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Driven by the needs of the drug industry and fueled by the ingenuity of chemists, sales of single-enantiomer chiral compounds keep accelerating
STEPHEN C. STINSON, C&EN NORTHEAST NEWS BUREAU
Worldwide, the market for chiral fine chemicals sold as single enantiomers was $6.63 billion in 2000 and will grow at 13.2% annually to $16.0 billion in 2007, according to a study by the market research firm of Frost & Sullivan, London. The drug industry is the engine that is driving this strong growth, according to senior industry analyst David Platt, accounting for 81.2% of the total, or $5.38 billion worth. The remaining $1.25 billion is divided among such uses as agricultural chemicals, electronics chemicals, and flavors and fragrances.
||CHIRAL CHROMATOGRAPHY Simulated moving bed installation at CarboGen subsidiary of Solutia, Aarau, Switzerland, separates 4 kg of racemate per day.
By geography, the U.S. is the biggest consumer of enantiomeric fine chemicals, Platt says, contributing to a total North American share of $3.98 billion, or 60.0% of the total. European and Asian consumption of enantiomeric fine chemicals isn't expected to grow as fast, with the North American share rising to 66.9% of the market in 2007, or $10.7 billion.
THE NUMBERS look even more impressive when considered as the sale of single-enantiomer compounds made into the pharmaceutical formulations that people actually consume. The worldwide market for dosage forms of single-enantiomer drugs was $123 billion in 2000, up 7.2% from $115 billion in 1999, according to data developed by Technology Catalysts International, Falls Church, Va. Sandra E. Erb, who is manager of chiral and fine-chemicals consulting, and senior research associate Jane Zhou point to respiratory, gastrointestinal, ophthalmic, and cardiovascular drugs as contributing to strong growth.
Among respiratory drugs, especially for asthma, Erb and Zhou cite the 72% sales growth of montelukast by Merck, Whitehouse, N.J. Also, some companies have introduced new steroids, at higher prices, to replace older ones.
In the gastrointestinal area, Erb and Zhou say that infliximab from Centocor, Malvern, Pa., was originally introduced to treat an inflammatory bowel disorder called Crohn's disease, but it now has approval for rheumatoid arthritis. And tamsulosin for benign prostate hyperplasia is now marketed in the U.S. by Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conn., and Abbott Laboratories, North Chicago.
Latanaprost, marketed by Pharmacia, Peapack, N.J., is a single-enantiomer ophthalmic drug for glaucoma that has become the leading drug for this disease in the U.S., Europe, and Japan.
Among cardiovascular drugs, Erb and Zhou say the so-called statins for inhibition of cholesterol biosynthesis are chiral drugs that are replacing other achiral cholesterol-lowering drugs. Examples are atorvastatin from Pfizer, New York City; cerivastatin from Bayer, West Haven, Conn.; and simvastatin from Merck.
The drug industry will continue to spur strong growth in chiral compounds, according to Erb and Zhou, because of efforts to improve drug efficacy and to cut development costs in the face of regulatory pressures. Medicinal chemists increasingly target enzymes, hormones, and other compounds in patients' cells and in cells of microorganisms. Additional targets are receptors on cell surfaces. These compounds and receptors are made up of chiral amino acids, carbohydrates, and lipids. Drugs that are intended to interact with them must be enantiomeric for increased chances of success.
On the regulatory front, the enantiomer-racemate interface is important either for simplicity of development or for life-cycle management of drugs. Erb and Zhou say it is simpler to choose one enantiomer and to develop that rather than to build evidence about a racemate, which from a regulatory point of view is like developing two different drugs.
But some drug companies patent and develop a racemic drug with the intention of patenting and developing a single enantiomer later. When the patent on the racemate expires, Erb and Zhou point out, the company can undercut generic competition by launching the single enantiomer.
IN THIS CLIMATE of yeasty growth for single-isomer chiral compounds, producers of fine chemicals are honing their enantioselective technologies. These producers realize that their customers will want syntheses of increasingly complex molecules. Also, there is a desire for new chemistries to improve manufacturing efficiency and to establish or get around patented technologies of others.
In addition to their in-house research, some fine chemicals companies have allied themselves with academic chemists to expand their portfolios. Entrepreneurial university faculty members have also founded their own companies and feed them with their continuing discoveries. And yet other chemistry professors explore enantioselective processes with no thought for present commercialization.
There is no letup in the search for new enantioselective methods, because each commercial project is unique. There is no sovereign method. No matter how effective one separation, synthesis, or conversion has been in the past, in the next project, economics, yield, or enantiomeric excess (ee) may be lacking.
At the beginning of development, however, there seems to be a definite place for chiral liquid chromatographic separation of the enantiomers of an active drug compound: Both enantiomers are usually needed for initial studies. Chiral chromatography often must be developed as an analytical method, so extending the methodology to preparative work is straightforward. And if a drug candidate fails early on, not much will be lost, having done preliminary work with chiral chromatography.
The increasing method of choice for such separation is simulated moving bed (SMB) chromatography (C&EN, June 19, 2000, page 17). Besides drug firms that have installed SMB for themselves, an increasing number of fine chemicals companies offer SMB as a contract service to special order. Examples include Aerojet Fine Chemicals of Rancho Cordova, Calif.; Bayer of Leverkusen, Germany; Chiral Technologies of Exton, Pa.; Universal Pharma Technologies of North Andover, Mass.; and the CarboGen Laboratories subsidiary of Solutia in Aarau, Switzerland.
In SMB, six to 12 chiral chromatographic columns are joined in a circle. Four to five pumps keep the liquid phase circulating through the system. As the racemate travels through the columns, a zone of one enantiomer starts to lead the rest of the bolus, while a zone of the opposite enantiomer lags behind. At intervals, under computer guidance, some of the lead enantiomer and some of the trailing enantiomer are withdrawn and saved separately. At the same time, a new charge of racemate is injected into the center of the traveling bolus, while some pure liquid phase is injected 180 opposite to that point.
At CarboGen, Markus Juza, director of SMB technology, says the company's system separates 4 kg of racemic drug per day when it is up and running. CarboGen has delivered 60 kg of resolved drug racemate in a total of 16 weeks, he says. The CarboGen system is divided among three separate suites for mixed solvent preparation, the SMB apparatus itself, and product recovery. This design allows maximum flexibility and minimizes chances of cross-contamination of solvents and products.
In conceiving new enantioselective technology, the search goes on among the usual alternatives: use of the chiral pool, resolution of racemates, and asymmetric synthesis. Either chemical or biocatalytic methods may be used. By chiral pool, practitioners mean all the carbohydrates, amino acids, lipids, terpenes, and alkaloids from plant and animal sources.
But recently there's been a change of thinking about what constitutes the chiral pool. The new thinking recognizes that any synthetic enantiomer that becomes available through large-scale production should also be included conceptually in the chiral pool. Perhaps the beginnings of this view came from availability of huge amounts of L-aspartic acid and L-phenylalanine at what is now Great Lakes Fine Chemicals, Mount Prospect, Ill., stemming from processes developed to make the synthetic sweetener aspartame.
SO PLENTIFUL is L-aspartic acid at Great Lakes that the company uses it as a substrate with transaminase enzymes to furnish the amino group in production of other single-isomer amino acids. This is actually a case of throwaway chirality.
The person who has formalized this expanded concept of the chiral pool is organic chemistry professor Eric N. Jacobsen of Harvard University. He presented his views at the San Diego national meeting of the American Chemical Society in April.
Jacobsen has contributed to such an expansion of the chiral pool by devising catalytic processes amenable to large-scale asymmetric epoxidation, epoxide ring opening, epoxide resolution, and Strecker syntheses of amino acids. Rhodia ChiRex, Boston, has licensed the Jacobsen processes and is producing 10-metric-ton quantities of single-isomer epichlorohydrin, 3-chloropropane-1,2-diol, propylene oxide, propylene glycol, propylene carbonate, styrene oxide, methyl glycidate, and glycidyl p-toluenesulfonate and m-nitrobenzene-sulfonate at the company's plant in Dudley, England.
One company that has taken its own such expansion of the chiral pool to further production is DSM Fine Chemicals. Chemists at the DSM technical center in Geleen and at the contract research firm Synthon in Groningen, both in the Netherlands, have reported using DSM's (R)-phenylglycine as a chiral auxiliary in an asymmetric Strecker synthesis of amino acids [Org. Lett., 3, 1121 (2001)]. DSM produces large amounts of (R)-phenylglycine to make the semisynthetic penicillin ampicillin and the cephalosporin cephalexin. The investigators include research fellows Q. B. (Rinus) Broxterman and Wilhelmus H. J. Boesten and chemist Ben de Lange at DSM and chemists Jean-Paul G. Seerden and Richard M. Kellogg at Syncom.
They choose a synthesis of (S)-tert-leucine (L-b,b,b-trimethylalanine) to exemplify the process. tert-Leucine is a component of some HIV protease inhibitors and matrix metalloprotease inhibitors. In the synthesis, (R)-phenylglycine amide reacts with pivalaldehyde in water to form an imine. The imine reacts reversibly with an added mix of sodium cyanide and acetic acid to give the two diastereomers of the corresponding amino nitrile.
The desired diastereomeric amino nitrile corresponding to (R)-phenylglycine and (S)-tert-leucine crystallizes out preferentially. Because the cyanide adds reversibly across the imine double bond, the upshot after 24 hours of stirring is the crystallization of a 93% yield of the desired diastereomer in a 99:1 ratio.
Acid-catalyzed hydrolysis of the nitrile amide yields the diamide. Because phenylglycine is a benzylamine, hydrogenation of the diamide cleaves the phenylacetic acid portion of the molecule, leaving the former amino group of phenylglycine with the new tert-leucine portion. The synthesis ends with further acid-catalyzed hydrolysis of tert-leucine amide to the amino acid.
Another development at DSM involves that firm's collaboration with academic investigators. Broxterman and senior researcher Birgit Schulze in Geleen work with chemistry professors Roland Furstoss and Alain Archelas of the University of the Mediterranean in Marseille and their Ph.D. student Yvonne Genzel.
The object is to develop epoxide hydrolase enzymes for kinetic resolution. The obvious means of getting at enantiomeric epoxides or the corresponding diols are the asymmetric epoxidation of olefins or hydrolytic kinetic resolution of epoxides invented by Jacobsen of Harvard or the asymmetric dihydroxylation of olefins invented by organic chemistry professor K. Barry Sharpless of Scripps Research Institute.
But these reactions involve metal catalysts. A hydrolase method has the advantage of involving only the substrate, product, water, and a biodegradable protein. Also, the DSM/Marseille workers want a method that would work with pyridyl-substituted epoxides, which are intermediates in making b-adrenergic receptor agonists and antiobesity drugs. The heterocyclic nitrogen, however, can form complexes with metals, interfering with metal-catalyzed reactions.
Furstoss and Archelas call their epoxide hydrolases "new enzymes," because chemists are finding them increasingly now in microorganisms, whereas until recently, knowledge of them was limited to mammalian sources. Availability of such a hydrolase from Aspergillus niger means that the gene can be cloned and overexpressed for production in commercial amounts. With 2-(2-pyridyl)oxirane from epoxidation of 2-vinylpyridine, they get a 43% yield (of a possible 50%) of (S)-epoxide in greater than 99% ee and 43% of diol in 62% ee. They can optimize enantiomeric excess of either the epoxide or diol by running the reaction short of or past the 50% mark.
One fine-chemicals company strategy is to construct a chemical "tree," in which the firm starts with a simple material and creates "branches" by reactions extending from the original compound. At DSM, such core materials are enantiomeric cyanohydrins, which the company makes from aldehydes and hydrogen cyanide, mediated by a hydroxynitrile lyase. The company has commercialized an (S)-lyase from the rubber tree Hevea brasiliensis and an (L)-lyase from jack beans.
Project manager Peter Poechlauer of DSM in Linz, Austria, described elaboration of cyanohydrins to heterocyclic intermediates at the San Diego ACS meeting. Working with R&D head Michael Hartmann and chemical engineer Herbert Mayrhofer, Poechlauer esterifies (S)-mandelonitrile, prepared from benzaldehyde, with a-bromopropionic acid. Treatment of that ester with zinc gives an aminofuranone in 96% ee, which hydrolyzes to a tetronic acid in 93% ee.
ANOTHER CHEMIST who has spent years working out the branches of his chemical tree is organic chemistry professor Rawle I. Hollingsworth of Michigan State University, East Lansing. He founded Synthon Chiragenics in Monmouth Junction, N.J., to sell the intermediates and technologies he has developed. And in November 2000, he signed a four-year agreement with Cambrex, East Rutherford, N.J., to develop and produce single-enantiomer compounds for making drugs. Hollingsworth will continue to develop intermediates, and Cambrex will produce them on a large scale.
Some years ago, Hollingsworth perfected an alkaline hydrogen peroxide oxidation of lactose to (S)-b-hydroxybutyrolactone and of L-arabinose to the (R)-lactone. Lactose is a coproduct of cheese making, while arabinose is plentiful in sugar beet processing waste. He has parlayed these lactone starting materials into several dozen three-, four-, and five-carbon asymmetric building blocks.
At the ACS meeting, he reported work with graduate student Guijun Wang to convert (S)-lactone to (S)-5-hydroxymethyl-1,3-oxazolidin-2-one. Single-isomer oxazolidinones are components of newest generation antibacterial drugs. Reaction of the lactone with ammonium hydroxide gives the b,g-dihydroxybutyramide. That amide reacts with benzeneboronic acid to form the protected ester 2-phenyl-1,3,2-dioxaborolane-4-acetamide. Hoffmann rearrangement of the amide with sodium hypochlorite goes through an intermediate isocyanate. But instead of hydrolysis to an amine as in the usual Hoffmann reaction, the isocyanate reacts internally to yield the oxazolidinone.
In what may become another chemical tree at Synthon, Hollingsworth and Wang have devised a method to convert ribose in complex carbohydrates to more valuable intermediates. Ribose comprises a large part of bacterial cell walls and algae. Thus fermentation wastes may become an inexpensive source.
In their first effort, the MSU chemists make 1,4-dideoxy-1,4-iminoribitol, in which ribose is missing an oxygen at C-1 and the heterocyclic oxygen is replaced by nitrogen. This aza sugar is an inhibitor of purine nucleoside phosphorylase, which is essential in synthesizing nucleosides for incorporation into DNA. The compound is in clinical trials as cancer therapy.
Hollingsworth has invented a proprietary process that converts the ribose content of complex carbohydrates to methyl (2R,3R,5)-triacetoxy-4-oxopentanoate. Reductive amination of that keto ester yields an amino ester, which cyclizes and saponifies on treatment with base to form the iminoribitol.
Yet another firm looking to grow chemical trees is the contract research/custom synthesis company CiVentiChem, Research Triangle Park, N.C. President Bhaskar R. Venepalli says the company's two chiral chemical trees are based on elaboration of d-mannitol and of diethyl L-tartrate.
The company takes advantage of the fact that the configurations at C-2 and C-5 of mannitol are mirror images. Thus mannitol reacts with two moles of acetone to form the C-1/C-2 and C-5/C-6 diacetonide. Oxidation of that with sodium periodate cleaves the molecule to two moles of the acetonide of d-glyceraldehyde. Condensation with methyl, ethyl, or benzyl acetate yields a five-carbon platform that CiVentiChem transforms into several other compounds. The tartrate ester likewise serves as starting material for a series of four-carbon intermediates with two asymmetric centers.
Another set of chiral compounds making a debut is a series of nonnatural amino acids from Wacker Chemie, Munich. According to research scientist Thomas Maier, the company taps into a metabolic pathway that bacteria use to synthesize cysteine.
One product of this fermentation is the dimeric proteinogenic amino acid L-cystine, which the company converts to monomeric L-cysteine by electrolysis. Those two amino acids, together with N-acetyl- and S-carboxymethylcysteine, are made by Wacker for drugs, cosmetics, and human and animal foods. These amino acids have previously been made by hydrolysis of hair and feathers and are often subject to vagaries of supply from East Asian countries.
The biosynthetic pathway goes via the intermediate O-acetyl-L-serine. This intermediate is converted to cystine/cysteine by a sulfur donor, mediated by O-acetylserine sulfhydrylase. To make the nonnatural amino acids, Wacker feeds various other compounds to the fermentation broth or to a cell-free reaction mixture involving the sulfhydrylase enzyme.
For example, adding 2-aminothiazole to the fermentation gives rise to S-thiazolyl-L-cysteine, while addition of 1H-1,2,4-triazole yields triaziolyl-L-alanine. But as Maier explains, some additives are toxic to bacteria or malodorous. In such cases, Wacker uses the cell-free enzyme route. Examples include adding cyanide to make cyanoalanine, the nitrile of aspartic acid; adding azide to make azidoalanine; or adding thiophenol to make (S)-phenylcysteine. For now, Wacker offers kilogram quantities of (S)-phenyl- and (S)-thiazolylcysteine, as well as pyrazolyl-, triazolyl-, and tetrazolylalanine, with the potential to produce on much larger scales.
Enzymes are a particular specialty with Biocatalytics of Pasadena, Calif. The company clones and expresses genes for enzymes, improves enzymes by directed evolution, and develops enzymatic processes. In recent developments, the company has added a seventh and eighth member to its line of keto reductases and has added a glutaryl acylase, Biocatalytics President David Rozell says.
The ketoreductases, which reduce prochiral ketones to secondary alcohol enantiomers, all use the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor. Biocatalytics supplies kits for customer evaluation. The company includes the cofactor in the kit, together with enenzyme and buffer, so that the customer has everything needed to run the reation. If an enzyme goes into a commercial process, then Biocatalytics designs a process that includes a parallel oxidation of glucose or formate to regenerate the cofactor.
The new glutaryl acylase finds use in resolving chiral amines. One substrate of this enzyme is racemic N-a-phenethyl monoamide of glutaric acid. The products are (R)-a-phenethylamine and unreacted N-(S)-a-phenethyl glutaric half-amide.
In addition to biocatalysts, fine- chemicals firms also continue to make advances in chemical catalysts. Ascot Fine Chemicals, London, has both developed asymmetric chemical catalyst ligands of its own and licensed such ligands developed by organic chemistry professors Royoji Noyori of Nagoya University and Takao Ikariya of Tokyo Institute of Technology, both in Japan.
Ascot's own catalyst ligands feature two asymmetric trans-dialkyl phosphetane units as substituents on each ring of a ferrocene molecule. Trade named FerroTANE, the ligands were invented by Mark J. Burk, who was head of research at the Ascot ChiroTech technical center in Cambridge [Angew. Chem. Int. Ed., 39, 1981 (2000)]. Burk had gained earlier fame as the inventor of the proprietary DuPHOS asymmetric catalyst ligands when he was a research chemist at DuPont. Burk is currently vice president for chemical development at Diversa, an enzyme development firm in San Diego. The Royal Society of Chemistry, under its Industrial Innovation Team Awards 2000 program, awarded Ascot a special commendation for the discovery of FerroTANE ligands.
The Noyori asymmetric catalysts licensed by Ascot from Japan Science & Technology Corp. are for either high-pressure hydrogenation or transfer hydrogenation. In transfer hydrogenation, the hydrogen comes from a donor such as 2-propanol, which is converted to acetone. The virtue of these catalysts is that each hydrogenates a carbonyl compound to an alcohol, yet leaves olefinic and acetylenic bonds unmolested.
Indeed, Raymond McCague, director of science and technology at Ascot Fine Chemicals, says: "One thing to note is that while the emphasis of the technology is on its application to chiral alcohols, it can also be used for the achiral, chemoselective hydrogenation of appropriate ketones or aldehydes, for instance, where the substrate also contains an olefin function."
The Noyori catalyst for asymmetric transfer hydrogenation is ruthenium(II) chelated by (R,R)- or (S,S)-N-p-toluenesulfonyldiphenylethylenediamine and p-complexed with mesitylene. With 2-propanol as the hydrogen donor, the (S,S)-form of this catalyst mediates hydrogenation of methyl phenylethynyl ketone to (S)-4-phenyl-3-butyn-2-ol in greater than 99% yield and in 98% ee.
THE NOYORI CATALYST for asymmetric pressure hydrogenation is ruthenium(II) chelated both by a single enantiomer of 2,2 -bis(di-3,5-dimethylphenylphosphino)-1,1 -binaphthyl (BINAP) and a single enantiomer of 1,1-dianisyl-2-isopropylethylenediamine. For example, this catalyst mediates reduction of benzalacetone to one enantiomer of 4-phenyl-3-buten-2-ol quantitatively in 97% ee.
"Also," McCague says, "one area of asymmetric hydrogenation technology we are increasingly looking at is diastereoselective hydrogenation; that is, where the molecule is already chiral, but we need to generate a subsequent stereocenter selectively. I think with increasing molecular complexity, there will be more calls for such work beyond having put in the first stereocenter." Thus it may be possible for a hydrogenation catalyst to force asymmetry in one sense at a second carbon atom, even though the asymmetry of another carbon atom is influencing the new asymmetry in the opposite sense.
The original inspiration to use ferrocene as the core of asymmetric catalyst ligands comes from discovery of the so-called Josiphos ligands at Solvias in Basel, Switzerland, which is the former catalyst group of Ciba-Geigy. The first examples of the class are said to have been made by a lab technician named Josi Puleo. The success of ferrocene catalysts is due to their enantioselectivity and catalytic efficiency, as measured in moles of product made per mole of catalyst per hour. In addition, because of the ease of substitution in the cyclopentadienyl rings, the catalyst ligands are modular and easily tunable. Basel-headquartered Lonza has used Josiphos catalysts for commercial processes to make single-enantiomer dextromethorphan and piperazinecarboxylic acids.
Modularity and tunability have also been the goals of organic chemistry professor Xumu Zhang at Pennsylvania State University. Like MSU's Hollingsworth, Zhang has founded a company, Chiral Quest, to commercialize the seven asymmetric catalyst ligand types he has invented to date.
MOST RECENTLY, the company opened an analytical laboratory at Penn State's Zetachron Center for Science & Technology Business Development. Workers there will take in reactions customers are interested in and screen the substrates against libraries of Zhang's catalysts for best fit.
Chiral Quest President Timothy B. Hurley emphasizes that the company will not compete with customers. "We do not aspire to participate in upstream drug discovery or downstream manufacturing of pharmaceutical ingredients," he says. "We believe that by focusing intensely on ligand design, discovery, and optimization, we will be able to provide customers with highly effective catalysts that improve the manufacture of chiral drugs."
Ligands with a BINAP-type structure continue to be developed. These are made from the corresponding binaphthols. Now, organic chemistry professor Chien-Tien Chen at National Taiwan Normal University in Taipei has developed a catalytic synthesis of substituted binaphthols in good yield and fair enantiomeric excess [Org. Lett., 3, 869 (2001)]. He subjects the naphthol to air oxidation, mediated by a catalyst of vanadium chelated by the Schiff base of salicylaldehyde with L-valine. The yield of binaphthol itself is 94%, with 62% ee. Such low enantiomeric excesses are usually unacceptable in asymmetric syntheses, but the end product is so useful that it may be worthwhile to upgrade the enantiomeric excess afterwards.
Most such enantioselective chemical catalysts are ligands that chelate transition metals. This raises concerns about transition-metal residues in drug products. One investigator who has been prospecting for all-organic catalysts is organic chemistry professor David W. C. MacMillan at the California Institute of Technology.
At the San Diego ACS meeting, Wendy S. Jen, MacMillan's graduate student, laid claim to the first asymmetric, all-organic 1,3-dipolar addition. And more recently, MacMillan reported the first asymmetric, all-organic Friedel-Crafts reaction [J. Am. Chem. Soc., 123, 4370 (2001)]. The catalyst is an imidazolidinone, made by reaction of L-phenylalanine, acetone, and methylamine.
Working with graduate student John J. M. Wiener, Jen made C-phenyl N-benzyl nitrone from N-benzylhydroxylamine and benzaldehyde. Catalyzed addition of the nitrone to cinnamaldehyde yielded an enantiomeric isoxazolidinone carboxaldehyde. In the Friedel-Crafts reaction, MacMillan and graduate student Nick A. Paras treated N-methylpyrrole with cinnamaldehyde to get an enantiomeric pyrrole phenylpropionaldehyde.
Beyond catalyst and ligand development, firms in the fine chemicals area hone their process development skills as a means of attracting clients. Two companies that have reported recent advances are Dow Contract Manufacturing Services, Midland, Mich., and PPG-Sipsy, Avrillé, France.
At Dow, a customer presented a multistep synthesis that began with alkylation of an amino acid with a perfluoroethyl group to make a fluorinated amino ketone. Preliminary study of the reaction indicated the requirement for a surprising ratio of 3 moles of alkylating reagents to 1 mole of substrate. Dow process chemists used a combination of reaction calorimetry, mass spectrometry of vapors over the reaction mixture, and infrared spectrophotometry of the reaction mixture to study the interactions.
IN PARTICULAR, the reaction called for L-valine methyl ester, protected at the amino group by a tert-butoxycarbonyl (Boc) group. The Dow workers learned that the pentafluoroethyl group could be tied up in unreactive complexes with methyllithium. Although the final stoichiometry of 3 moles of fluoro compound and 3 moles of organolithium was costly, it drove the reaction to completion, resulting in a satisfactory yield of the fluorinated amino ketone to go on with the rest of the synthesis.
At PPG-Sipsy, process chemists wanted to devise a fast, high-yield synthesis of a six-carbon chiral fragment to go into production of LY-333531 at Eli Lilly & Co., Indianapolis. That compound is an inhibitor of protein kinase C and is in clinical testing to avert retinal and kidney degeneration as complications of diabetes.
Jean-Claude Caille, manager of innovation and development at PPG-Sipsy, presented results of the project last week to the 15th French-Japanese Symposium on Medicinal & Fine Chemistry in Nara, Japan. Caille credits senior research scientist John Burks of Lilly for supplying analytical data about the chiral intermediate.
The route finally decided on is a hetero-Diels-Alder reaction between butadiene and ethyl glyoxylate. The product is a racemic dihydropyrancarboxylate. A protease hydrolyzes the unwanted (R)-ester. Further operations on the (S)-ester lead finally to a protected derivative of the required (S)-2-hydroxyethoxy-1,4-butanediol.
Caille said organic chemistry professor Marvin J. Miller of Notre Dame University, consulting for PPG, made the suggestion that a protease might best separate the racemic ester. PPG-Sipsy chemists went to Altus Biologics for a cross-linked crystal version of the protease. Altus specializes in purifying such proteins as enzymes and growing crystals of them. The company then treats the crystals with a cross-linking agent such as glutaraldehyde. The resulting cross-linked crystalline enzymes are more stable to heat, pH extremes, and organic solvents than are the native proteins.
Protecting groups occur frequently in substrates destined for enantioselective reactions. Chemists seek armories of as many protecting groups as possible in order to plan strategies of sequential application and removal. Polycarbon Industries of Leominster, Mass., has rights to a new protecting group as a result of acquiring Oryza Laboratories of Chelmsford, Mass. And chemists at the University of South Florida in Tampa have devised a way to apply alkoxycarbonyl protecting groups to amines without phosgene-based intermediates.
Oryza had licensed the protecting group known by its acronym Bsmoc, whose patent belonged to the University of Massachusetts, Amherst, where the protecting group was invented by organic chemistry professor Louis A. Carpino. The reagent is based on 2-hydroxymethylbenzothiophene dioxide, which reacts with phosgene to form the chloroformate. Polycarbon offers both the chloroformate and the N-hydroxysuccinimide ester.
Carpino tells C&EN that he has demonstrated how the new reagent acts in concert with his earlier invented 9-fluorenylmethoxycarbonyl (Fmoc) protecting group. He cites the case of the dipeptide leucylphenylalanine protected at its N-terminus with Bsmoc and at the carboxylate end with Fmoc. Treatment with diisopropylamine in dimethylformamide removes the Bsmoc group, leaving the Fmoc. Treatment with tris(2-aminoethyl)amine removes Fmoc and leaves Bsmoc.
Preparation of reagents to apply such protecting groups as Fmoc and Bsmoc involves reaction of the precursor alcohol with phosgene to make the chloroformate ester. Organic chemistry professor Kyung Woon Jung at the University of South Florida, Tampa, has devised a way to protect amines using only carbon dioxide and the alkyl halide [J. Org. Chem., 66, 1035 (2001)]. In a demonstration of the method, he treats b-phenethylamine with benzyl chloride and carbon dioxide in dimethylformamide, mediated by cesium carbonate and tetrabutylammonium iodide. The product is the Boc-protected amine in 96% yield.
The world fine chemicals industry continues to develop enantioselective technology, ranging from the newest biocatalytic transformations at DSM Fine Chemicals to the protecting groups that aid asymmetric synthesis as developed by academic chemists such as Carpino. The focus of all these efforts is supplying the needs of the drug industry, which takes more than 80% of the enantiomeric products of the fine chemicals industry and spurs its 13% average annual growth rate.
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Worldwide sales of single-enantiomer drugs head past $123 billion
|Central nervous system
|SOURCE: Technology Catalysts International
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Expositions and Symposia Highlight Chiral Chemistry
June 2021, ChemSpec Europe 2001. Amsterdam. For the exposition, contact DMG World Media, 2 Queensway, Redhill, Surrey RH1 1QS, U.K.; phone 44 1737 768611, fax 44 1737 855469, e-mail: firstname.lastname@example.org. For symposium, contact the British Association for Chemical Specialities, The Gatehouse, White Cross, Lancaster LA1 4XQ, U.K.; phone 44 1524 849606, fax 44 1524 849194, e-mail: email@example.com.
July 1518, International Symposium on Chirality. Orlando, Fla. Contact Barr Enterprises, P.O. Box 279, Walkersville, MD 21793; phone (301) 898-3772, fax (301) 898-5596, e-mail: firstname.lastname@example.org, Internet: www.chiral.com.
Sept. 2526, ChemSource. Manchester, U.K. For the exposition, contact DMG World Media; phone 44 1737 855523, fax 44 1737 855474, e-mail: email@example.com. For the symposium, contact the Royal Society of Chemistry, Howell Croft, Cow La., Norley, Frodsham, Cheshire WA6 8PW, U.K., fax 44 1928 788071; e-mail: firstname.lastname@example.org.
Oct. 810, Conference on Pharmaceutical Ingredients. London. For both the conference and exposition, contact Miller Freeman, Industrieweg 54, 3606 AS Maarssen, the Netherlands; phone 31 346 559444, fax 31 346 573811, e-mail: Nklein@unmf.com.
Oct. 1112, Chiral Europe 2001. Contact Scientific Update, Wyvern Cottage, High St., Mayfield, East Sussex TN20 6AE, U.K.; phone 44 1435 873062, fax 44 1435 872734, e-mail: email@example.com.
Nov. 1214, ChiraSource. Philadelphia. Contact Catalyst Group, P.O. Box 637, Spring House, PA 19477; phone (215) 628-4447, fax (215) 628-2267, e-mail: firstname.lastname@example.org.
Nov. 1920, Fine Chemicals Conference 2001. London. Contact Folio Consultants, Braeside, High St., Oxshott, Surrey KT22 OJP, U.K.; phone 44 1372 841010, fax 44 1372 841012, e-mail: Paulfolio@aol.com.
Feb. 26March 1, 2002, Informex. New Orleans. Contact Synthetic Organic Chemical Manufacturers Association, 1850 M St., N.W., Washington, DC 20036; phone (202) 721-4100, fax (202) 296-8120, e-mail: email@example.com.
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