Chiral Catalysis

Catalysis for asymmetric reactions is generating tremendous academic and industrial interest, even if it is not yet widely used in pharmaceutical production. Several critical considerations surface when contemplating a catalytic step in a synthetic route: material availability, speed of development, ease of implementation, access to the technology, and cost. In short, asymmetric catalysis must be competitive against alternative methods for producing a chiral target.

All this is balanced against performance factors--such as activity, selectivity, productivity, and stability--in achieving a desired transformation effectively and efficiently. And although catalyst and ligand structure significantly influence conversion, yield, and selectivity, what configuration will work is often unpredictable and dependent on reaction conditions and substrates. Nevertheless, researchers strive to find and understand where the positives outweigh the negatives.

"From a process development viewpoint, catalysis in the production of chiral compounds is essential, because we are always looking for cost-effective and environmentally friendly solutions," Trevor Laird, editor of Organic Process Research & Development, told C&EN. "Catalysis offers the possibility of both." Laird is managing director and founder of Scientific Update, as well as organizer of the annual Chiral USA conference, held in July in Princeton, N.J., and Chiral Europe, held in May in Cambridge, England.

At Chiral USA, Yongkui Sun, director of Merck's Catalysis & Reaction Discovery & Development Laboratory, presented his case for catalysis in the pharmaceutical industry. "Increasing competitive pressures and time to market are key factors in process development," he said, "and significant drivers for more efficient and cost-effective processes." Asymmetric catalysis is an efficient synthetic methodology for making complex active pharmaceutical ingredients (APIs), he noted. "We plan to use more and more asymmetric catalysis in drug synthesis."

Merck established a simple goal when creating its catalysis lab a few years ago--namely, the early and rapid implementation of efficient catalytic processes in API synthesis. The company replaced ad hoc efforts with a centralized catalysis lab that works closely with the project chemists who design overall synthetic routes. The lab takes advantage of automated and high-throughput experimentation. Asymmetric hydrogenation was chosen as an initial emphasis.

"Despite being the most powerful form of asymmetric catalysis, there are actually a very limited number of asymmetric hydrogenations being used in drug manufacturing," Sun pointed out. But he offered examples of recent work at Merck, including process development for MK-0431, a diabetes treatment now in clinical trials. A key step is the economic and efficient rhodium-catalyzed hydrogenation of an unprotected enamine using a ferrocenyl phosphine Josiphos-type ligand. The novel asymmetric hydrogenation was discovered by Merck and codeveloped with Solvias (C&EN, Sept. 13, 2004, page 28).

Since then, the Merck lab has used a similar Josiphos-type ligand for the ruthenium-catalyzed asymmetric hydrogenation of N-sulfonylated--dehydroamino acids (Org. Lett. 2005, 7, 3405). The highly enantioselective reaction has been employed late in the synthesis of an anthrax lethal factor inhibitor to streamline the process by avoiding lengthy protecting and deprotecting steps.

SIMILARLY, Pfizer has established an in-house catalyst development effort among its competencies for chiral drugs, which include the world's biggest selling drug, Lipitor. The effort was created in part to own catalyst-related intellectual property generated in process development so that it could be freely used in manufacturing, explained Garrett Hoge of Pfizer Global R&D in Ann Arbor, Mich. Another goal, he said, is "a balance between Pfizer utility and novel science."

The Pfizer group has designed the C₁-symmetrical bisphosphine ligand trichickenfootphos (TCFP), which is used in synthesizing Pfizer's new -amino acid-based drug, pregabalin (C&EN, May 3, 2004, page 25). "Asymmetric hydrogenation with TCFP is good for a variety of substrates, offering high enantioselectivities and high activity under mild conditions," Hoge remarked.

TCFP is proving to be versatile. Hoge and coworker He-Ping Wu have used it in the rhodium-catalyzed asymmetric hydrogenation of β-acetamido dehydroamino acids to produce chiral β-amino acids (Org. Lett. 2004, 6, 3645). Likewise, a Pfizer team in Kalamazoo, Mich., headed by group leader Thomas Nanninga, has used TCFP to make a β-amino acid-based drug candidate with two chiral centers. After screening many catalysts, the team found only two--using TCFP or Chiral Quest's Binapine ligand--that provided greater than 90% enantiomeric excess (ee), had acceptable conversions at reasonable catalyst loadings, and were commercially available, Hoge said.

In this particular reaction, to balance the higher selectivity but slower rate seen with the Binapine ligand with the faster rate and lower catalyst loading of TCFP, the Pfizer team conducted a "piggyback" reaction to reach the minimum 95% ee they needed to then purify the product in just one crystallization. To achieve this goal, they first reacted the substrate with Rh-Binapine until the reaction stopped at 85% conversion and 97% ee.

"Then we added TCFP and continued the hydrogenation, and in about eight hours we had greater than 99% conversion and 96% ee," Hoge said. "It looks like a parlor trick, but we actually do this on a production scale." Since then, however, they have found with TCFP alone that the addition of water--about 15% in tetrahydrofuran--increases the enantiomeric excess to a little better than 95%. "If we were to scale this reaction up again, we could use Rh-TCFP exclusively," he added.

Developments in asymmetric catalysis often involve efforts among pharmaceutical researchers, catalyst developers, and academic scientists. "The close collaboration between academic labs and industry has helped to ensure that discoveries are quickly scaled," Laird commented. Implementation can slow, however, when one party patents a catalyst and seeks licenses from those wishing to use it, he warned, because pharmaceutical companies in particular are wary of licensing.

Nevertheless, collaboration and licensing, particularly from academic institutions, are widely practiced. For example, DSM has worked closely with scientists at the University of Groningen, in the Netherlands, in developing the MonoPhos family of monodentate phosphoramidite ligands for asymmetric hydrogenation. When working with the catalysts, they discovered that adding an achiral phosphine to reactions dramatically enhances rates and enantioselectivity (Angew. Chem. Int. Ed. 2005, 44, 4209). Using such a combination, the rhodium-catalyzed reduction of an ,β-disubstituted unsaturated acrylic acid is being run at ton scale to produce an intermediate for a new renin inhibitor.

Chemists continually toy with catalyst design to improve performance and create new proprietary structures. For example, the DSM and Groningen researchers have found that subtle structural changes in the phosphoramidite ligands can have dramatic effects on enantioselectivity (J. Org. Chem. 2005, 70, 943). These can, in the rhodium-catalyzed hydrogenation of enol acetates and enol carbamates, deliver up to 98% ee (Org. Lett. 2005, 4, 4177).

Catalyst developers rely on automated and high-throughput experimentation methods to create and screen catalyst libraries. Thus they take advantage of structures that are both modular and tunable. With modular ligands, simple structural modifications can be achieved easily by synthesis. Tuning involves incrementally changing steric or electronic properties believed to be important.

At Chiral USA, Thomas H. Riermeier, senior R&D manager at Degussa Homogeneous Catalysts, described the results of extensive catalyst profiling for enantioselectivity along with high conversion. "Even for a very narrow group of ligands, there was no general trend that we could deduce," he conceded. He believes that it's best to combine rational approaches to ligand design, as a starting point, with timesaving high-throughput experimentation.

"Catalyst developers have only so much knowledge about what is really going on," he admitted. "We have some concept for some substrates and ligands, but I think we are far from having a general understanding of asymmetric homogeneous hydrogenation after 30 years of research."

MODULAR SYNTHESIS was key in creating Degussa's catASium M chiral bisphospholane ligands. The ligand family is tunable by attaching trimethylsilylphospholane to different building blocks and creating stepwise variations in the PC5C angle, Riermeier explained. When the ligands are complexed with rhodium, the resulting catalysts also vary in PRhP bite angles. The catalysts have high activities and enantioselectivities in hydrogenating itaconic acid derivatives (Adv. Synth. Catal. 2004, 346, 1263).

Riermeier also introduced Degussa's new catASium T catalysts (Chimica Oggi 2005, 23, 48). Based on inexpensive, naturally occurring terpenes, the ligand backbone combines a chiral cycloolefinic unit with a heteroaryl moiety. The entire ligand can be tuned by introducing a disubstituted phosphorus group on each part of the backbone. Riermeier noted that the ligand performs well in the rhodium-catalyzed hydrogenation of poorly substituted enamides and β-amino acid precursors.

Erick M. Carreira, chemistry professor at the Swiss Federal Institute of Technology, Zurich, presented a similar approach to creating modular ligands based on easily prepared substituted [2.2.2]-bicyclooctadienes. The ligands, also derived from terpenes, are useful for asymmetric catalysis involving late transition metals without the necessity of added phosphine groups. Initially, Carreira and coworkers tested the diene ligands in the iridium-catalyzed kinetic resolution of allylic carbonates and achieved up to 98% ee (J. Am. Chem. Soc. 2004, 126, 1628).

"We've been trying to understand why these olefins function in the capacity that they do and, in certain processes, are capable of effecting transformations phosphines can't," Carreira said. "The interaction of an olefin with a metal center is a curious balance of donation and back donation." Although the olefin bonding energies can be weaker than those displayed by the more commonly used phosphines, strain in the diene ligand structure may help stabilize the metal complex.

Using other substituted variants of the dienes in rhodium-catalyzed reactions, Carreira and coworkers have conducted asymmetric conjugate additions of arylboronic acids to enals (J. Am. Chem. Soc. 2005, 127, 10850); to enones, enamides, and coumarins (Org. Lett. 2004, 6, 3873); and to unsaturated tert-butyl esters (Org. Lett. 2005, 7, 3821). The method gives rise to compounds incorporating diarylmethine stereogenic centers, otherwise challenging to prepare, but important in natural products and some notable drugs.

Carreira also briefly described a new biaryl phosphorus and nitrogen, or P,N-containing, ligand. "We wanted a ligand scaffold structurally similar to QUINAP [1-(2-diphenylphosphino-1-naphthyl)isoquinoline] that, unlike QUINAP, would be easy to make, inexpensive, and much more amenable to modification," he said.

His lab developed PINAP, based instead on phthalazine and 2-naphthol, which has reactivity comparable with that of QUINAP in hydroboration and C5N addition reactions (Angew. Chem. Int. Ed. 2004, 43, 5971). Using PINAP, Carreira noted, his lab has accomplished the first catalytic, enantioselective, conjugate addition involving direct use of terminal acetylenes (J. Am. Chem. Soc. 2005, 127, 9682).

Jeffrey S. Johnson, chemistry professor at the University of North Carolina, Chapel Hill, also presented work on coupling reactions--namely, metal cyanide- and metallophosphite-catalyzed cross silyl benzoin reactions between acyl silanes and aldehydes. "Our goal was an enantioselective version of an -hydroxyketone synthesis," he said. And the researchers achieved a "proof of concept for the first nonenzymatic cross benzoin reaction that was enantioselective."

Using potassium cyanide and a phase-transfer catalyst, his group initially found that racemic unsymmetrical aryl-, heteroaryl-, and alkyl-substituted benzoin adducts could be generated in moderate to excellent yield with complete regiocontrol (J. Am. Chem. Soc. 2005, 127, 1833). They then speculated that metallophosphites might offer the needed mechanistic functions as a nucleophile, anion stabilizing group, and leaving group in cross silyl benzoin reactions that involve phosphite addition and Brook rearrangement.

The best metallophosphite catalyst, a tetra(o-fluorophenyl) Taddol phosphite, generated good yields (65-88%) and enantiomeric excesses generally between 80 and 90% with aryl acylsilane and aryl or heterocyclic aldehyde substrates (J. Am. Chem. Soc. 2004, 126, 3070). Catalyst loadings of 5-20 mole % are not yet practical, Johnson pointed out; yield and selectivity can be addressed through modifying the tunable ligand structure. His group next worked on metallophosphite catalysis, facilitated by a diastereoselective retro [1,4] Brook rearrangement, in the acylation of ,ß-unsaturated amides to produce 1,4-dicarbonyls and achieved similar success (Angew. Chem. Int. Ed. 2005, 44, 2377).

In another approach to constructing effective catalysts, this time for environmentally benign synthesis, University of Tokyo chemistry professor Shu Kobayashi reported work on osmium tetraoxide. Combined with a chiral ligand, OsO₄ is an effective catalyst for the asymmetric dihydroxylation of olefins in synthesizing natural products. That it is expensive, highly toxic, and very volatile, however, has limited its use on an industrial scale.

TO MAKE IT more stable and easier to handle, Kobayashi's lab has produced microencapsulated OsO₄, using a poly(phenoxyethoxymethylstyrene-co-styrene) polymer. The catalyst also shows higher activity than the nonimmobilized version. "In almost all cases, the reactions run well, with diols in high yield and high enantiomeric excess," Kobayashi reported. "Recovery of the catalyst was quantitative, and no leaching was observed."

Although microencapsulated OsO₄ catalyzes asymmetric dihydroxylations well even in water, the linear polymers are soluble in some solvents. To avoid this problem, Kobayashi has since moved to using cross-linked polymers (Adv. Synth. Catal. 2005, 347, 1189). Similarly, Steven V. Ley at Cambridge University has developed a cross-linked polyurea-encapsulated OsO₄ catalyst that is being commercialized by Reaxa, a company founded by Ley and others.

Meanwhile, Bruce H. Lipshutz, chemistry professor from the University of California, Santa Barbara, has been extending his work with homogeneous copper catalysts for asymmetric hydrosilylations. Inexpensive base-metal catalysts, such as nonracemically ligated copper hydride, have led to ligand-accelerated catalysis with turnover numbers in the thousands, along with generally better than 90% yields and enantioselectivities (J. Am. Chem. Soc. 2004, 126, 8352).

Recently, Lipshutz and graduate student Bryan A. Frieman found that not only is CuH complexed with the (R)-()-3,5-di-tert-butyl-4-methoxy-SegPhos ligand extremely reactive and selective, but it is also robust (Angew. Chem. Int. Ed., published online Aug. 28, dx.doi.org/10.1002/anie.200500800). The catalyst--prepared from copper acetate, SegPhos, and sodium tert-butoxide or phenoxide with an excess of polymethylhydrosiloxane--is room-temperature stable. Dubbing it "CuH in a bottle," he said, "you can make it up, put it on the shelf, leave it there for months, and it doesn't lose any activity."

At Chiral USA, Lipshutz described a version starting with copper deposited within a carbon support. In various test reactions it performed as well as the homogeneous version; in some cases, however, it became necessary to speed up the heterogeneous reaction. "Heterogeneous reduction of enoates typically are only about 50-60% complete in two days," he noted. But with ultrasonication, they discovered, the supported CuH catalyst reduces β-substituted methyl cinnamate in greater than 99% yield and enantioselectivity in a few hours.

Lipshutz also pointed out the applicability of the catalyst in the synthetic route for (R)-fluoxetine, or Prozac. Likewise, Huw M. L. Davies, from the University of Buffalo, discussed work targeting pharmaceutical applications. Davies presented results on enantioselective CH activation by means of rhodium carbenoid-induced CH insertion, an equivalent and alternative means to many classic reactions in organic synthesis, such as the aldol and Mannich reactions.

The key to the success of this chemistry is the use of carbenoids functionalized with both donor and acceptor groups. "CH activation is actually quite a practical reaction, with good regiochemistry, that is tolerant of many functional groups," Davies said. "Typically, the enantioselectivity is between 85 and 95%, and in certain systems it is also highly diastereoselective." Two negatives, however, are a limited range of donor groups and very substrate specific diastereoselectivity.

To address these limitations, Davies offered a combined CH activation/Cope rearrangement catalyzed by Rh₂(S-DOSP)₄ and demonstrated its very high diastereoselectivity and enantioselectivity with certain cyclic structures. For example, he has found 1,2-dihydronaphthalenes to be "spectacular substrates" in reactions with vinylcarbenoids that involve CH activation/Cope rearrangement followed by a retro-Cope rearrangement to form functionalized dihydronaphthalenes.

These same substrates, Davies has found, undergo double CH activation to generate products with four new stereogenic centers in greater than 94% diastereomeric and 98% ee (Org. Lett. 2005, 7, 2293). Graduate student Abbas M. Walji has used the C-H activation/Cope rearrangement method starting with a racemic dihydronaphthalene to construct the three stereogenic centers in the total sy nthesis of (+)-erogorgiaene, one of a class of diterpenes isolated from the coral Pseudopterogorgia elisabethae (Angew. Chem. Int. Ed. 2005, 44, 1733).

Two months earlier, catalyst development, not surprisingly, was also big on the agenda at Chiral Europe. Several speakers whose work has focused on catalysis with organometallic complexes and organocatalysis shared their developments with C&EN after the meeting.

Modularity and tunable ligand structures were again common themes in creating new organometallic catalysts for hydrogenation, particularly those based on ruthenium and iridium.

For example, Martin Wills, professor of chemistry at the University of Warwick, in England, has devised tethered ruthenium catalysts for the asymmetric reduction of ketones via transfer hydrogenation. In the mid-1990s, Nobel Laureate Ryoji Noyori reported highly active ruthenium catalysts with amino alcohol or monotosylated diamine ligands. Reactions with them, however, are not particularly fast. The catalyst's structure is also fluxional, and to change this, Wills's group tied down the -arene ring through a three-atom tether.

"We wanted to make the structure rigid and stereochemically well-defined so that we could alter it later and tune the catalyst toward different substrates," he explains. In fact, they found that tethering alone increased activity for both the amino alcohol (J. Org. Chem. 2005, 70, 3188) and the diamine (J. Am. Chem. Soc. 2005, 127, 7318) ligands. "By being more active, the catalysts can take on more challenging substrates and have slightly increased scope," he adds.

For pressure hydrogenation of ketones, on the other hand, notable catalysts include a Noyori system containing a diphosphine and a diamine, typically DPEN (1,2-diamino-1,2-diphenylethane). Wills and coworkers have created a variant of this, combining DPEN with monodonor binol-derived phosphorus ligands, similar to MonoPhos, which are more commonly used in reducing C=C bonds (where binol is 2,2'-dihydroxy-1,1'-binaphthyl) (J. Org. Chem., published online Aug. 27, dx.doi.org/10.1021/jo051176s). According to Wills and others, monodonor ligands are exceptionally easy to prepare and less expensive than most chiral bidentate ligands.

"For quite a long time people thought that you needed to have a bidentate phosphine for the catalyst to be any good," he says. "What really surprised us was how specific the R group on the phosphorus has to be, because it makes a huge difference in the selectivity." For example, in the ligand family XuPhos, named after graduate student Yingjian Xu, one with an orthobromophenyl group, BrXuPhos, produced chiral alcohols with greater than 92% conversion and up to 99% ee. Rhodia helped fund the work and has patented and added XuPhos to its ligand portfolio.

IRIDIUM IS another popular transition metal. Andreas Pfaltz, professor of chemistry at the University of Basel, in Switzerland, and chemistry professor Kevin Burgess from Texas A&M University, use it to effect asymmetric hydrogenations of unfunctionalized alkenes. Such alkenes are challenging substrates because they don't contain a heteroatom to coordinate to the catalyst. Inspired by the achiral (1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine) iridium catalyst created in 1979 by Yale University chemistry professor Robert H. Crabtree, both researchers have created new chiral ligands. Pfaltz uses P,N-complexes, such as phosphine-oxazolines (Phox), while Burgess employs a carbene-oxazoline structure.

"Despite more than a decade of effort in this field, the number of substrates that are actually covered in hydrogenation reactions of unfunctionalized alkenes is a relatively limited set," Burgess explains. His favored catalyst uses an imidazolylidine-oxazoline ligand and gives high conversions and enantioselectivities for several aryl-substituted alkenes under mild conditions.

Burgess has started expanding the scope of these reactions, using the same catalyst for hydrogenating aryl-substituted dienes with similar success (Chem. Commun. 2005, 672). "Dienes are relatively unexplored," he explains, "but interesting in that you generate two chiral centers and can start to look at diastereoselectivity and enantioselectivity."

"Iridium catalysts really have enhanced the range of substrates that you can hydrogenate with high enantioselectivity," Pfaltz agrees. "And they are complementary in their scope to classical hydrogenation catalysts with ruthenium and rhodium."

Pfaltz has extensively studied variations in the P,N-ligand structure to produce a range of related ligands (Adv. Synth. Catal. 2003, 345, 33). He points out that the precatalysts are air and moisture stable and easily prepared. For example, the phosphinite ligand SimplexPHOX can be made in just two steps from simple precursors (Org. Lett. 2004, 6, 2023). Two derivatives of his ThrePHOX ligand, derived from threonine, are available from Strem Chemicals.

His lab has also explored the kinetics of these reactions and has found that the use of BAr_F--tetrakis-[3,5-(trifluoromethyl)-phenyl]borate--as the counterion to the iridium complex has a significant effect on catalyst activity. "At first we used normal weakly coordinating counterions like hexafluorophosphate, but the catalyst did not live for very long," Pfaltz says. "Anions like BAr_F have a big effect on stability--you can get up to 10,000 turnovers--and thanks to this effect, these catalysts have the potential to be industrially useful."

Although counterion effects have received little attention, Pfaltz observes, interest is now growing. "There are groups studying ligands where the anion is incorporated into the backbone," he explains, "and the ligand then forms a neutral zwitterionic metal complex." Along these lines, his group has synthesized bisoxazolines with an anionic boron bridging the backbone that show promise for asymmetric Cu-catalyzed acylation of 1,2-diols and other reactions (Angew. Chem. Int. Ed. 2005, 44, 4888).

For the past few years, metal-containing bisoxazoline catalysts have been a focus of Karl Anker Jørgensen, professor of chemistry at Aarhus University and head of the Danish National Research Foundation's Center for Catalysis. He has studied them in asymmetric C-C bond formation via Friedel-Crafts, aldol, and Mannich reactions, as well as in the amination and halogenation of β-ketoesters and β-ketophosphonates. More recently, he has been using organocatalysts to explore many of these same reactions.

"Organocatalysis offers opportunities to do things that you normally cannot do in metal-mediated catalysis," Jørgensen says. Organocatalysts are relatively easy to handle and require mild reaction conditions, he adds. And they avoid metal-related impurities in the product or waste stream.

"With organocatalysis you can easily approach addition to carbonyl compounds, such as aldehydes and ketones," he continues. Jørgensen's lab has reported the catalytic asymmetric epoxidation of ,β-unsaturated aldehydes using chiral amines and hydrogen peroxide with greater than 95% ee (J. Am. Chem. Soc. 2005, 127, 6964). "It's a very simple organocatalyzed reaction that was not possible with Lewis acids," he adds.

Jørgensen and coworkers have used cinchona alkaloid derivatives as catalysts for stereoselective nucleophilic aromatic substitutions, asymmetric Mannich reactions, and enantioselective allylic aminations. They have also used chiral amines in various other enantioselective reactions, including a-sulfenylation, -chlorination, -fluorination, and, most recently, -bromination of aldehydes and ketones. (Chem. Commun., published online Aug. 30, dx.doi.org/10.1039/b509366j).

A keen interest in halogenation reactions stems from their application in constructing chiral compounds of value in medicinal chemistry. Within a few weeks of each other earlier this year, the labs of Jørgensen, David MacMillan at California Institute of Technology, Carlos F. Barbas at Scripps Research Institute, and Dieter Enders at the Institute of Organic Chemistry in Aachen, Germany, published on the asymmetric -fluorination of aldehydes. The groups tested various fluorine sources along with proline-, prolinol-, and pyrrolidine-based catalysts, including imidazolidinone, to various effect on different substrates and with different catalyst loadings.

"The literature abounds with new organocatalysts and new reactions, which should be attractive for scale up and complement existing efforts in biocatalysis and homogeneous organometallic catalysis," Laird comments. "Modern academics and industrial chemists are pushing forward with new asymmetric catalytic processes that I think will be very important in the future of fine chemical and pharmaceutical production."