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Meeting Challenges in Asymmetric Synthesis
Assessing the market
A better route to prostaglandins
Researchers at the University of Bristol in England recently reported on an improved method for making prostaglandins, natural, hormone-like chemicals that have pharmaceutical applications. The prostaglandin analog latanoprost, which is used to treat glaucoma and ocular hypertension, is a well-known prostaglandin. It is the active ingredient in Pfizer's Xalatan, which generated 2011 sales of $1.25 billion; the patent for the drug expired in 2011 (1).
Due to prostaglandins' biological activity, but difficulty in synthesizing them, strategies for better synthetic routes for prostaglandins are an active area of research. For example, the current synthesis of latanoprost requires 20 steps and uses the methodology and strategy developed by E.J. Corey, winner of the 1990 Nobel Prize in Chemistry, according to an Aug. 15, 2012, University of Bristol press release.
The University of Bristol researchers reported on a synthesis of prostaglandin PGF2α, which relies on the use of an organocatalyst, a small organic molecule, to catalyze a key step in the process, which produced high levels of control of relative and absolute stereochemistry and fewer steps, according to the university press release and recent article detailing the research (2). The new process uses a new disconnection that enabled the researchers to complete the synthesis in only seven steps, according to the university release. The key step is an aldol cascade reaction of succinaldehyde using proline organocatalysis to create a bicyclic enal in one step with enantiomeric excess of 98%. This intermediate bicyclic enal is fully primed with the appropriate functionality for attachment of the remaining groups (1). The route to the bicyclic enal is important for a more efficient and potentially cost-effective route but also serves as a basis for examining related chemical structures of prostaglandin analogs (1, 2).
"Despite the long syntheses and the resulting huge effort that is required for the preparation of these molecules, they are still used in the clinic because of their important biological activity, said Varinder K. Aggarwal, professor in the School of Chemistry, University of Bristol, in the university release. "Being able to make complex pharmaceuticals in a shorter number of steps and, therefore, more effectively, would mean that many more people could be treated for the same cost."
Biocatalysis at work
Researchers at the School of Chemical and Biomolecular Engineering at the Georgia Institute of Technology and Merck & Co. recently developed an amine dehydrogenase for the synthesis of chiral amines. Specifically, the researchers successfully altered a leucine dehydrogenase through protein engineering to an enantioselective amine dehydrogenase. Instead of the wild-type α-keto acid, the new amine dehydrogenase accepted the analogous ketone, methyl isobutyl ketone, which corresponded to exchange of the carboxy group by a methyl group to produce chiral (R)-1,3-dimethylbutylamine (3).
Earlier this year, Codexis, a biocatalysis company, reported on its work with Merck & Co. for developing an enzyme-based production method for a key intermediate in the production of boceprevir, the API in Merck's Victrelis, a drug to treat hepatitis C. The companies reported on a chemoenzymatic process for manufacturing the boceprevir bicyclic proline intermediate based on amine oxidase-catalyzed desymmetrization. The key structural feature in boceprevir is the bicyclic proline moiety, which during development stages, was produced by a classical resolution. As the drug candidate advanced, Codexis and Schering–Plough (now Merck) jointly developed a chemoenzymatic asymmetric synthesis where the net reaction was an oxidative Strecker reaction. The key part of the reaction sequence is an enzymatic oxidative desymmetrization of a prochiral amine substrate (4, 5).
According to Codexis, the new method increased chemical intermediate yield 150% over the previous process. It also reduced raw material use by 60%, water use by 61%, and overall process waste by 63%. Codexis used its proprietary CodeEvolver directed evolution technology to develop the custom enzyme for use in the commercial-scale manufacturing of the boceprevir intermediate (5).
Codexis had earlier partnered with Merck & Co. for another biocatalytic route. The companies developed a biocatalytic asymmetric synthesis of chiral amines from ketones in the manufacture of sitagliptin, the API in Merck's antidiabetes drug Januvia (5). In May 2012, Merck extended its pact for biocatalysis with Codexis for another three years to 2015. The initial agreement was announced in April 2007.
Heterocyclic compounds are important in pharmaceutical applications, and researchers at the California Institute of Technology (Caltech) recently reported on an advance in the synthesis of such compounds. They reported on their work in the enantioselective construction of quaternary N-heterocycles by palladium-catalyzed decarboxylative allylic alkylation of lactams (5, 6).
"We think it's going to be a highly enabling reaction, not only for preparing complex natural products, but also for making pharmaceutical substances that include components that were previously very challenging to make," said Brian Stoltz, professor of chemistry at Caltech, in a Jan. 13, 2012, university press release. "This has suddenly made them quite easy to make, and it should allow medicinal chemists to access levels of complexity they couldn't previously access."
Specifically, the researchers reported on the highly enantioselective palladium-catalyzed decarboxylative allylic alkylation of lactams to form 3,3-disubstituted pyrrolidinones, piperidinones, caprolactams, and structurally related lactams. The researchers asserted that the synthesis provides a new approach for the asymmetric synthesis of such structures, an important development given the prevalence of quaternary N-heterocycles in biologically active alkaloids and pharmaceutical agents. The researchers reported that the catalysis provided enantiopure quaternary lactams that intercept synthetic intermediates previously used in the synthesis of the Aspidosperma alkaloids, quebrachamine and rhazinilam, but that were previously produced by chiral auxiliary approaches or as racemic mixtures (5, 6).
Other catalytic approaches
BINOL and its derivatives are widely used classes of ligands in asymmetric synthesis, such as in Diels–Alder reactions, carbonyl addition, and reductions (7). Researchers at the University of Texas, Austin, recently developed a bifunctional catalyst derived from BINOL for producing highly enantioselective bromolactonizations of unsaturated carboxylic acids (8, 9). Specifically, the catalyst promoted highly enantioselective bromolactonizations of 4- and 5-aryl-4-pentenoic acids, but it also catalyzed the highly enantioselective bromolactonizations of 5-alkyl-4(Z)-pentenoic acids. The researchers assert that these reactions represent the first catalytic bromolactonizations of alkyl-substituted olefinic acids that proceeded by means of 5-exo mode cyclizations to give lactones in which new carbon–bromine bonds are formed at a stereogenic center with high enantioselectivity. The researchers also reported on what they say is the first catalytic desymmetrization of a prochiral dienoic acid by enantioselective bromolactonization (8, 9).
Patricia Van Arnum is executive editor of Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, firstname.lastname@example.org
1 B. Halford, Chem. & Eng. News 90 (34), 9 (2012).
2. G. Coulthard, W. Erb, and K. Aggarwal, "Stereocontrolled Organocatalytic Synthesis of Prostagladin PGF2α in Seven Steps," Nature, online DOI10.1038/nature11411, Aug. 15, 2012.
3. M.J. Abrahamson, Angew. Chem. Int. Ed. Engl. 51 (16), 3969–3972 (2012).
4. T. Li et al., J. Am. Chem. Soc. 134 (14), 6467–6472 (2012).
5. P. Van Arnum, Pharm. Technol. 36 (5), 56–60 (2012).
6. B.M. Stoltz et al., Nature Chem. 4 (2) 130–133 (2012).
7. W. Sommer and D. Weibel, Aldrich ChemFiles 8.2 (56), 2008.
8. D.H. Paull, J. Am. Chem. Soc., 134 (27), pp 11128–11131 (2012).
9. C. Drahl, Chem. & Eng. News 90 (28), 29 (2012).