Seeking Chemocatalytic and Biocatalytic Solutions

June 6, 2012
Patricia Van Arnum

Patricia Van Arnum was executive editor of Pharmaceutical Technology.

PTSM: Pharmaceutical Technology Sourcing and Management

PTSM: Pharmaceutical Technology Sourcing and Management-06-06-2012, Volume 8, Issue 6

Advances in palladium-catalyzed hydrogenation, visible-light photocatalysis, and chemocatalyisis for heterocycles are some recent developments.

Catalysis plays a crucial role in the synthesis of pharmaceutical intermediates and APIs. Catalysts can enable more efficient chemical transformations, improve reaction conditions, better product yields, and produce greater enantioselectivity. Some key recent developments involve palladium-catalyzed hydrogenation, visible-light photocatalysis, chemocatalytic approaches for making heterocyclic compounds, and advances in biocatalysis.

Patricia Van Arnum

Palladium-catalyzed hydrogenation

Palladium-catalyzed hydrogenation reactions are important in industrial chemistry and fine-chemicals manufacture, but precious metal catalysts, such as palladium, are costly. Researchers at Tufts University's School of Arts and Sciences and School of Engineering in Medford, Massachusetts, recently reported on the arrangement of individual atoms in a metal alloy and their ability to catalyze hydrogenation reactions.

Hydrogenation requires the presence of a catalyst, usually a metal or an alloy of both precious and common metals, which allows the hydrogen atoms to bind with other molecules. It is difficult to produce alloys that are selective hydrogenation catalysts and are able to attach the hydrogen atoms to specific sites of another molecule. Tufts chemists and chemical engineers reported that when single atoms of palladium were added to copper, which is much cheaper and readily available, the resulting "single atom alloy" became active and selective for hydrogenation reactions, according to a Mar. 9, 2012, Tufts University press release.

NICHOLAS EVELEIGH/STOCKBYTE/GETTY IMAGES

The Tufts scientists scattered single atoms of palladium less than half a nanometer wide onto a copper support. For this research, the Tufts team heated small amounts of palladium to almost 1000 °C. At that temperature, individual atoms embedded themselves on the copper surface. A scanning tunneling microscope enabled the team to see how these single atoms dispersed in the copper and how molecular hydrogen could then dissociate at individual, isolated palladium sites and spill over onto the copper surface layer, according to the Tufts release.

Specifically, the researchers used desorption measurements in combination with high-resolution scanning tunneling microscopy to show that the individual, isolated palladium atoms in a copper surface substantially lowered the energy barrier to both hydrogen uptake on and subsequent desorption from the copper metal surface. The hydrogen dissociation at the palladium atom sites and weak binding to copper allowed for very selective hydrogenation of styrene and acetylene as compared with pure copper or palladium metal alone (1).

Visible-light photocatalysis

A team of University of Arkansas (US) researchers reported on using visible-light photocatalysis with a ruthenium catalyst to produce a building block in pharmaceutical synthesis. Specifically, the researchers reported on a visible-light-mediated intermolecular [3+2] cycloaddition of mono- and bicyclic cyclopropylamines with olefins catalyzed by [Ru(bpz)3](PF6)2•2 H2O to produce aminocyclopentane derivatives in good yields. Saturated 5,5- and 6,5-fused heterocycles were obtained in synthetically useful yields and diastereoselectivity (2).

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 (3).

"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 assert 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 (3).

Advances in biocatalysis

Codexis, a biocatalysis company, reported last month 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).

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.

Codexis had earlier partnered with Merck & Co. for another biocatalytic route. In 2010, Merck and Codexis reported on the biocatalytic asymmetric synthesis of chiral amines from ketones in the manufacture of sitagliptin, the API in Merck's antidiabetes drug Januvia. The biocatalytic process replaced a rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of sitagliptin. The researchers started from an (R)-selective transaminase that showed slight activity on a smaller truncated methyl ketone analogue of the sitagliptin ketone. After creating this transaminase, which had marginal activity for the synthesis of the chiral amine, they further engineered the enzyme through directed evolution to optimize its use for large-scale manufacturing (5–8).

The initial (R)-selective transaminase was a homologue of an enzyme from Arthrobacter sp., which previously was used for (R)-specific transamination of methyl ketones and small cyclic ketones. For the sitagliptin synthesis, the researchers generated a structural homology model of this transaminase and found that the enzyme would not bind to the prositagliptin ketone because of steric interference and potentially undesired interactions. The evolved transaminase was a successful biocatalyst that synthesized the chiral amines that previously were accessible only through resolution (5–8).

Codexis and Merck were recognized in 2010 with an Environmental Protection Agency's Presidential Green Chemistry Challenge Award, an annual recognition of advances in green chemistry. Codexis also submitted for consideration in 2010 and 2011 a biocatalytic route for making simvastatin, the active ingredient in Merck & Co.'s anticholesterol drug Zocor, which is now off patent (5, 8, 9).

For the simvastatin route, Codexis licensed technology from Yi Tang, professor in the Department of Chemical and Biomolecular Engineering at the University of California at Los Angeles. The previous synthetic routes to simvastatin involved converting lovastatin into simvastatin by adding a methyl group that required protecting and then deprotecting other functionalities in the lovastatin molecule in a multistep synthesis. In the first route, lovastatin was hydrolyzed to the triol, monacolin J, followed by protection with selective silylation, esterification with dimethyl butyryl chloride, and deprotection. The second route involved protecting the carboxylic acid and alcohol functionalities, methylating the C2' carbon with methyl iodide, and deprotecting the product. These routes were inefficient because they produced less than 70% overall yield and were mass-intensive due to protection and deprotection (5, 8).

The route developed by Tang and his group circumvented protection and deprotection and resulted in greater atom economy, reduced waste, and overall less hazardous reaction conditions. First, they cloned LovD, a natural acyltransferase produced by Aspergillus terreus that is involved in synthesizing lovastatin and that can accept nonnatural acyl donors. Recognizing that LovD might be a type of simvastatin synthase and a starting point for creating a new biocatalytic process, they evolved the enzyme toward commercial utility (5, 8–10). Codexis licensed Tang's technology, engineered the enzyme further, and optimized the process for pilot-scale simvastatin manufacture.

Codexis is an example of a firm specializing in biocatalysis. Another is evocatal GmbH, which was founded in 2006 as a spin-off of the Institute for Molecular Enzyme Technology at the University of Düsseldorf in the Research Center Jülich. Last November, evocatal issued a carbon–carbon coupling kit using thiamine pyrophosphate-dependent (TPP) enzymes to produce enantiopure 2-hydroxy-ketones, an important intermediate class for pharmaceutical syntheses. The kit includes seven different TPP-enzymes with the relevant cofactor.

Patricia Van Arnum is executive editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, pvanarnum@advanstar.com.

References

1. C.H. Sykes, Science 335 (6073), 1209–1212 (2012).

2. S. Maity et al., Angew. Chem. Int. Ed. 51 (1), 222–226 (2012).

3. B.M. Stoltz et al., Nature Chem. 4 (2) 130–133 (2012).

4. T. Li et al., J. Am. Chem. Soc. 134 (14), 6467–6472 (2012).

5. P. Van Arnum, Pharm. Technol. 35 (9), 54–58 (2011).

6. P. Van Arnum, Pharm. Technol. 34 (8) 42–44 (2010).

7. C.K. Savile et al., Science 329 (5989), 305–309 (2010).

8 EPA, "The Presidential Green Chemistry Challenge Awards Program: Summary of 2010 Award Entries and Recipients" (Washington, DC, 2010).

9. EPA, "The Presidential Green Chemistry Challenge Awards Program: Summary of 2011 Award Entries and Recipients" (Washington, DC, 2011).

10 Y. Tang, Science 326 (5952), 589–592 (2009).