Advances in Asymmetric Synthesis

The goal of reaching desired enantioselectivity of active pharmaceutical ingredients (APIs) is an ongoing challenge for process chemists. Chemocatalysis and biocatalysis play an important role in asymmetric synthesis.

Patricia Van Arnum

Catalytic hydroformylation

"Catalytic hydroformylation is the largest application of homogeneous organotransition metal catalysis today," says Professor Clark L. Landis at the Department of Chemistry at the University of Wisconsin-Madison. Landis outlined these advances at the "Modern Synthetic Methods and Chiral USA" conference, which was held in mid-July in Philadelphia and organized by Scientific Update LLP, based in Mayfield, UK. "Although hydroformylation produces synthetically useful aldehydes in a perfectly atom economical transformation using readily available alkenes, dihydrogen, and carbon monoxide, enantioselective hydroformylation is not well developed" (1–5).

This state, however, does not reflect a lack of opportunities, says Landis, pointing to potential applications of asymmetric hydroformylation in the synthesis of pharmaceuticals and insecticides (see Figure 1). "Even simple, commodity-scale alkenes such as vinyl acetate, present opportunities for hydroformylation by providing efficient access to common chiral synthons," he says. Despite these applications, enantioselective hydroformylation has not been used significantly for fine chemical synthesis. "Until recently, the primary culprit has been a lack of catalysts that combine high rates with high selectivity," says Landis. "This situation is rapidly changing with developments of new chiral ligands that afford highly active and selective catalysts" (6-10).

Figure 1: Potential applications of enantioselective hydroformylation for the synthesis of pharmaceuticals and insecticides. (UNIVERSITY OF WISCONSIN-MADISON)

Approximately three years ago, Landis and his research group began a collaboration with Dowpharma (Midland, MI) to apply 3,4-diazaphospholane ligands to the problem of enantioselective hydroformylation. Some examples of the 3,4-diazaphospholane ligand class are shown in Figure 2 (11–14). These compounds are easily synthesized by the condensation of primary phosphines with azines. With bisphospholane ligands (see Figure 2a), rapid hydroformylation of substrates such as styrene, allyl cyanide, and vinyl acetate is effected with high enantiomeric excess (89%, 90%, and 97%, respectively), high branch:linearratios (20:1, 6:1, and 50:1, respectively) at rates similar to commodity scale, nonenantioselective hydroformylation (>1 turnover/s, >100,000 total turnovers) (6, 10).

Figure 2: Examples of 3-4 diazaphospholanes. (UNIVERSITY OF WISCONSIN-MADISON)

"These demonstrations of excellent selectivity have rekindled interest in the application of similar phosphine and phosphite ligands, many which were developed for application in enantioselective hydrogenation, to asymmetric hydroformylation," says Landis. He cites several notable results, particularly for asymmetric hydroformylation of vinyl arenes (15, 16).

"Because the synthetic versatility of aldehydes is so great, enantioselective hydroformylation could be a key step in the synthesis of many pharmaceutical building blocks," says Landis. The synthesis of β-siloxyisobutyraldehyde, a key starting material for polyketide syntheses, shows the opportunities provided by enantioselective hydroformylation (6). As shown in Figure 3, the traditional synthesis of β-siloxyisobutyraldehyde (6) begins with an expensive Roche ester and, in three steps, converts the acid to an aldehyde. The hydroformylation route, in contrast, begins with a commodity chemical, allyl alcohol, and converts it into the desired product in a two-step process, the second of which generates no byproducts that must be separated and disposed.

Figure 3: Comparison of the hydroformylation route (left) to β-siloxyisobutraldehyde with conversion of the Roche ester (right) (6). (UNIVERSITY OF WISCONSIN-MADISON)

"Preliminary results in my group demonstrate that the hydroformylation step can be effected with high enantioselectivity (97% enantiomeric excess) and high rates (10,000 catalyst turnovers/h), making hydroformylation a vast improvement over traditional synthesis," says Landis. "Should hydroformylation prove similarly effective for other functionalized alkene substrates, the barrier to the application of enantioselective hydroformylation technology will shift from catalyst performance to incorporating chiral aldehydes into retrosynthetic thought processes when devising new syntheses," he adds.

Asymmetric hydrogentation

While a catalyst selection is crucial in an asymmetric reaction, so is the choice of the substrate, an approach researchers at Sepracor (Marlborough, MA) showed in making an enamide substrate for asymmetric hydrogenation for the large-scale stereoselective process for (1R, 4S)-trans-norsertraline, a chiral amine structurally similar to sertraline, the API in Pfizer's (New York) "Zoloft."

Upcoming conferences on chirality

"Our first approach used to produce kilogram quantities of clinical study material began with (S)-tetralone and a chiral auxiliary (R)-tert-butylsulfinamide," outlines Surenda Singh, research fellow at Sepracor. Singh also spoke at Chiral USA. "The synthesis was very quick to develop and was scaled up to produce ~5 kg of API in >50% overall yield" (17).

Sepracor, however, wanted a more efficient and economical process for larger-scale commercial applications. "After an extensive route-scouting effort, we selected the approach of catalytic asymmetric hydrogenation of the enamide," says Singh. Initial in-house catalyst screening efforts resulted in identification of R,R-Me-BPE-Rh(COD)BF₄, a commercially available catalyst. Later in collaboration with Dowpharma another catalyst, Norphos, was identified. "Once we identified the multiple catalysts," says Singh, "we were then faced with two new challenges on how to make the enamide approach a scalable process: availability of limited methods for an efficient synthesis of enamides, and as one would expect, the hydrolysis of the resulting chiral amide did not prove to be a trivial task."

"Fortunately, we were able to solve both of these issues for our substrate, and in a short time developed novel chemistries for the efficient synthesis of enamides and also for the facile cleavage of chiral acetamides," says Singh. The process was scaled up to produce more than 50 kg of API in 63% overall yield and in 99.9% chiral purity with total impurities of < 0.05 A% by high-performance liquid chromatography.

Biocatalysis in asymmetric reactions

Enzymes can be an economic alternative to chemocatalysts in asymmetric reactions. Biocatalysis may be used, for example, to make precursors for RNA interference drugs. As an example, David Rozell, vice-president of enzyme products and services of the Pharma Services Group at Codexis (Redwood City, CA) points to 2'-O-methoxyethyl guanosine derivatives that are produced by means of a chemo-enzymatic sequence that relies on a reaction catalyzed by adenosine deaminase as a key step.

Biocatalysts may also be used in reductive amination. Amino-acid dehydrogenases may be used to convert 2-ketoacids to the corresponding ±-amino acid, says Rozzell. L-tert-leucine and L-cyclopentylglycine are two examples of unnatural amino acids that are manufactured by Codexis.

"While enzymes for producing L-amino acids are well-known, nature does not provide amino-acid dehydrogenases for the reductive amination of ketoacids for the synthesis of D-amino acids," says Rozzell. Codexis recently commercialized D-selective amino-acid dehydrogenases developed by BioCatalytics (18). Codexis acquired Biocatalytics (Pasadena, CA) earlier this year.

Other new enzyme platforms developed by BioCatalytics include transaminases for producing chiral amines and enone and enoate reductases for the selective reduction of C=C bonds.

Chiral separations

In addition to asymmetric synthesis and synthesis from chiral pools, resolution by chromatography is a widely accepted method for obtaining single enantiomers.

"Chromatography is one possible way to reach pure enantiomers," explains Geoffrey B.Cox, vice-president of Chiral Technologies (West Chester, PA). "In working under tight time constraints, the development groups in the pharmaceutical industry use chiral chromatography as the fastest method to obtain single enantiomer materials." Modern preparative chromatography systems allow for easy separation of racemic mixtures and the production of gram to multikilo quantities in a few days.

Separations at larger scale are carried out by simulated moving bed (SMB), which is essentially a binary chromatographic separator and has the advantage of being a continuous process. This technique is therefore particularly suited to the separation of enantiomers at pilot and production scale.

In one recent case study, "we needed a process capable of delivering 90 metric tons per year of a specific pharmaceutical intermediate," explains Cox. After economic analysis of the possible processes, the decision was made to use SMB technology for this project. Based on the throughput that was achieved in this particular case, the cost to separate the single enantiomer from the racemic mixture was less than $100/kg. Even more compelling are cases in which the undesired enantiomer can be reracemized and recycled through the SMB. There are seven pharmaceuticals that use this process.

Supercritical fluid chromatography used with chiral stationary phases also is a way to resolve enantiomers.With SFC, most of the liquid solvent is replaced by pressurized carbon dioxide, and only a small percentage of an organic solvent is required to solubilize the compound and serve as a cosolvent with the carbon dioxide (19). Regis Technologies (Morton Grove, IL) recently added SFC to its separations services.

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

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14. C.R. Landis, et al., "Synthesis, Characterization, and Transition-Metal Complexes of 3,4-Diazaphospholane Organometallics 25 (21) 1377–1391 (2006).

15. A.T. Axtell, J.Klosin, and K.A. Abboud, "Evaluation of Asymmetric Hydrogenation Ligands in Asymmetric Hydroformylation Reactions: Highly Enantioselective Ligands Based on Bis-phosphacycles," Organo-metallics 25 (21), 5003–5009 (2006).

16. Y. Yan and X. Zhang, "A Hybrid Phosphorus Ligand for Highly Enantioselective Asymmetric Hydroformylation," J. Am. Chem. Soc 128 (22), 7198–7202 (2006).

17. S. Singh et al., "Development of a Large-Scale Stereoselective Process for (1R,4S)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine Hydrochloride," Org. Process Res.Dev. 11 (4) 726–730 (2007).

18. K. Vedha-Peers et al., "Creation of a Broad-Range and Highly Stereoselective D-Amino Acid Dehydrogenase for the One-Step Synthesis of D-Amino Acids," J. Am. Chem. Soc 128 (33), 10923–10929 (2006).

19. P.Van Arnum, "Chiral Separations: Developments in SMB Liquid Chromatography and SFC," Pharm. Technol. 30 (4), 60 (2006).