COVER STORY TEAMWORK Merck's Mirlinda Biba (left), Welch, Mohamed Shaimi, and Jennifer Chilenski explore fast analysis and separation methods for chiral mixtures.
TAKING A MEASURE OF CHIRAL RICHES Researchers respond to high demand for ways to measure enantioenrichment quickly A. MAUREEN ROUHI, C&EN WASHINi
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rapidly has become a nagging question for researchers in the field. "Everyone is try ing to get an answer in a matter of a few sec onds," Welch says. Usually, ee is determined by separating enantiomers by high-performance liquid chromatography (HPLC) or gas chro matography with chiral stationary phases and measuring how much of each enantiomer was originally in the mixture. "Chi ral HPLC is still the most important ana lytical technique for stereochemical analysis in the pharmaceutical industry',7Welch says. With modifications, throughput high er than a few dozen measurements per day can be achieved with these workhorse methods. For example, high-throughput HPLC with chiral detection can cut anal ysis time to 20 seconds per sample with 10% accuracy, which, Welch says, "is good enough when we just want to categorize reactions into lousy, middle-of-the-road, and really, really good."
•
HE CHIRAL TECHNOLOGY
I revolution was founded on I the ability to measure I enantiomeric purity," says I Christopher J. Welch, a process research fellow at Merck Research Laboratories, Rahway, Ν J. Research in chiral technology exploded only after chiral columns for liquid chromatography be came commercially available in 1981, he notes. The columns offered away to meas ure enantiomeric excess (ee) that is much better than polarimetry "Without the re liable measurement techniques, no one could have done very much," he notes. Making chiral compounds through asymmetric catalytic reactions is a key chi ral technology. The pace of catalyst dis covery has been ratcheted up on the syn thesis side by combinatorial and other techniques. Identifying which potential catalysts in a library work, however, re quires measurement of ee. How to do this HTTP://PUBS.ACS.ORG/CEN
Using shorter columns and smaller sol vent volumes could further increase HPLC throughput. The ability to scale down is limited by detector sensitivity at small vol umes, however. On this front, work by Darryl J. Bornhop, an associate professor of chemistry at Texas Tech University, Lubbock, may provide an answer. Bornhop has developed a micropolarimeter that measures optical rotation in nanoliter volumes. The inven tion achieves "a quantum leap in sensitiv ity," according to M. G. Finn, a chemistry professor at Scripps Research Institute, in a review that will appear in Chirality [14, 534(2002)]. Bornhop's micropolarimeter is based on the interaction between a plane-polarized laser and a silica capillary Backscattered interference fringes are produced when the laser illuminates the capillary. De pending on how the fringes are analyzed, different measurements can be made. For example, monitoring the relative changes in intensity of a pair of adjacent high-fre quency fringes can sense microdegrees of rotation. And with minor changes in the optics and detector, the polarization state of the fringes can be analyzed, allowing ee measurements by calibrating the system against a standard. BECAUSE THE micropolarimeter is com patible with flowing streams, it can be used as a detector for capillary-scale separations and high-throughput methods requiring real-time analysis of small volumes. For high-throughput applications, Bornhop is configuring the micropolarimeter in a capillary array format, as well as investigat ing the use of chip-scale embodiments. Measurement of ee could be even faster if chiral separation is bypassed. But deter mining ee would then require use of chiral differentiators. Various groups are work ing on methods along these lines. At Scripps, Finn's group has focused on mass spectrometry because it avoids the need to use a sophisticated tag—such as a chromophore or a radiolabel—to give a signal. It could be applicable to many situations. In the Scripps method, the products of a catalytic asymmetric reaction are made to react with a chiral reagent consisting of two enantiomeric forms of different mass es. For example, if the catalytic reaction C & E N / J U N E 10, 2002
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COVER STORY forms alcohol products, mass-tagged chiral acids might be used as the chiral reagent. The masses of the two different esters produced from the alcohols reacting with two different mass-tagged acids give the ee. Meanwhile, in Germany, Manfred T. Reetz, a chemistry professor at the Max Planck Institute for Coal Research, has developed a mass spectrometric method based on isotopically labeled substrates. Reetz discovers and optimizes enantioselective catalysts through directed evolution. In his method, one enantiomer of a racemic substrate is labeled with deuterium. After the substrate reacts, the products of that enantiomer are differentiated from those of the other by their masses. The ee can be calculated from the parent peaks. The system is completely automated. In a recent review, Reetz says a secondgeneration system using an eight-channel multiplexed sprayer for ionization can do up to 10,000 determinations per day [Angew. Chem. Int. Ed., 41,1335 (2002)}. "Several companies are in the process of licensing this technology from us," he says. THE METHOD is ideal for kinetic resolution; that is, when the substrate is a racemate. "In the ideal case, the asymmetric catalyst will pick out only one enantiomer and transform it to product, which can be easily separated from the unreacted enantiomer," Reetz explains. It is also useful for desymmetrizingprochiral compounds into chiral products. But the method does not cover all possibilities. For example, it cannot be used in the reduction of acetophenone to (R)or (S)-phenylethanol because the precursor cannot be labeled in such a way that the products can be differentiated. Finn's method, however, can be used for kinetic resolution and desymmetrization, as well as the ketone reduction that Reetz describes. "We take the ketone, subject it to our catalyst, and then take the reaction product and derivatize it with a masstagged chiral reagent," Finn explains. Accuracies are ±3% for Reetz's method and ±10% for Finn's method. As Welch says, accuracy of ±10% is good enough to separate the good catalysts from the bad ones. Reetz, however, needs greater accuracy "In the last phases of directed evolution, when the ee has reached 90% and you want to go even higher, an assay that's ±10% is not good enough," he says. In fact,
E A R T H B O U N D
A Chemist's Eye For Chirality
C
onsider the curl of a pig's tail or the spiral on a seashell. Does it turn left or right? Many of us would not notice these natural manifestations of chirality. But stereochemists such as Christopher J. Welch, a process research fellow at Merck Research Laboratories, do. Stereochemists' eyes get trained in seeing shape and chirality, he says. And chirality "pops up all over the place." Such as in Welch's home, where he grows orchids as a hobby. About 10 years ago, Welch noticed that some orchid species have flowers in which the usual bilateral symmetry is broken by the presence of twisted petals. The orchid literature contained little mention of asymmetric flowers, so he researched the topic himself. Welch asked members of an Internet list of orchid enthusiasts to which he belongs to examine their collections for chiral flowers. These data, along with his observations at botanical gardens, orchid shows, commercial greenhouses, and private collections, turned up several species with chiral flowers [Malay. Orchid Rev., 32, 86 (1998)]. Interestingly, closely related species might bear petals twisted in the opposite direction. Welch has suggested that botanical descriptions should describe petal twist through the helix S P I R A L A C C E S S O R I E S Petals nomenclature used in stereochemistry. twisted in left-handed helices adorn the flowers of this orchid, Trichopilia When stereochemists exchange their tortilis. favorite stories about chirality, Welch talks about orchids. He also mentions the Hindu god Vishnu when speculating about when humans became aware of the idea of chirality. Even in centuries-old statues, Vishnu is portrayed holding a left-handed chank shell. In nature, this form is exceedingly rare, probably fewer than one in a million, Welch says. "For many centuries, the left-handed chanks have been highly prized treasures," he says. "That Vishnu is always shown with the rare enantiomer is an unambiguous sign that the people who built those statues had an appreciation of chirality." The exchange of favorite stories about handedness has inspired Welch to write a review on chirality at the organismic level in a new book, "Chirality in Natural and Applied Science" (W. J. Lough and I. Wainer, Eds., Blackwell Publishing, 2002). Here he surveys exterior asymmetry in microorganisms; plants; invertebrates; fish; birds; reptiles; amphibians; and mammals, including humans. Observing chirality in nature may be "a source of amusement for stereochemists," he writes, but there are also fundamental discoveries being made, such as those by developmental biologists about the role of chirality in the development of complex organisms.
Reetz says his group has developed a method based on nuclear magnetic resonance spectroscopy (NMR) that can perform 1,400 assays per day with an accuracy of ±2%. Last year, Harvard University chemistry professor Matthew D. Shair excited the chiral chemistry community by showing that DNAmicroarray technology could be adapted to ee measurement. With the new technology, called reac-
tion microarrays, picoliter amounts of a mixture are spotted onto a glass surface and then made to react with fluorescent chiral probes. When a spot is excited by laser, the fluorophores of the chiral probe emit with intensities proportional to the ee at that spot. Spots can be applied at densities of up to 100,000 per 3-sq-in glass slide, making for very high-throughput ee measurements. Shair and graduate student Gregory A.
"As measurement techniques get better, the job of making chiral materials will get easier and easier." 52
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Korbel have been optimizing the reaction microarray system. Currently, they are developing a general way to attach molecules to a glass surface through the carbon-hydrogen insertion chemistry of nitrenes. "Every molecule we care about would have a C - H bond," Shair tells C&EN. "If you could come up with a chemistry that attached any compound irrespective of the structure, you could use reaction microarrays for almost any reaction product, as long as that molecule also had some handle to which a chiral probe can be attached." Nitrenes are species in which a nitrogen atom bears two unpaired electrons. To generate nitrenes, Korbel coats the glass slide with an azide and then irradiates the slide with a handheld ultraviolet lamp. "What we believe happens is that N 2 is removed photochemically from the azide, leaving a nitrene." In principle, the nitrene would insert into enantiomers of a mixture whose ee is to be determined. Preliminary results are promising, but Shair says it's difficult to know for sure what's going on. "It's hard to find out what you've done on a glass surface," he explains. "That has slowed our
progress." Still, Shair is optimistic that his tiomer to phenyl ethyl ketone, and the rate lab can soon use reaction microarrays to of this oxidation is a direct measure of ee. screen a new catalytic aldol reaction that One hundred samples can be assayed in 30 he and his coworkers have been developing. minutes, with an accuracy of ±10%. A second assay using an alcohol dehydrogenase Other new ideas for detennining ee inivomLactobacilluskefir, which oxidizes the clude use of enzymes, immunoassays, colR enantiomer, enables calculation of the or indicators, molecularly imprinted polyextent of conversion. mers, and metal-organic supramolecules. Some of these methods are menAccording to Abato and Seto, tioned in the reviews by Finn and alcohol dehydrogenases could be Reetz and in another by Henri used to analyze alcohol products B. Kagan and Masaki Tsukamofrom a wide variety of reactions, to of the University of Parisincluding hydrogénation of keSouth in Orsay, France [Adv. tones, aldol reactions, nucleoSynth. Catal., 344,453 (2002)}. philic ring opening of epoxides, and kinetic resolution of alcoAt Brown University, associhols. Other enzymes could be ate chemistry professor Chrisharnessed for other compound topher T. Seto has been develtypes: lipases and esterases for oping a high-throughput method CHIRAL ester products of allylic oxidathat uses an enzyme to selectively CHEMISTRY tions with tert-buty\ peroxybentransform one enantiomer of a zoate, alkene cyclopropanation with alkyl catalytic reaction product. As an example, diazoacetate, and the glyoxylate ene reache and graduate student Paul Abato use the tion; and acylases and proteases for amide addition of diethylzinc to benzaldehyde, products of catalytic hydrogénation of Nproducing (R)- or (S)-l-phenyl-l-propanol acetyleneamines. \J.Am. Chem. Soc, 123,9206 (2001)}. Early this year, a team led by Charles An alcohol dehydrogenase from a Thermoanaerobium species oxidizes the S enan- Mioskowski and Alain Wagner at the Uni-
Chiral 3-Aminopyrrolidines Ο II
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Cisr
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Η R',R2=H
R=Me
3-Aminopyrrolidine (3RH+)-98+% (GC) [ A l l 67] (3S)-(-)- 98+% (GC) [ A l l 68]
Ri =H,R2=Me 3-(Methylamino)pyrrolidine
R=CF3
WH+Y 96+% (GC) [Ml 107] (3S)-(-)-95+% (GC) [Ml 108]
R=0^ Bu
(3ff)-(+)- 96+% (GC) [E0433] (3S)-(-)- 96+% (GC) [E0434]
3-(Dimethylamino)pyrrolidine (3K)-(+)- 95+% (GC) [D2149] (3S)-(-)-96+% (GC) [D2193]
C NEW CATALOG (
Ml
mm i
3-(Trifluoroacetamido) pyrrolidine Hydrochloride
H,R2=Me 1~Bermd-3-|ii pyrrolidine (3/?)-(-)- 98+% (GC) [B1582] (3S)-(+)-98+% (GC) [B1583]
3-(fert-Buk»ycarbonylamino)pyrrolidine
2
Rl: =H,R =Et 1 -Benzyl-3-(ethylamino)-
pyrrolidine
(3K)-(+)- 98+% (GC)(T) [ A l l 71] (3S)-(-)-98+% (GC)(T) [ A l l 72]
(3/?)-(-)- 95+% (GC) [B1580] (3S)-(+)- 95+% (GC) [B1581]
Tokyo Kasei Kogyo Co., Ltd., Jpn. Kokai Tokkyo Koho JP 90-218664 (1990) ; Tokyo Kasei Kogyo Co., Ltd., Jpn. Kokai Tokkyo Koho JP 88-41453 (1988) ; Tokyo Kasei Kogyo Co., Ltd., Jpn. Kokai Tokkyo Koho JP 88-41452 (1988) ; Tokyo Kasei Kogyo Co., Ltd., Eur. Pat. 218249 (1987)
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1-Benzyl-:
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Ri=H,R2=Et 3-(Ethylamino)pyrrolidine
R1 ,R2=Me
3-Acetamidopyrrolidine (3R)-(+)-98+% (T) [ A l l 6 9 ] (3S)-(-)-98+% (Τ) [Α1170]
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Reflections on where new chiral chemistry begins.
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COVER STORY E X T R A T E R R E S T R I A L
How To Detect Enantioenrichment On Saturn's Moon Titan
O
n Oct. 15,1997, the seven-year voyage of the Cassini spacecraft to Saturn and its largest moon, Titan, began. The orbiter is expected to reach Saturn in mid-2004 and to release the Titan probe Huygens in November 2004. Huygens will acquire data about Titan's atmospheric chemistry as it descends and about Titan's surface chemistry when it lands. Even now, scientists are considering missions to Titan beyond Cassini-Huygens. One proposal is to send a so-called Titan Organics Explorer, a robotic analyzer that will perform detailed studies of Titan's atmosphere, surface, and oceans. Among analytes of interest are enantioenriched organic compounds. Although not a signature of life, enantioenrichment is widely believed to indicate chemical complexity that leads to life. The resemblance of Titan's environment to that of prebiotic Earth's leads researchers to believe that the organicrich world of Titan bears clues to how life on Earth began.
circularly polarized light over a range of wavelengths is called circular dichroism (CD). A plot of differential absorbance versus wavelength constitutes a CD spectrum. Host-guest interactions between receptors and chiral analytes generate complexes that may produce amplified CD spectra. In some cases, the absolute configuration of the analyte may be assigned from the CD spectra. James W. Canary, an associate professor of chemistry at New York University, New York City, says the method can be used to detect enantioenrichment because the spectra of nonracemic mixtures are shaped similarly to that of the enantiopure compound but have different amplitudes, which are linearly related to enantiomeric excess (ee). The method has not been tested for measurement of ee, but Canary and coworkers have established the linear relationship between ee and amplitude for chiral copper(ll) complexes with derivatized amino acids {Chirality, in press). To determine the absolute configurations of chiral compounds with Last year, the challenges of deR E N D E Z V O U S Computer-rendered image very low ee, chemists Kenso Soai tecting chirality on Titan were consid- shows Cassini having just crossed the plane of and Itaru Sato, at the Science Uniered in a special issue of Enantiomer, Saturn's rings. versity of Tokyo, propose to apply the edited by Christopher J. Welch, a asymmetric amplification of the autocatalytic reaction between process research fellow at Merck Research Laboratories, and 2-methylpyrimidine-5-carbaldehyde and diisopropylzinc to form Jonathan I. Lunine, a professor of planetary sciences and of IS}- or (/?)-2-methyl-1-(2-methyl-5-pyrimidyl)propan-1-ol. physics at the University of Arizona, Tucson. The goal was "to get our heads together thinking about what could work for a mission In the presence of an amino acid, a slight excess of the S or R that, if approved and funded, might launch in 2011," Welch says. product is formed, depending on the absolute configuration of the amino acid. Because the product catalyzes the reaction with Suggestions include Earth-tested methods such as gas chroamplification of ee, the product with the same absolute configumatography and chemical sensors, with modifications to meet ration as the amino acid initiator will be formed in great excess. the requirements of a mission to Titan. Others are still conceptuInitiation is possible with other enantioenriched materials, inal, such as circular dichroism and asymmetric catalysis. cluding powder from a crushed quartz crystal. A chiral molecule's differential absorbance of left- and right-
versity Louis Pasteur, in France, reported a method based on competitive enzyme immunoassays for high-throughput screening of catalysts for enantioselective ketone reduction [Angew. Chem. Int. Ed., 41,124 (2002)}. The team demonstrated the principle with reduction ofbenzoyl formic acid to mandelic acid. Binding of the products to an indiscriminate antibody gives the total yield of the reaction. Binding of one enantiomer with an enantioselective antibody gives ee with an accuracy of ±9%. Testing a catalyst library prepared by combining four metals and 22 chiral diamine-based ligands, the researchers were able to complete 176 assays in one day. With the routine use of competitive enzyme immunoassays in biology and diagnostics, the researchers believe that antibody-based methods have great potential in high-throughput screening for catalyst discovery. Others have proposed using 56
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However, the helical twisting power of most simple organic molecules is too weak for color induction. To overcome this problem, van Delden and Feringa modify the analyte by attaching a "mesogenic unit"— MEANWHILE, in the Netherlands, a color a structure that resembles the LC host test for ee has been developed by chemists molecules. The change dramatically inRichard A. van Delden and Ben L. Feringa creases the helical twisting power, and even at the University of Groningen. The test is at low dopant concentrations colored LC based on the unique optical properties of phases are obtained. cholesteric liquid crystal (LC) phases. Dopants with high chiral induction—or "The method requires no chiral auxilhelical twisting power—induce these LC iaries and only microgram quantities of anphases to reflect in the visible range. The alyte," van Delden says. 'And it should be wavelength of reflection is inversely propossible to custom design the method for portional to the dopant ee. Enantiomeric a large variety of analytes." excesses of50% and higher can be visualized In addition, "automation should be read[Angew. Chem. Int. Ed., 40, 3198 (2001)}. ily feasible," van Delden says. "Microarrays In a recent study with methyl phenyl glyof colored dots would allow high-throughcine, the researchers demonstrated visual put screening since color inspection is indetection of the full range of ee by monistantaneous. It should even be possible to toring the color of the doped LC [Chem. calibrate the method to allow ee determiCommun., 2002,174}. nation in the presence ofother compounds; immunosensor techniques in space missions to detect extraterrestrial enantioenrichment [Enantiomer, 6,153 (2001)}.
HTTP://PUBS. ACS.ORG/CEN
for example, starting materials, side prod ucts, or even a chiral catalyst." A similar approach has been proposed by Gloria Proni, of New % r k University, N e w a r k City and Gian Hero Spada, of the University of Bologna, in Italy, to detect enantioenrichment in an extraterrestrial environment [Enantiomer, 6,171 (2001)}. Closer to home, at the American Chem ical Society national meeting held in April in Orlando, Fla., Ken D. Shimizu, an assis tant professor of chemistry at the Univer sity of South Carolina, Columbia, described a rapid assay ofee based on molecularly im printed polymers (MIPs). "It's difficult to measure ee, because it is hard to differentiate enantiomers based on chirality," Shimizu says. "It's a lot easi er to measure concentrations. So we've been developing ways to differentiate enan tiomers such that the outcome is a differ ence in concentrations." MIPs are highly cross-linked polymers that are prepared in the presence of a tem plate molecule, for example, one enan tiomer. The template molecules form cav ities within the polymer, and when the molecules are removed, the cavities remain.
These cavities enable the polymer to bind the imprinted enantiomer to a greater ex tent than its opposite enantiomer. MIPs are easy to make and fairly inex pensive, Shimizu says. Measurement of ee involves simply adding ground polymer to a reaction mixture and then determining the total concentration of enan tiomers remaining in solution. MIPs deplete the mixture ofthe enantiomerwith which they were originally imprint ed to a far greater extent than they deplete the other enan tiomer. Through calibrations, the concentration of the re maining mixture can be correlated to the initial enantiomeric composi tion. Potentially 1,000 measurements can be done in one day instead of the two weeks they might take with conventional chiral chromatography The method also can be general, in that MIPs could be easily tailored to just about any molecule, Shimizu says. Also at the ACS meeting, \Xfenbin Lin, an assistant professor of chemistry at the University ofNorth Carolina, Chapel Hill, described a family of metal-organic
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supramolecules that can be applied to highthroughput sensing of ee. The molecules are squares with rhenium carbonyl com plexes at the corners and 4,4'-bis(pyridyl)Ι,Γ-binaphthyl units at the sides \J. Am. Chem. Soc, 124,4554 (2002)]. Mole cular squares of this type fluoresce strong ly, and the fluorescence is quenched in the presence of chiral amino alcohols. The extent of quenching can be related to the alcohol's ee. "If you have an optical means to detect optical pu rity, all you have to do is add this sensory material, shine light, and see which ones light up and which ones don't," Lin tells C&EN. He adds that optical techniques based on fluorescence are some of the best for sensing because they are very sensitive, able to detect concentrations as low as 10~7 M. 'As measurement techniques get better, the jobs of people making chiral materials will get easier and easier," Welch says. 'Any revolution from nothing to something al ways requires away to keep score." •
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