Meeting Challenges in Asymmetric Synthesis - Pharmaceutical Technology

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Meeting Challenges in Asymmetric Synthesis
Industry and academia advance novel approaches for achieving enanioselectivity.


Pharmaceutical Technology
Volume 36, Issue 9, pp. 48-50

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.

Enantioselective N-heterocycles

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).


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