SCIENCE/TECHNOLOGY
Research into Enantiomers Advances Drug, Catalysis Investigations Enantiomer intermediates for enantiopure catalysts and pharmacologically, biologically active products are outcome of recent research New York Chemical Congress
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Stephen C. Stlnson C&EN Northeast News Bureau
pharmacologically and biologically active products. Hahn notes that enantiomeric glycidyl intermediates are already commercially available. But he says glycidyl alcohol can be unstable in storage and handling. Glycidyl butyrate is available only as the (R)-enantiomer. And glycidyl arenesulfonates, benzyl ether, and chloride are too costly or inconvenient to obtain in greater than 98% enantiomeric excesses in mole quantities. The catalytic conversion process involves homogeneous nucleophile
exchanges, in which removal of a low-boiling coproduct shifts the equilibrium in the desired direction. Because the exchanges do not depend on exothermic gradients, they are thermally neutral. Thus they can be scaled up to 22-L flasks without much difficulty. The one drawback to the process is that trace amounts of acids or bases might trigger an exothermic ring-opening polymerization. Hahn recognizes that epibromohydrin is costly; it's available at about $120 per kg. Thus he has also
Equilibration maximizes yields of isomers Impressive advances in producing enantiomeric intermediates have been fashioned by a number of research groups. Such advances are increasingly important because of the attention the Food & Drug Administration is giving to differing properties of drug enantiomers. Also, these advances have the advantage of involving catalysis. This means that workers can use minute amounts of costly enantiopure catalysts rather than stoichiometric amounts of enantiomeric reagents. Details of the work underlying these advances were reported to the Division of Organic Chemistry. For example, chemistry professor Roger C. Hahn of Syracuse University described catalytic conversion of epibromohydrin to either diastereoisomer of a glycidyl camphor-10sulfonate in greater than 98% enantiomeric excess. The unwanted diastereoisomer is reequilibrated to a racemic mixture that can be recycled into the process until all the diastereoisomer is converted to the desired one. Diastereoisomeric camphorsulfonates can be converted to enantiomeric glycidyl derivatives— valuable intermediates in making
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September 16, 1991 C&EN
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Science/Technology developed a nucleophile exchange to make epibromohydrin from epichlorohydrin, which costs less than one tenth as much. In this method, epichlorohydrin reacts with n-propyl bromide catalyzed by a tetrabutylammonium salt to yield epibromohydrin and highly volatile w-propyl chloride, which distills out of the reaction mixture to shift the equilibium. To make glycidyl diastereoisomers, Hahn reacts epibromohydrin in threefold excess with, for example, ethyl (lS)-camphor-lO-sulfonate catalyzed by tetrabutylammonium bromide. He recovers the ethyl bromide coproduct that distills out, recovers the excess epibromohydrin by further distillation under reduced pressure, and isolates a 1:1 mixture of (2R)- and (2S)-glycidyl (lS)-camphor-lO-sulfonates in greater than 90% yield. Four crystallizations give the higher melting (2R)-glycidyl (1S)camphor-10-sulfonate diastereoisomer in greater than 98% enantiomeric excess. Hahn adds "mother" liquors from these crystallizations to successive batches so as to increase their yields. Next he places the crude mother liquor containing 33% of (2R)- and 67% of (2S)-glycidyl (lS)-camphor10-sulfonate in one pot with one equivalent of fresh, racemic epibromohydrin. He charges a second pot with the crude mother liquor from a preparation with (lR)-camphor-lOsulfonate plus fresh epibromohydrin, connects the two pots through a common reflux condenser, and heats. Epibromohydrin distills back and forth between the two pots. Tetrabutylammonium catalyst that remains in the mother liquors equilibrates them to a 1:1 mixture of (2R)-
Bulky groups guide substrate into catalyst
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September 16, 1991 C&EN
and (2S)-glycidyl camphor-10- that the greater efficacy of the new sulfonates in each pot. This 1:1 mix- catalyst resulted from the tert-butyl ture is the starting point for further groups and cyclohexane ring. The crystallization of (2R)-glycidyl (1S)- bulky tert-butyl groups fend off a camphor-10-sulfonate from the ap- too rapid interaction of the catalyst propriate pot. and olefin from some directions and Use of enantiomeric glycidyl cam- the less bulky cyclohexane ring easphor-10-sulfonates to make other es a slower, more enantioselective glycidyl derivatives leaves the cam- interaction from the one remaining phor-10-sulfonic acid as an alkali direction. metal salt. Hahn recovers this by reJacobsen demonstrated the power action with triethyl phosphite and of the new catalyst by synthesizing sulfuric acid to give enantiomeric two drugs originally discovered by ethyl camphor-10-sulfonate and di- E. Merck, Darmstadt, Germany, that ethyl phosphite. The ethyl camphor- show promise for treating high 10-sulfonate is thus ready for anoth- blood pressure. He epoxidized 6-cyer round of the cycle. ano-2,2-dimethylchromene (a benChemistry professor Eric N. Jacob- zopyran) to the correct enantiomer sen of the University of Illinois, Ur- in 96% yield and 97% enantiomeric bana, also reported on preparation excess. Reaction of the epoxidized of enantiomeric epoxides, but by di- chromene with pyrrolidone gave rect, asymmetric, catalytic epoxida- the enantiomeric form of the drug tion of olefins (C&EN, April 2, 1990, chromakalim, while treatment with page 20). He has improved his sali- 2,3-dihydro-6-hydroxy-2-methylpycylidene-ethylenediamine catalysts ridazin-3-one yielded a compound to increase both yields and enantio- code-named EMD 57283. meric excesses. Research Corp. TechIn another presentation, postdocnologies of Tucson, Ariz., is licens- toral fellow Larry J. Westrum of ing the Illinois patent on Jacobsen's Trinity University, San Antonio, retechnique. His work has been sup- lated the extension of dirhodium ported by the National Science carboxamide catalysts to asymmetric Foundation, National Institutes of syntheses of butyrolactones. InventHealth, Monsanto, Merck, ICI Phar- ed by organic chemistry professor maceuticals, and Rohm & Haas. Michael P. Doyle, these catalysts Jacobsen makes the newest ver- have previously been applied to sion of his catalyst by condensing asymmetric cyclopropanations. Reenantiomeric frans-1,2-diaminocyclo- search Corp. Technologies also is lihexane with 3,5-di-terf-butyl-2-hy- censing the patents for these catadroxybenzaldehyde, adding manga- lysts. nese(II) acetate to the bis(ylidene) The catalysts are complexes of product, and oxidizing with air to four molecules of a D- or L-pyrogluthe manganese(III) chelate. Jacobsen tamate [2-oxo-(5R)- or -(5S)-pyrrolitold his audience that cheap trans- dinecarboxylate] ester around two 1,2-diaminocyclohexane is readily rhodium(II) ions. They catalyze deresolved into its enantiomers by a compositions of diazoalkanes to carsingle crystallization of a tartrate benes, which in this case insert into salt. And the other starting material C-H bonds. Thus with neopentyl is easily made from commercially pyrrolidonecarboxylate catalyst, available 2,4-di-terf-butylphenol. 2,3,4-trimethyl-3-pentyl diazoacetate Jacobsen epoxidized 0-methylsty- gave 7-isopropyl-ß,0,7-trimethylburene in 84% yield and 92% enantio- tyrolactone in 82% yield and 70% meric excess with the new catalyst enantiomeric excess. and 5% sodium hypochlorite as oxyWestrum's other coworkers in gen source, compared with 73% these studies were undergraduate yield and 84% enantiomeric excess Arjan van Oeveren who is on leave with the old catalyst. And the ethyl- from the University of Groningen, eneketal of 2-cyclohexenone gave the Netherlands; staff member Mari63% yield and 94% enantiomeric ex- na Protopova of the Zelinski Institute cess with the new catalyst, com- of Organic Chemistry, Moscow; and pared with 52% and 93% with the organic chemistry professor Tom old one. Clayton Jr. of Trinity. Their work The Illinois chemist suggested was supported by NSF and NIH. D
Emerging spectroscopy benefits analytical chemistry ^4
New York Chemical Congress
Ward Worthy, C&EN Chicago
New spectroscopic techniques, some based on nonlinear approaches, are emerging as important tools in the analytical chemist's kit. They can provide chemical measurement ca pabilities difficult or impossible to obtain by other means. Details of some of these new methods were among the presentations at a sympo sium, "The New Face of Analytical Chemistry," sponsored by the Divi sion of Analytical Chemistry. For example, John C. Wright, a professor of chemistry at the Univer sity of Wisconsin, Madison, de scribed multiresonant nonlinear spectroscopy, a technology based on the ability to control the propagation of light by using other light beams. The new approach, he says, provides capabilities for chemical measure ment applications that cannot be du plicated by present methods. Wright explains that light propa gation through a sample takes place because the electron clouds of the molecules are rapidly polarized in a sinusoidal pattern by the electric fields of incoming light waves. The oscillating polarization generates new waves that form the basis for refraction in the material; losses in the polarization result in absorption effects. If other intense light beams are present, the index of refraction changes and the absorption is satu rated or shifted, so that the propaga tion of light is changed, and the changes are nonlinear. These nonlinear effects have im portant applications to spectroscopic chemical measurements, Wright says, because the chemical samples themselves can profoundly affect the efficiency with which the light beams interact. Consequently, the physical organic chemistry commu nity is working to develop new ma terials that are particularly efficient at coupling the effects of two light beams. It turns out that the beam-
coupling efficiency becomes very large when the exciting light fre quencies match vibrational and elec tronic states within molecules. At Madison, Wright and cowork ers have applied the principles to the development of four-wave mix ing methods. Three laser beams with different frequencies, for ex ample ων ω2, and ω3, are simulta neously focused into a material, pro ducing new coherent light beams at combinations such as ωλ— ω 2 +ω 3 . The four-wave mixing (three beams mix in the sample to produce a fourth beam) provides three simul taneous resonances, in contrast to most spectroscopic methods, where there is only one resonance. "We have allocated these reso nances to specific tasks," Wright says. One resonance is used to choose the component of interest in
the sample mixture, targeting it by tuning a laser's frequency to match one of its electronic absorption lines. That component then has an extra resonance that enhances its transi tions 1000-fold, compared with oth ers in the mixture. A specific envi ronment or conformation of that component can also be selected, so that the resulting spectrum is linenarrowed as well as amplified. A second resonance is used to se lect a specific mode of the compo nent of interest. The mode is select ed by tuning a combination of the lasers' frequencies to match either a vibrational or a vibronic mode. (Wright notes that a vibronic mode is a vibrational mode of an excited electronic state.) Then a third reso nance is scanned to read the spectro scopic information obtained with the first two resonances.
Nonlinear spectroscopy highlights vibrational modes 1380.3 1370.1 > T ° 1414.8
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Spectra of pentacene-doped benzoic acid. Wave-mixing spectra (c, d, e) at selected frequencies clearly show ground-state vibrational transitions that are only weakly revealed by conventional fluorescence spectrum (a). Absorption spectrum (b) shows lines from vibrational states of pentacene in excited electronic state. There, arrows indicate correspondence with dominant ground-state transition features (D) in c, d, and e
September 16, 1991 C&EN 25
Science/Technology
Symposium notes concerns over future supply of chemists Demonstrations of chemical wizardry by University of Wisconsin, Stevens Point, chemistry professors C. Marvin Lang (left) and Donald L. Schowalter twice punctuated a congress symposium that underscored widespread concern about the future supply of chemists. The symposium, "Future Chemists, Future Chemistry," came about, according to Columbia University chemistry professor Ronald Breslow, the symposium's organizer, as an expression of the concern, not just in the U.S., but elsewhere as well, over whether enough students will be going into science. Francisco Barnes de Castro, a chemical engineer at the Autonomous National University of Mexico, noted concern, for example, that with only 10 to 12 schools in Mexico offering master's degree programs in chemistry and two to four with Ph.D. programs, Mexico has a much smaller rate of graduation than it should have to be able to compete with the U.S. and Canada under the free trade agreement now being negotiated. Begun with some thoughts on the satisfactions of a career in chemistry, the symposium wound up with a panel of college students from the New York area and an international panel of high school teachers and students who discussed how they felt about the various fields and why they are going into science.
The technique yields a spectrum with features selectively enhanced by the resonances held constant. Thus, it's dominated by transitions from the chosen component and by the vibrational or vibronic modes that are coupled to the chosen mode. The mode-coupling information is particularly important, Wright says, because it provides topological information about the relationships between modes. For two modes to be coupled, the vibrational motion of one mode must affect the same electrons that are involved in the motion of the other mode. Wright showed a number of spectra (prepared by former graduate student Roger Carlson) of pentacenedoped benzoic acid, made with conventional as well as wave-mixing 26
September 16, 1991 C&EN
techniques. Examples were chosen to show how an absorption spectrum can be "dissected" into the contributions of different modes with the wave-mixing approach, and how features that are weakly or poorly resolved in a normal fluorescence or absorption spectrum can be highlighted in the nonlinear spectra. "The new nonlinear spectroscopic methods are very different from conventional spectroscopies," Wright says. But "it is becoming clearer that there is great potential for chemical measurement, because of their unique capabilities." David S. Moore, section leader for photochemistry and spectroscopy at Los Alamos National Laboratory, described the use of another nonlinear method, coherent anti-Stokes Ra-
man spectroscopy (CARS) to investigate the behavior of high-temperature, high-pressure, dense molecular fluids resembling those found in detonating explosives. Explosions present a formidable challenge to chemists, Moore notes. The chemical reactions take place in only billionths of a second. Reaction products are very hot, so that they exist as a dense fluid rather than a solid. Until recently, the limitations of measuring devices have made microscopic studies of explosions virtually impossible. Recent developments in lasers and electronics have made it possible to probe explosive detonation waves experimentally, offering the prospect of solving some of the mysteries of detonation chemistry, Moore says. One key to success is the fact that the complex process of explosion can be mimicked by simpler systems, he explains. And it makes sense, he adds, to begin with simpler, more tractable materials at temperatures and pressures of the order of those found in detonations. To obtain these temperatures and pressures under controlled conditions, Moore and associates use a high-velocity gas gun that accelerates a projectile to between 5000 and 13,000 mph. Fired at a liquid target, such a projectile generates a shock wave that compresses the liquid to less than half its original volume, generating a pressure of nearly 6 million psi and heating it to temperatures up to 5000 K. Then CARS is used to probe the dense fluid to obtain molecular information. Moore explains that CARS is a nonlinear optical technique that mixes two laser beams in the sample to produce a third beam that contains information about molecular vibrations in the molecules. Comparing the frequencies of that beam with those of the original beams reveals information about the changes in vibrational frequencies of the molecules—the Raman shift. The changes in the spectra show very precisely how the increased pressure and temperature change molecular properties, Moore says. For example, with most of the molecules studied, vibrational frequencies increase at higher shock pressure. Since the molecules are packed
Molecule forced into planar orientation at interface Water + Acridine Η orange /
Ν n-Octadecylsilane monolayer
Silica
closer together, it takes more energy for them to vibrate. The experiments have produced some surprises. For example, liquid nitrogen and carbon monoxide have many similar properties—boiling point, molecular weight, density, and so on. So they are modeled sim ilarly in detonation calculations. However, the CARS measurements show that the Raman shifts are quite different for the two molecules at similar shock pressures and temper atures. And at very high shock pres sures, the vibrational frequency of nitrogen stops increasing and starts to decrease. That possibly implies the onset of a chemical reaction, Moore says. The CARS technique has also helped determine how fast the collisional and vibrational energies come into equilibrium. For nitrogen, equilibration is a billion times faster at high shock pressures than at am bient pressure, Moore notes, adding that the finding confirms an as sumption made in current models of detonations. Progress to date represents "only a small toehold on our path toward understanding dense fluid behavior at the molecular level," Moore says. Nevertheless, it's an important step toward the ultimate goal of under standing the explosion process so well that the sensitivity and perfor mance of new "engineered explo sives" can be predicted and then verified with a minimum of trialand-error development. Knowledge of the orientational dynamics of adsorbates on surfaces can provide fundamental insights into the physical basis of such im
portant analytical methods as chro matography and electrochemistry, according to University of Delaware chemistry professor Mary J. Wirth. Accordingly, Wirth and graduate student John D. Burbage have de veloped frequency-domain spectro scopic methods in which the rota tions of adsorbates through in-plane and out-of-plane angles with surfac es and interfaces can be separately probed by controlling the polariza tions of both the evanescent wave and the fluorescence emission. "We believe these are the first studies of molecular reorientations at interfac es," Wirth says. Wirth described the application of the new technique to a study of ac ridine orange at a water-hydrocar bon interface. She notes that the hy drocarbon, in this case n-octadecylsi-
lane, is a self-assembled monolayer, on a silica substrate, having the den sity of a liquid-expanded phase. Thus, it's comparable to a typical chromatographic surface. The dye acridine orange has a very high affinity for the water-hy drocarbon interface. Spectroscopic studies show that the acridine or ange can freely diffuse rotationally in the plane of the interface. But it is completely unable to rotate out of the plane of the interface. "We at tribute this restriction to the very high potential energy barrier for solvating the charged part of acri dine orange by the medium having a low dielectric constant," Wirth says. "The absence of any restriction to in-plane rotation presumably [re sults from] the liquidlike behavior of the hydrocarbon monolayer." D
Fruits, vegetables, green tea may cut cancer risk New York Chemical Congress
WMl To help reduce your risk of cancer, eat lots of fruits and vegetables. And it wouldn't hurt to drink lots of green tea, too. That was one of the main messages to emerge from a symposium on phenolic compounds in foods and health, held under the auspices of the Division of Agricul tural & Food Chemistry. In an overview lecture, organic chemist and cancer researcher John H. Weisburger, a director emeritus of the American Health Foundation, asserted that phenols, as a class, are not genotoxic. On the other hand, laboratory studies have shown that phenols can sometimes be cocarcinogens or pro moters, increasing the effects of oth er environmental genotoxic carcino gens. The effect is highly dependent on dosage and on chronicity of expo sure. According to Weisburger, criti cal reviews of occupational health data have revealed no cancer risk in the production and use of phenolic compounds. Nevertheless, he says, it's prudent to minimize exposures. In the area of nutrition and can cer, however, it's "a universal find-
ing," Weisburger says, that a regular intake of vegetables and fruits and the consumption of tea, particularly green tea, reduces the risk of diverse cancers in humans. The reason is the presence in vegetables, fruits, and tea of specific phenols and polyphe nols such as quercetin, ellagic acid, and chlorogenic acid. A number of speakers offered evi dence in support of green tea's anticarcinogenic properties. For example, Hirota Fujiki, a biochemist at Ja pan's National Cancer Research Insti tute, described two-stage carcinogen esis experiments on mouse skin, initiated with 7,12-dimethyl-benz[a]anthracene. In those studies, (-)-epigallocatechin-3-gallate (EGCG), a ma jor constituent of Japanese green tea, inhibited tumor promotion by teleocidin, one of the 12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters, and by okadaic acid, an other promoter. Fujiki and associates also found that a diet containing EGCG reduced the incidence of tumor develop ment, induced by N-ethyl-N'-nitro-N-nitroso-guanidine, in mouse duodenum and also reduced the in cidence of spontaneous liver tumors in a susceptible strain of mice. Biochemist Jeffrey D. Laskin, of the University of Medicine & Den tistry of New Jersey, Rutgers, reportSeptember 16, 1991 C&EN
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Some natural polyphenols may have anticancer properties OH
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