COVER STORY
SPECIFIC Bromine atoms (red) are key in the selectivity of BrXuPhos, a new ruthenium asymmetric hydrogenation catalyst with 1,2-diamino-1,2-diphenylethane and 2,2 '-dihydroxy-1,1'-binaphthyl-based monodonor phosphorus ligands.
CHIRAL CATALYSIS Recent chiral chemistry advances underpin the growing importance of catalyst design to accomplish a range of asymmetric reactions
ANN M. THAYER, C&EN HOUSTON
C
ATALYSIS FOR ASYMMETRIC REACTIONS IS GENERAT-
ing tremendous academic and industrial interest, even if it is not yet widely used in pharmaceutical produc tion. Several critical considerations surface when con templating a catalytic step in a synthetic route: ma terial availability speed of development, ease of implementation, access to the technology, and cost. In short, asymmetric cataly sis must be competitive against alternative methods for pro ducing a chiral target. All this is balanced against performance factors—such as ac tivity selectivity productivity and stability—in achieving a desired
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transformation effectively and efficiently. And although catalyst and ligand structure significantly influence conversion, yield, and selectivity, what configuration will work is often unpredictable and depen dent on reaction conditions and substrates. Nevertheless, researchers strive tofindand understand where the positives outweigh the negatives. "From a process development view point, catalysis in the production of chiral compounds is essential, because we are al ways looking for cost-effective and envi ronmentally friendly solutions," Trevor Laird, editor of Organic Process Research & Development, told C&EN. "Catalysis offers the possibility ofboth." Laird is managing director and founder of Scientific Update, as well as organizer of the annual Chiral WWW.CEN-0NLINE.ORG
USA conference, held inJuly 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 costeffective 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 highthroughput 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 MK0431, 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 similarJosiphos-type ligand for the ruthenium-catalyzed asymmetric hydrogenation of N-sulfonylated-a-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 inhouse 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 manufactairing, 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 C r symmetrical bisphosphine ligand trichickenfootphos (TCFP), which is used in synthesizing Pfizer's new y-amino acid-based drug, pregabalin (C&EN, May 3, 2004, page 25). "Asymmetric hydrogenation with T C F P is good for a variety of sub-
strates, 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 (3-acetamido dehydroamino acids to produce chiral (3-amino acids (Org. Lett. 2004,6,3645). Likewise, a Pfizer team in Kalamazoo, Mich., headed by group leader Thomas Nanninga, has used T C F P to make a (3-amino acid-based
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C&EN
/ SEPTEMBER
5,
2005
41
COVER STORY PRACTICED Hydrogenation leads catalytic asymmetric processes used by industry PRODUCTION SCALE > 5 TONS < 5 TONS PER YEAR PER YEAR
NUMBER OF PROCESSES EMPLOYING TRANSFORMATION
Hydrogenation of Enamides C = C-COOR and C - C - C H - O H Other C = C systems a- and p-functionalized ketones C= N Hydrogenation/ reduction of other keto groups Dihydroxylation of C=C Epoxidation of C=C, oxidation of sulfide Isomerization, epoxide opening & addition reactions TOTAL
PILOT SCALE 50KG PER YEAR PER YEAR
BENCH SCALE
1 2 1 2 1
1 0 0 3 0
2 3 1 3 1
6 k 1 2 0
4 6 2 U 0
0 0 2
0 1 2
2 0 1
2 0 0
4 4 2
2
4
2
0
1
11
11
15
15
27
SOURCE: Solvias
drug candidate with two chiral centers. Af ter screening many catalysts, the team found only two—using T C F P 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-
= phenyl, isobutyl = benzyl, allyl, n-propyl, 3-butenyl
catASium T 1 : R = R = phenyl catASium T2: R = 3,5-xylyl, R = phenyl catASium T3: R = phenyl, R = 3,5-xylyl
VARIETY Although both Ugands are based on terpenes, Carreira's (top) is used in rhodium-catalyzed conjugate additions, whereas Degussa's (bottom) is for hydrogenations.
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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% conver sion and 96% ee," Hoge said. "It looks like a parlor trick, but we actually do this on a production scale." Since then, however,
covered that adding an achiral phosphine to reactions dramatically enhances rates and enantioselectivity (Angew. Chem. Int. Ed. 2005, 44, 4209). Using such a com bination, the rhodium-catalyzed reduction of an a,|3-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 cre ate new proprietary structures. For exam ple, 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 li braries. Thus they take advantage of struc tures 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.
"Asymmetric catalysis is a very efficient synthetic methodology for making complex active pharmaceutical ingredients." they have found with TCFP alone that the addition of water—about 15% in tetrahydrofuran—increases the enantiomeric ex cess to a little better than 95%. "Ifwe were to scale this reaction up again, we could use Rh-TCFP exclusively," he added. Developments in asymmetric catalysis often involve efforts among pharmaceuti cal researchers, catalyst developers, and academic scientists. "The close collabora tion between academic labs and industry has helped to ensure that discoveries are quickly scaled," Laird commented. Im plementation can slow, however, when one party patents a catalyst and seeks licenses from those wishing to use it, he warned, because pharmaceutical companies in par ticular are wary of licensing. Nevertheless, collaboration and licens ing, particularly from academic institu tions, 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 dis-
At Chiral USA, Thomas H. Riermeier, senior R&D manager at Degussa Homo geneous Catalysts, described the results of extensive catalyst profiling for enantiose lectivity along with high conversion. "Even for a very narrow group of ligands, there was no general trend that we could de duce," he conceded. He believes that it's best to combine rational approaches to li gand 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 under standing of asymmetric homogeneous hy drogenation after 30 years of research." MODULAR SYNTHESIS was key in creating Degussa's catASium M chiral bisphospholane ligands. The ligand family is tun able by attaching trimethylsilylphospholane to different building blocks and creating stepwise variations in the P - C = C angle, Riermeier explained. W h e n the li gands are complexed with rhodium, the WWW.CEN-0NLINE.ORG
87% yield 91% enantiomeric excess
Ph * phenyl, Et * ethyl, Ar * 2-fluorophenyl, n-Bu«n-butyl
COUPLING Metallophosphite catalysis promotes enantioselective cross sityl benzoin reaction.
resulting catalysts also vary in P-Rh-P bite angles. The catalysts have high activities and enantioselectivities in hydrogenating itaconic acid derivatives {Adv. Synth. Catal. 2004,346,12631 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 li-
gand performs well in the rhodium-catalyzed hydrogenation of poorly substituted enamides and P-amino acid precursors. ErickM. Carreira, chemistry professor at the Swiss Federal Institute ofTechnology, 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-cat-
alyzed kinetic resolution of allylic carbonates and achieved up to 98% ee (J. Am. Chem.Soc. 2004,126,1628). "WeVe 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 unsaturatedfcrf-butylesters (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.
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IReaxa^ C & E N / S E P T E M B E R 5. 2 0 0 5
43
COVER STORY Carreira also briefly described a new biaryl phosphorus and nitrogen, or P,Ncontaining, ligand. "We wanted a ligand scaffold structurally similar to QUINAP {l-(2-diphenylphosphino-l-naphthyl)isoquinoline] that, unlike QUINAP, would be easy to make, inexpensive, and much
Chapel Hill, also presented work on cou pling reactions—namely, metal cyanideand metallophosphite-catalyzed cross silyl benzoin reactions between acyl silanes and aldehydes. "Our goal was an enantioselective version of an a-hydroxyketone synthesis," he said. And the re-
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[email protected] pounds by SFC is often unsuccessful, pos sibly because the analytes interact with the mobile and stationary phases. Just 0.1% ethanesulfonic acid in 20% ethanol formed ion pairs with the amines that were stable to SFC separation. Separations were ob tained for 36 out of 45 diverse compounds, many of which were not previously sepa rable by SFC. Like Kraml, ChristopherJ. Welch, who heads the analysis and preparative separa tions group within process research at Merck, advocates careful consideration of where separations might best be applied. Strategies for the efficient use of prepara tive-scale chromatography within syn thetic routes are still evolving, according to Welch and coworkers (Chirality 2004,16, 609). But they have shown how SFC led to a key enantiomerically pure 3-aryl-d-lactone intermediate to support rapid route exploration and optimization. Welch and other coworkers also used SFC to facilitate early synthetic studies of an H I Vprotease inhibitor (Org. Process Res. Dev. 2 0 0 4 , 8, 186). During the past few years, the Merck lab has routinely used semipreparative SFC for purifying up to about 20 g. In the H I V project, after ini tially using SFC, the group scaled up, using a 30-cm-diameter column HPLC system, to produce 5.6 kg of a key intermediate. Since then, the lab has acquired larger SFC equipment and has used it for what Welch believes are the first kilogram-scale SFC separations in the pharmaceutical in dustry (JLC-GC 2005,23,16). Preparativescale SFC helps support and expedite pre clinical and early development work, he says, and is where the most dramatic cost and time savings come into play Scaling up SFC is rapid and straightfor ward, generally requiring only a simple ex tension ofthe results obtained in small-scale screens. "The labor input for developing a chromatographic method is very small, so the cost of defining the chromatographic option is very low compared with the cost of developing a synthetic route," he says. 'That's really a core issue and one ofthe key drivers behind the increasing use of chro matography in industry today" Overall, Welch believes, it's a matter of striking a balance between synthetic qual ity and speed—that is, between produc ing material quickly for rapid evaluation and developing syntheses that maybe suit able for very large scale production. Currently, SFC equipment costs more than comparable HPLC systems. One fac tor, Berger says, is that SFC instrumenta tion has only recently moved beyond its first generation, whereas major instrument
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companies are competing against each oth er in larger markets with more mature LC technologies. Despite having to compete against technology from these companies, "SFC will drive HPLC out of the semiprep and prep business," he believes. Lower operating costs for SFC compared
Seeing that "there's more money to be made in providing a service than in selling hardware," Berger has started up AccelaPure, based in Newark, Del., to offer con tract SFC separations and consulting. The company opened its doors in March and has been hiring scientists, building labs,
DEMANDS Neod for chiral compounds differs in slagts of drug R&D STAGE
EARLY DISCOVERY DEVELOPMENT
Amount Needed isomer Needed within Cost considerations Scale-up feasibility
mg-50g Both Days Minor Minor
100g-10kg Both Weeks Minor Medium
FULL DEVELOPMENT
PRODUCTION
5-10 kg Active enantiomers Months Medium Major
Tons Active enantiomers Ongoing Major Precondition
SOURCE: Adapted from E. Francotte, J. Chromatogr. A 2001,906. 379
with HPLC quickly make up for the cost difference, users claim. "Pharmaceutical companies spend about $25 million per year on chromatography hardware for early drug discovery/' Berger says. "If it were all HPLC, it then would cost them be tween $750 million and $1 billion to oper ate;' and about $300 million if all SFC.
and buying and modifying equipment for increased throughput. It has already done some work for customers. AccelaPure is competing with many technology and custom chemical providers that also offer separations services using HPLC or SFC. For very large scale sepa rations, even some commercial produc
tion, the method of choice has been sim ulated moving-bed chromatography (SMB), a multicolumn, continuous method that makes more efficient use of solvents than does single-column HPLC. Production scale might be the next stage in SFC's evolution, although the equip ment doesn't yet exist and the economics relative to other purification or resolution methods are uncertain, Berger cautions. Some users believe, however, that it's on ly a matter oftime and that the "greenness" of SFC and environmental concerns in manufacturing will spur further adoption. Separately, Novasep and collaborators (Jnd. Eng Chem. Res. 2001, 40, 4603) and re searchers at the University of Hamburg (J. Chromatogr. A 1999, 865,175) have built prototype systems combining SFC and SMB that some users consider promising. Although fast to develop, chromato graphic methods tend to be "the method of last resort, and part of the reason is it's been hard to make it cheap enough," Ber ger says. "There's always been that bar to jump over, but the bar has gotten lowered in large part because of the significantly lower operating costs for SFC." ■
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COVER STORY CLEANING UP Reaxa scientist prepares EnCat encapsulated palladium catalysts at the company's facility in Manchester, England.
REMOVING IMPURITIES Metal scavengers and immobilized catalysts may make for cleaner pharmaceutical products ANN THAYER, C&EN HOUSTON
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a hidden cost or a flip side," says Christopher J. Welch, head of the analysis and preparative separations group within process research at Merck. "Asymmetric catalysis is a great boon but carries with it the problem of having to deal with residual metals." As the use of organometallic catalysts in syn thesizing chiral and nonchiral compounds has been increasing, so too has the need for chemists to find ways to remove metalrelated impurities. Contributing to the problem are ever more stringent regulatory restrictions on the level of metals allowed in pharma ceutical products. Routine testing with a validated method is required for specific metal residues from catalysts, explains Da vid Pears, chief scientific officer of Reaxa. This testing is in addition to regulatory
still may find dealing with residual metals to be a stumbling block in developing new synthetic routes. "Five or 10 years ago, it would have been very difficult to obtain the required lev els," says Kapa Prasad, distinguished fel low in process R&D at Novartis. "With the combination of methods available and the knowledge that has developed, we can reach those levels routinely." Al though not difficult to carry out, finding the right method is still largely trial and error, Prasad points out. Prasad and coworker Christine E. Gar rett have reviewed what they call "the art of meeting palladium specifications" in active pharmaceutical ingredients (APIs), describing four possible attacks: distilla tion, adsorption, extraction, and crystalli zation (Adv. Synth. Catal. 2004,346,889). Key to choosing a method, Prasad tells C&EN, "is not adding another operation to a process." For example, using an adsor bent when there's already a filtration step maybe fine, but needing to switch solvents to make it work is to be avoided.
A COMMON PROBLEM with widely used palladium catalysts, Prasad points out, is that the state of the metal at the end of a reaction is not easily predicted. "In a given reaction all forms could coexist, in which requirements that may stipulate general case a single method may not be able to re heavy-metal tests relating to overall pro move everything," he says. The metal also duction quality, including metal from all is expensive, and many researchers want to contamination sources. recover, not just remove, it. "Catalysis is now such a major feature in Before taking on potential pharmaceutical production that metal problems, it's worth con trace-metal reduction to low sidering how much value a cat parts-per-million levels is an in alytic step offers. At the Chiral creasingly important challenge USA2005 meeting inPrinceton, for the industry," Pears says. "Pa NJ., inJuly, Yongkui Sun, direc tient safety is clearly the domi tor of Merck's Catalysis & Reac nant consideration and the key tion Discovery & Development driver that dictates critical high Laboratory, described using a performance from metal-scav critical rhodium-catalyzed asym enging products and processes." metric hydrogenation late in the Specifically, transition-metal CHIRAL synthesis of MK-0431 (C&EN, catalysts are being explored in a CHEMISTRY Sept. 13, 2004, page 28). "You variety of reactions and chemis can strategically place the high-value asym tries (see page 40). On the plus side, as cat metric hydrogenation step at the end of the alyst use is developed and optimized, cata synthesis so you don't lose Value' as you go lyst performance improves and required along the synthesis," he said. loadings decrease. Nevertheless, chemists
"Asymmetric catalysis is a great boon but carries with it the problem of having to deal with residual metals/' WWW.CEN-0NLINE.ORG
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Peptide Building Blocks CTC Resin cGMP Custom Synthesis Fmoc-L-Asparagine(Trt)OH Fmoc-L-Aspartic Acid(OtBu)OH Fmoc-L-Glutamine(Trt)OH Fmoc-L-Glutamic Acid(OtBu)OH Fmoc-L-Histidine(Trt)OH Fmoc-L-Lysine(Boc)OH Fmoc-L-Threonine(OtBu)OH Fmoc-L-Tryptophan(Boc)OH Fmoc-L-Tyrosine(OtBu)OH
o„
OH
{R)-Olph«nytprollnol
