SCIENCE/TECHNOLOGY
Phase-Transfer Catalysis Offers Practical a-Amino Acids Synthesis Indiana chemists develop industrially attractive procedure that works at room temperature and uses low-cost reagents Chemists at Indiana UniversityPurdue University, Indianapolis, have achieved what they describe as "the first practical asymmetric synthesis of α-amino acids using phase-transfer catalysis/' For exam ple, the team has used the method to synthesize 4-chloro-D-phenylalanine of high purity in multigram amounts \J. Am. Chem. Soc, 111, 2353 (1989)]. Chemistry professor Martin J. O'Donnell, leader of the research group, says the method is amenable to scaleup and "could become a prin cipal method for the synthesis of α-amino acids." New syntheses of α-amino acids are important, O'Donnell points out, because of the widespread and rap idly growing use of the compounds in the physical and life sciences and in a number of industrial products, including pharmaceuticals, agrochemicals, and foods. In the past 20 years, he notes, major advances have been made in the asymmetric synthesis of amino acids. However, most of those methods require the use of chiral auxiliaries in stoichiometric amounts; relatively few use the enantiocontrol element in catalytic quantities. In phase-transfer catalysis, reac tions are run in two-phase systems with reagents that are not soluble in one phase or the other, O'Donnell explains. For instance, sodium hy droxide, often used as a base in the procedure, is soluble in water but insoluble in many common organic
Chiral catalyst is key to stereoselective alkylation (C 6 H 5 ) 2 =N-CH 2 -C0 2 tBu
19.2 g
1) 4-CIC6H4CH2Br, Q*X (catalyst) 50% Aqueous NaOH, CH2CI2 25°C, 15 hours (95% yield, 64% ee) 2) Flash chromatography 3) Recrystallization
(C6H5)2 = N N / C 0 2 t B u +
(C6H5)2-Nvv-C02tBu CH;
CI
CH2
CI
Racemic crystals 8.8 g (32% yield, 8% ee)
Filtrate 16.8g(>99%ee) Hydrolysis
H2N
C0 2 H
CH2—(\
tr
CI
4-Chloro-D-phenylalanine 6.5 g (50% yield, > 99% ee)
solvents. In the amino acid synthe sis, the starting material, a protected glycine derivative, is dissolved in an organic solvent such as dichloromethane. At the interface between the two phases, the sodium hydrox ide deprotonates the precursor, leav ing an anion at the interface associ ated with a sodium cation in the aqueous phase. The anion would just sit there, O'Donnell says, were it not for the catalyst—a quaternary ammonium compound, for example— that facilitates its transfer into the organic phase, w h e r e alkylation takes place. Phase-transfer catalysis has fea tures that make it industrially at tractive, O'Donnell notes. Many
tBu = iert-Butyl (C4H9) ee = Enantiomeric excess
such reactions, including the aminoacid synthesis, run at room temper ature. The reactions run in the pres ence of water, so unlike some organ ic reaction systems, there's no need for stringent exclusion of moisture. The reagents and solvents are in expensive and relatively safe to use. O'Donnell has been investigating the use of phase-transfer catalysis for amino acid synthesis for more than a decade. Earlier efforts led to the first general method for prepar ing racemic mixtures with such re actions (C&EN, Sept. 17, 1979, page 24). It was obviously desirable to broaden the method to achieve ste reoselective syntheses. Using a chiral catalyst and a prochiral-protected April 10, 1989 C&EN 25
Science/Technology glycine derivative appeared to pro vide a good method for the prepa ration of optically active α-amino acids. Achieving that goal, O'Donnell says, involved combining what he had learned about phase-transfer ca talysis synthesis of amino acids with the "elegant and pioneering asym metric" phase-transfer catalysis work by U.-H. Dolling and associates at Merck. Although there had been prior reports of asymmetric reac tions involving phase-transfer ca talysis, the levels of chiral induc tion had been " d i s a p p o i n t i n g l y low." The Merck effort represented "the first practical use of asymmet ric phase-transfer catalysis alkylation to achieve high levels of induc tion." The Merck group, using a cata lyst derived from cinchona alkaloids, had, among other things, achieved high chiral induction in the alkylation of a substituted i n d a n o n e . O'Donnell saw similarities between
O'Donnell: method can be scaled up the substituted indanone and the benzyl esters of protected glycine derivatives [(CoHshC^NC^CCfeR]. He and graduate student Shengde Wu, working with former postdoc toral associate William D. Bennett,
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NH-&NH
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April 10, 1989 C&EN
set out on a systematic study of asymmetric alkylation of the gly cine derivatives. However, O'Donnell says, the method developed in the Indianap olis group's work is "not just an obvious extension of the Merck work; there are complicating fac tors with our substrates." For one thing, the glycine derivatives are acyclic. Also, they have the poten tial for dialkylation and for product racemization. Thus, it's necessary to selectively monoalkylate the sub strate to yield an active methine product that won't be racemized af ter alkylation. In fact, the first experiments, made under conditions similar to those for alkylation of the indanone, re sulted in only small induction—5% enantiomeric excess, 52.5% R, 47.5% S—and modest chemical yield, even after long reaction time, O'Donnell says. Later experiments aimed to im prove induction by varying the es ter group on the protected glycine substrate. Best results were obtain ed with the tert-butyl ester [R = (CH 3 ) 3 C]. Alkylation of that com pound, using a cinchonine catalyst, gave 56% enantiomeric excess of the R enantiomer. Changing to a cinchonidine catalyst resulted in an in duction of 56% enantiomeric excess for the S enantiomer; thus, the meth od had the potential for making ei ther enantiomer. A study of other variables in the process revealed that increasing the concentration of aqueous base re sulted in an increase in optical yield and also a decrease in reaction time. With 50% aqueous sodium hydrox ide as base, the best leaving group was bromide. Increasing the concentra tion of (C6H5)2C=NCH2C02C(CH3)3 (in dichloromethane) from 0.04M to 0.64M dramatically shortened the reaction time, from 24 hours to as little as one hour. A variety of alkyl halide types could be used: allylic, benzylic, methyl, or primary. The resulting products were formed in up to 66% enantiomeric excess. The separation of enantiomers is important in any asymmetric syn thesis that's less than 100% stereo selective. Although there are a num ber of methods, both classical and enzymatic, that can be used on de-
rivatives of particular α-amino acids, O'Donnell is involved with find ing a general method by which one or the other enantiometer could be purified directly after asymmetric alkylation. O'Donnell notes that the Nation al Institutes of Health is supporting the work being done on asymmetric synthesis. Ward Worthy
Complex parts made in photochemical process Stereolithography, a budding tech nology that combines chemistry, la ser control, and computer graphics, is providing design engineers and manufacturers with a new, poten tially cost-effective tool for turning computer-generated design data di rectly into prototype plastic parts. The method could also be useful for scientific and medical applica tions—for example, to make solid models directly from computerized axial tomography (CAT) or magnetic resonance imaging data. According to 3D Systems—the Va lencia, Calif .-based company that has pioneered the technique—stereolitho graphy is a method that automati cally builds complex plastic parts by "printing" successive cross sec tions, positioning one on top of an other until the part is formed. The process depends on the rapid cur ing (solidifying) of certain polymer resins by exposure to UV light. Essential parts of the stereolitho graphy apparatus include a vat of liquid photopolymer (usually an acrylic resin), a laser that generates a small, intense spot of UV radia tion, a galvanometer mirror X-Y scanner, an elevator mechanism, and a computer and software for con trol. However, that apparatus re quires digitized design data to tell it what to do. Usually the input data come from a computer-aided design system but other data sources, such as a CAT scan or a mechanical digitizer, may also be used. The company provides interfaces that convert the input data to the pro per format for the stereolithography apparatus and its internal com puter.
At the start of the model-building process, the platform of the eleva tor is positioned just below the sur face of the liquid photopolymer. The UV laser spot, guided by the com puter data, moves back and forth, causing the liquid to solidify wher ever it impinges, and thereby forms a thin, solid cross section on the plat form. When the first cross section is completed, the platform is lowered a step—as little as 0.008 mm. The just-formed solid layer is covered by a fresh layer of liquid. Instruc tions for the formation of the next cross section are received, and the process is repeated. That goes on until the part is formed. After the part is finished, the ele vator raises it from the vat to allow excess liquid to drain. Although the part looks and feels solid, it still contains large amounts of uncured resin. It must undergo further treat ment with intense UV radiation to complete the curing process. Then the support structure, if any, is trimmed away. Normally no fur ther tooling is needed, but the part can be s a n d e d a n d finished as desired. Stereolithography was developed and patented by physicist Charles W. Hull while at UVP Inc., a Califor nia firm specializing in UV prod ucts. He left UVP in 1986 to form 3D Systems, where he is now presi dent. Cofounder Raymond S. Freed,
Parts are formed layer by layer Movable UV light source
Movable UV-curable platform liquid Liquid
surface Formed object
Stereolithography apparatus A pinpoint laser beam travels across the surface of the liquid. The liquid cures where it is hit by the laser beam, forming a solid layer of the part that rests on the platform. Once this first layer is formed, the platform descends one step and the next layer is formed.
Technique turns computer design data directly in to prototype parts a physicist and former aerospace en gineer, is chairman and chief exec utive officer of the firm. Not sur prisingly, both executives predict a bright future for the process. They note that some potentially competitive systems are under de velopment. But, they say, the com petitors don't yet have any equip ment to sell. The 3D Systems executives point out that model building, prototype construction, soft tooling, and pat tern making are key steps in de signing new products. Those steps are also expensive and time-consum ing. In the aerospace industry, for ex ample, developing a complex part using traditional methods may take six to nine months and cost an av erage $25,000, according to the com pany. In contrast, they say, the same part could be made with stereolitho graphy in about a week, at a cost of only about $4500. Although a de luxe system w o u l d cost around $200,000, it would soon pay for itself. Early customers have included such major firms as General Mo tors, Eastman Kodak, Pratt & Whit ney, AMP, and Baxter Travenol, among others. That list suggests the versatility of the process. 3D Sys tems sees six major areas in terms of market applications. Most important, at least for now, are industrial de sign (where models are used main ly to demonstrate form and conApril 10, 1989 C&EN
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