also also undergo efficient heterodimerization with ethylene with yields up to 99% for several 1-vinylcycloalkenes and 1-substituted 1,3-butadienes (1). Phospholanes and phosphoramidites can be used for ligands for an asymmetric variation of this reaction with yields up to 99% and enantiomeric excess of 95% for select substrates. An exocyclic chiral center can be used to install other stereocenters in the ring. His work also has involved the synthesis of several new ligands for improving enantioselectivity and the use of hemilabile ligands and their synergy with highly dissociated counterions to enhance selectivity (1, 7).
Synthetic routes to natural products
Paul Wender, professor of chemistry at Stanford University in Palo Alto, California, has developed an approach called function-oriented synthesis (FOS), which involves step economy in the organic synthesis of biologically active compound, including compounds from natural products. Although natural products are a good source for potential drug targets, there are often challenges in developing cost-effective synthetic routes to these complex molecules. FOS addresses this problem by seeking to refine or enhance the biologically active lead structure using simpler scaffolds that are more readily synthesized (1, 8)
Wender has applied the FOS approach to several natural product lead compounds. These compounds include: arenes that modulate protein kinase C and mimic the more complex phorbols; simplified enediyne compounds for cancer treatment; simplified bryostatin analogs, also used as potential anticancer agents; laulimalide analogs with simplified structures that remove the inherent functional instability of natural laulimalide; the design, synthesis, and optimization of polyarginine drug transporters used to improve potency and circumvent multidrug resistance pathways in cancer cells; and a process to convert the natural product, phorbol, into prostratin, an HIV drug adjuvant (1, 8).
1. Environmental Protection Agency, Green Chemistry ChallengeAgency Awards Program: Summary of 2009 Award Entries and Recipients (Washington, DC, 2009), available at www.epa.gov/greenchemistry.
2. B.H. Lipshutz et al., “Olefin Cross-Metathesis Reactions at Room Temperature Using the Nonionic Amphiphile PTS: Just Add Water,” Org. Lett.10 (7), 1325–1328 (2008).
3. B.H. Lipshutz et al., “Heck Couplings at Room Temperature in Nanometer Aqueous Micelles,” Org. Lett. 10 (7), 1329–1332 (2008).
4. B.H. Lipshutz et al., “Room Temperature Suzuki-Miyaura Couplings in Water Facilitated by Nonionic Amphiphiles,” Org. Lett. 10 (7), 1333–1336 (2008).
5. L.R. MacGillivray,“Organic Synthesis in the Solid State via Hydrogen-Bond-Driven Self-Assembly,”J. Org. Chem. 73 (9), 3311–3317 (2008).
6. L.R. MacGillivray et al., “Supramolecular Control of Reactivity in the Solid State: From Templates to Ladderanes to Metal-Organic Frameworks,” Acc. Chem. Res. 41 (2), 280–291 (2008).
7. T.V. RajanBabu et al., “Conformationally Driven Asymmetric Induction of a Catalytic Dendrimer,” J. Am. Chem. Soc., 130 (25), 7845–7847 (2008).
8. P.A. Wender, “Function Oriented Synthesis, Step Economy, and Drug Design,” Acc. Chem. Res. 41 (1), 40–49 (2008).