Rolling Out Advances in Chiral Chemistry

The prevalence of chiral medicinal compounds in the current pharmaceutical market and in the pipeline is a driving force for synthetic chemists to optimize reaction routes for making single enantiomers. To meet this goal, pharmaceutical manufacturers, fine chemical companies, and academia are advancing approaches in asymmetric synthesis.

DSM optimizes ligand selection in asymmetric hydrogenation

Catalysis is a critical tool to drive reactions to produce higher yields and enantiomeric purity. Combinatorial catalysis and high-throughput screening is one technique in catalyst design. DSM Pharma Chemicals (Heerlen, Netherlands, www.dsm.com) is using combinatorial catalysis and high-throughput screening to optimize the selection of chiral ligands in asymmetric hydrogenation, explains André de Vries, senior scientist at DSM Pharma Chemicals. de Vries outlined this approach at "Modern Synthetic Methods & Chiral Europe 2006," which was held in early June in Lucerne, Switzerland and organized by Scientific Update LLP (Mayfield, East Sussex, UK, www.scientificupdate.com).

DSM is using its "MonoPhos" library of chiral ligands for designing catalysts for asymmetric olefin hydrogenation. The MonoPhos library is a collective name for a class of monodentate phosphoramidite ligands, in particular those prepared from 1,1'-binaphthyl-2,2'-diol (BINOL), which are used in the rhodium-, iridium- and ruthenium-catalyzed asymmetric hydrogenation of a variety of substrates leading to enantiopure α- and β-amino acids, cinnamic acids, and amines.

DSM is positioning these ligands, which can be synthesized in one or two steps, as low-cost alternatives to existing bisphosphine ligands such as 1,2-bis (-2,5-dimethylphospholano) benzene (DuPhos), which are synthesized by multistep sequences.

To optimize ligand selection, DSM uses high-throughput screening. "The challenge of industrial asymmetric catalysis is to find within a short time frame, a catalyst, which is not only highly selective for the specific substrate, but also economic," explains de Vries. "The economics are largely determined by the cost of the catalyst (transition metal and the chiral ligand) and the activity of the catalyst as measured by the turnover number (TON) and the turnover frequency (TOF)." The TON refers to the absolute number of passes through the catalytic cycle before the catalyst becomes deactivated. The TOF is the number of passes through the catalytic cycle per unit time.

To realize a short time frame for the development of a catalytic process, DSM used high-throughput experimentation (1), explains de Vries. The high throughput experimentation encompasses the use of automated equipment for parallel synthesis and screening and the use of large libraries of chiral ligands.

To build large libraries of cost-effective ligands, DSM developed an automated synthesis protocol for chiral monodentate phosphoramidites (2). "In this way, we can synthesize 96 new chiral ligands and test them the following day for any specific catalyzed transformation," says de Vries.

In a collaboration with the University of Groningen (Groningen, Netherlands, www.rug.nl/corporate/index), DSM research showed that the chiral monodentate phosphoramidites ligands have strong performance in the asymmetric hydrogenation of a variety of substituted olefins, giving access to enantiomerically enriched phenyl alanine derivatives (3), benzylic amines (4), and β-amino acid derivatives (5).

As an additional advantage, explains de Vries, monodentate ligands, such as the phosphoramidites, give the opportunity to form complexes with two different ligands bound to the same metal center. "Thus, using ligand L₁ (ligand one) and L₂ (ligand two) will lead to a mixture of L₁L₁-, L₂L₂-, and L₁L₂-complexes, all in equilibrium with each other, giving rise to more diversity in the search for the active and enantioselective catalyst," (6, 7) he explains. "By using a mixture of nonchiral tri-phenylphosphine (PPh3) and a chiral phosphoramidite, we observed a tremendous increase of enantiomeric excess (e.e.), and reaction rate in the asymmetric hydrogenation of a real-life substrate: the α-substituted cinnamic acid derivative." This reaction scheme is depicted in Figure 1. Without PPh3, only 78% e.e. and 20% conversion could be obtained with an estimated TOF of 5 mol/mol/h (8), outlines de Vries.

Figure 1: Reaction scheme for the asymmetric hydrogenation of an a-substituted cinnamic acid derivative using a mixture of nonchiral triphenylphosphine (PPh3) and a chiral phosphoramidite.

"As chiral phosphoramidites are also excellent ligands for asymmetric carbon-carbon bond formations, we were curious to see if the automated ligand synthesis protocol could also be applied for these transformations," says de Vries. To this end, the DSM team tested a library of 96 different ligands in the asymmetric 1,4-addition of a vinylboron derivative to cyclohexenone. DSM found that one specific ligand derived from enantiomerically pure octahydroBINOL, phosphorus (III) chloride (PCl₃), and diethylamine affords the product 3-vinyl-cyclohexanone in 87% e.e., while other combinations of diol and amines are less selective, showing the advantage of having an automated ligand synthesis and screening protocol (9), explains de Vries.

Stereochemical controllers in biaryl Suzuki couplings

Suzuki coupling, which involves the palladium-catalyzed coupling of aryl halides and arylboronic acids, is a widely used approach to synthesize active pharmaceutical ingredients. Françoise Colobert, professor and vice-director of the Ecole de Chimie, Polymères, Matériaux (ECPM) at the Université Louis Pasteur (Strasbourg, France, www-ulpu-strasbg.fr/) outlined at Modern Synthetic Methods & Chiral Europe a methodology for efficient catalytic access to axially chiral biaryls bearing a benzylic stereocenter. Such a process route may be applied to bioactive molecules such as the anticancer therapy (-)-steganacin, the antimalaria therapy korupensamine A, and the antibiotic vancomycin and its derivatives.

Colobert and her team developed the methodology in connection with a program devoted to asymmetric biaryl Suzuki coupling. As part of that program, her research team forwarded a new atropo-diastereoselective Suzuki coupling reaction that allows for the synthesis of biphenyl, binaphthyl, and phenylnaphthyl derivatives with strong control of the axial chirality (up to 98% diastereomeric excess) and yields as much as 99% (10–12). She explains that a 1,3-chirality induction from a stereogenic benzyloxy group to the chiral axis is mainly responsible for the atropo-diastereoselectivity as outlined in Figure 2.

Figure 2: An atropo-diastereoselective Suzuki coupling reaction that allows for the synthesis of biphenyl, binaphthyl, and phenylnaphthyl derivatives.

The stereogenic benzylic group was introduced by the reduction of a β-ketosulfoxide (13) ortho to the arylhalide unit, explains Colobert.

"Excellent stereoselectivities also were obtained in the coupling reaction with aromatic halides bearing a p-tolylthioether or dimethylamino group instead of a p-tolylsulfoxide," says Colobert.

A plausible mechanism responsible for the high selectivity, explains Colobert, may be due to the formation of a palladacycle during oxidative addition in which palladium is coordinated to the internal chelating ligand such as p-tolylsulfoxide, p-tolylthioether (coordination by the sulfur atom) or dimethylamino group (coordination by the nitrogen atom) as outlined in Figure 3. "This methodology provides an efficient catalytic access to axially chiral biaryls bearing a benzylic stereocenter such as (-)-steganacin, korupensamine A, and a vancomycin biaryl unit," says Colobert.

In the July issue of Pharmaceutical Technology Sourcing and Management Monthly

Chiral and green chemistries

Although the primary focus of approaches in asymmetric synthesis is to improve yield and enantiomeric purity, such approaches also may produce other benefits such as forwarding a more environmentally favored approach to a particular synthesis. Such was the case with Merck & Co., Inc. (Whitehouse Station, NJ, www.merck.com) and Codexis, Inc. (Redwood City, CA, www.codexis.com). The two companies recently were recognized by The Presidential Green Chemistry Challenge Awards Program (14), which provides annual rewards for individuals, groups, and organizations for innovations for cleaner and more economical chemistry. Merck was selected for an efficient catalytic synthesis for sitagliptin, a chiral β-amino acid derivative and the active ingredient in "Januvia," Merck's investigational treatment for Type II diabetes.

Codexis was recognized for developing a biocatalaytic process for making ethyl (R)-4-cyano-3-hydroxybutyrate, a key chiral building block used to manufacture atorvastatin, the active ingredient in Pfizer Inc.'s (New York, NY, www.pfizer.com) "Lipitor."

Figure 3: A possible reaction mechanism accounting for the high selectivity in the coupling reaction with aromatic halides bearing a p-tolylthioether or dimethylamino group.

References

1 J.G. de Vries and A.H.M. de Vries, "The Power of High-Throughput Experimentation in Homogeneous Catalysis Research for Fine Chemicals," Eur. J. Org. Chem. (5), 799–811 (2003).

2. L. Lefort et al., "Instant Ligand Libraries. Parallel Synthesis of Monodentate Phosphoramidites and in Situ Screening in Asymmetric Hydrogenation," Org Lett. 6 (11), 1733–1735 (2004).

3. M. van den Berg et al., "Highly Enantioselective Rhodium-Catalyzed Hydrogenation with Monodentate Ligands," J. Am. Chem. Soc. 122 (46), 11539–11540 (2000).

4. M. van den Berg et al., "Rhodium–MonoPhos-Catalyzed Asymmetric Hydrogenation of Enamides," Adv. Synth. Catal. 344 (9), 1003–1007 (2002).

5. D. Peñaet al., "Highly Enantioselective Rhodium-Catalyzed Hydrogenation of β-Dehydroamino Acid Derivatives Using Monodentate Phosphoramidites," J. Am. Chem.Soc. 124 (49), 14552–14553 (2002).

6. M.T Reetz et al., "A New Principle in Combinatorial Asymmetric Transition-Metal Catalysis: Mixtures of Chiral Monodentate P Ligands," Angew. Chem. Int. Ed. 42 (7), 790–793 (2003).

7. D. Peñaet al., "Improving Conversion and Enantioselectivity in Hydrogenation by Combining Different Monodentate Phosphoramidites: A New Combinatorial Approach in Asymmetric Catalysis," Org. Biomol. Chem. 1 (7), 1082–1087 (2003).

8. A.H.M. de Vries et al., "Instant Ligand Libraries Beat the Time-to-Market Constraint," Chimica Oggi, 23 (2), Supplement on Chiral Technologies, 18–22 (2005).

9. A. Duursma et al., "Synthesis and Application in Asymmetric C-C Bond Formation of Solution Phase Ligand Libraries of Monodentate Phosphoramidites," Org. Biomol. Chem. 2 (12), 1682–1684 (2004).

10. P-E. Broutin and and F. Colobert, "Enantiopure β-Hydroxysulfoxide Derivatives as Novel Chiral Auxiliaries in Asymmetric Biaryl Suzuki Reactions," F. Org. Lett. 5 (18), 3281–3284 (2003).

11. P-E. Broutin and and F. Colobert, "An Asymmetric Biaryl Suzuki Cross-Coupling Reaction: Stereogenic Benzylic Carbinols as Chiral Auxiliaries," Eur.J. Org. Chem, (6), 1113–1128 (2005).

12. P-E. Broutin and F. Colobert, "Efficient Stereochemical Controllers in Biaryl Suzuki Coupling Reactions: Benzylic Carbinols Bearing in β-Position Thioether, Dimethylamino, or Sulfoxide Groups," Org. Lett. 7 (17), 3737–3740 (2005).

13. G. Solladié and M.C.Carreñn Organosulfur Chemistry : Synthetic Aspects P.C.B. Page, Ed. Academic Press: New York, NY, 1995, pp.1–47.

14. US Environmental Protection Agency, "Presidential Green Chemistry Challenge Awards," (EPA, Washington, DC, 2006), http://www.epa.gov/greenchemistry/pubs/pgcc/presgcc.html accessed July 15, 2006.