Achieving Enantioselectivity

Strategies for asymmetric synthesis are of continuing importance to the pharmaceutical industry. Single enantiomers accounted for 75% of the new small molecules approved by the US Food and Drug Administration in 2006 (1). Carbon–hydrogen functionalization through carbene catalysis, ketone α-alkylation, and biocatalysis using enoate reductases and ketoreductases are some recent examples of improving enantioselectivity of pharmaceutical compounds.

Patricia Van Arnum

Carbon–hydrogen functionalization

Huw Davies, professor in the Department of Chemistry at the University of Buffalo and cofounder of Dirhodium Technologies (Buffalo, NY), recently reported on an alternative method for metal-induced carbon–hydrogen insertion. Carbon–hydrogen activation is an important tool in asymmetric synthesis. It typically involves the insertion of a highly reactive metal complex into a carbon–hydrogen bond, thereby activating the system for transformation. A challenge of this approach is being able to achieve the desired catalytic activity of the metal complex. One strategy to address this problem is to use neighboring functional groups to direct the metal complexes to the carbon–hydrogen bond. An alternative approach, forwarded by Davies, is to use a divalent carbon, or carbene, or a monovalent nitrogen, or nitrene, coordinated to a metal complex for insertion into a carbon–hydrogen bond. The benefits of this approach are higher levels of regioselectivity and steroselectivity (2).

Davies reported on using carbon–hydrogen functionalization to synthesize "Ritalin" (methylphenidate), a drug to treat attention-deficit hyperactivity disorder. The synthesis involves the Rh₂ (S-biDOSP)₂ -catalyzed reaction of N-protected piperidine with methyl phenyldiazoacetate, followed by the removal of the protecting group to form (R, R')-(+)-methylphenidate in 86% enantiomeric excess (ee) (1). Carbon–hydrogen functionalization by metal carbenoids and metal nitreonoids may also be used for synthesizing diterpene natural products, for the enantioselective synthesis of 4-substituted indoles, and for enantioselective carbon–hydrogen amination (2).

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Ketone α-alkylation

Don Coltart, an associate professor at Duke University, reported a new method for ketone α-alkylation, a reaction used to create chiral ketones with alkyl groups on the α-carbons. These structures are found in many natural products and pharmaceuticals. In traditional approaches to asymmetric ketone α-alkylations, chiral hydrazine auxiliaries are often used to direct enantioselectivity through the formation and subsequent deprotonation of hydrazones. This approach, however, requires the reaction to be run at low temperatures (–110 to –78 °C), and the chiral auxiliaries are difficult to recycle.

Coltart reported by substituting conjugated electron-withdrawing groups onto the chiral hydrazine auxiliaries, a ketone can be combined with chiral N-amino cyclic carbamates to form a hydrazone, which is reacted with an alkyl halide to form the enantiomeric product. The reactions can be run at higher temperatures (–40 to 0 °C), and the chiral auxiliaries can be recycled with an acid treatment (3). Coltart and Duke recently applied for a patent on the process, according to a Duke University press release.

Other carbene catalysis

Karl Scheidt, an assistant professor of chemistry at Northwestern University, is exploring catalytic multicomponent coupling processes, organosilicon chemistry, and new catalytic reactions with N-heterocyclic carbenes. In carbene catalysis, his research group has developed several approaches to carbonyl/acyl anion equivalents, homoenolate reactivity, hydroacylations of ketones, formal [3 + 3 ] cycloadditions, Michael reactions, aldol reactions, and acylvinyl anion equivalents (4, 5).

Scheidt's work further focuses on the construction of complex natural products containing oxygen heterocycles. Using new Lewis acid-catalyzed cyclization reactions with dioxinones, his group is researching the synthesis of tetrahydropyran-containing natural products with antitumor activity, and it recently reported the catalytic enantioselective synthesis of flavanones. The group used bifunctional thiourea catalysts to promote an asymmetric oxo-conjugate addition to β-ketoester alkylidene in high yields with enantioselectivity of 80–94% ee for aryl and alkyl substrates. Decarboxylation of the β-ketoester proceeds in a one-pot procedure to produce enantioenriched flavanones and chromanones (4, 5).

Asymmetric Diels–Alder reactions

Eric Jacobsen, professor of the Department of Chemistry at Harvard University, recently reported on transannular reactions for achieving desired enantioselectivity. Specifically, Jacobsen reported on a catalytic transannular asymmetric Diels–Alder (TADA) reaction for producing polycyclic products in high enantiomeric excess. The catalyst system (derivatives of oxazaborolidine-based Lewis-acid compounds) were used to alter the diastereoselectivity of cyclizations with substrates containing chiral centers. The catalytic enantioselective TADA was used as the key step in synthesizing sesquiterpene 11, 12-diacetoxydrimane. This route may also provide a general approach to the polycyclic carbon framework shared by other terpene natural products (6).

Biocatalysis

BASF (Ludwigshafen, Germany) is using a class of enzymes, enoate reductases, for the industrial production of chiral intermediates. The asymmetric reaction catalyzed by the enoate reductases can take place at low temperatures and standard pressures, according to a company press release. BASF and researchers at the University of Graz recently reported on using three cloned enoate reductases (12-oxophytodienoate reductase isoenzymes [OPR1 and OPR3] from Lycopersicon esculentu and YqjM from Bacillus subtilis) in the asymmetric bioreduction of activated alkenes. According to the research, the biocatalysts were able to reduce α, β-unsaturated aldehydes, ketones, maleimides, and nitroalkenes with absolute chemoselectivity (with reduction of only the conjugated carbon–carbon double bond) with enantioselectivity > 99% ee (7).

Codexis (Redwood City, CA) is ausing ketoreductases to produce chiral secondary alcohols. Chiral secondary alcohols are commonly produced using boron-based reducing agents or chemocatalysis. Although a biocatalytic route could improve reaction conditions, ketoreductases have had drawbacks, including narrow substrate-specificity, low activity, poor in-process stability, inadequate stereoselectivity, and productivity-limiting product inhibition. To resolve these problems, Codexis launched ketoreductase biocatalyst panels that consist of 180 variants of one wild-type ketoreductase that are pre-evolved for in-process thermal and solvent stability. The variants are arrayed on microtiter plates for screening to find the desired activity on a new ketone substrate and to obtain amino-acid sequence versus activity data for further evolution if needed (8). The company launched the panels in 2007.

Codexis developed an improved route to (S,E)-2-(3-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-hydroxypropyl)-benzoate (MLK-III), a chiral intermediate used in the synthesis of the anti-asthama drug "Singulair" (montelukast sodium) (see Figure 1) using biocatalysis. In the traditional approach, the ketone reduction to this chiral alcohol requires at least 1.8 equivalents of the reductant (–)-β-chlorodiisopinocampheylborane ((–)-DIP-Cl) in tetrahydrofuran at –20 to –25 °C. After quenching, an extraction removes spent borate salt waste. The reduction produces the S-alcohol in 97% ee and requires crystallization to give 99.5% ee in 87% yield (8).

Figure 1: Biocatalysis offers an improved route for producing a chiral intermediate used in the synthesis of montelukast (pictured), the active ingredient in Merck Singulair. (FIGURE IS COURTESY OF US FOOD AND DRUG ADMINISTRATION.)

Using another approach, Codexis developed a biocatalytic reduction for MLK-III using a ketoreductase biocatalyst evolved to reduce MLK-II. Codexis evolved the ketoreductase to increase its activity and stability by more than 2000-fold, replacing one-third of the amino acids in its active site in the process and under improved reaction conditions: 100 g/L in isopropanol–water–toluene at 45 °C. Isopropanol is the reductant, which the ketoreductase uses to regenerate its catalytic cofactor, NADPH, producing acetone as the coproduct. The process runs as a slurry-to-slurry conversion with product precipitation driving the reaction to completion. The precipitated chiral alcohol is of high chemical purity and stereopurity. Codexis has scaled up the manufacture of MLK-III using this biocatalytic reduction and has provided samples of MLK-IV to manufacturers of generic montelukast. The company is planning commercial-scale manufacture on a multiton scale in 2008 (8).

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.

For insight on chiral separations, seeChiral Separations.

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References

1. I. Lennon, N.B. Johnson, and P.H. Moran, "Manufacture of Asymmetric Hydrogenation Catalysts," Pharm. Technol. 31 (9) supplement Pharm. Ingredients, s6–s13 (2008).

2. H. Davies and J.R. Manning, "Catalytic C–H Functionalization by Metal Carbenoid and Nitrenoid Insertion," Nature 451, 417–424 (2008).

3. D. Lim and D. Coltart, "Simple and Efficient Asymmetric α-Alkylation and α,α-Bisalkylation of Acyclic Ketones by Using Chiral N-Amino Cyclic Carbamate Hydrazones," Angew. Chem. Int. Ed. 47 (28), 5207–5210 (2008).

4. M.M. Biddle, K. Lin, and K.A. Scheidt, "Catalytic Enantioselective Synthesis of Flavanones and Chromanones," J. Am. Chem. Soc. 129 (13), 3830–3831 (2007).

5. K.A. Scheidt, "New Discoveries with Carbene Catalysis," presented at Vision of Chemistry Symposium (North Branch, NJ, May 2008).

6 E. Balskus and E. Jacobsen, "Asymmetric Catalysis of the Transannular Diels–Alder Reaction," Science 317 (5845), 1736–1740 (2007).

7. B Hauer et al., "Asymmetric Bioreduction of C=C Bonds Using Enoate Reductases OPR1, OPR3 and YqjM: Enzyme-Based Stereocontrol," Adv. Syn. Catal.350 (3), 411–418 (2008).

8. EPA, "The Presidential Green Chemistry Challenge Awards Program: Summary of 2008 Award Entries and Recipients" (Washington, DC, 2008).