Stephen C. Stinson
C&EN Northeast News Bureau

Boston is a showcase for enantioselective technology this spring. This week, organic chemistry professor Roger A. Sheldon of the Technological University of Delft in the Netherlands gives a short course on industrial production of optically active compounds. And next week, Boston hosts the annual conference and exposition, Chiral USA 2000. In both forums, there will be plenty of discussion about advances in chirotechnology that both industrial and academic chemists have disclosed recently.

For example, Michael Schwarm, manager of research and development for fine chem-icals at Degussa-Hüls in Hanau, Germany, described his firm's progress in amino acid synthesis to the Conference on Pharmaceutical Ingredients in Frankfurt last November. The Hanau team seeks new routes to amino acids that do not occur in nature (nonproteinogenic amino acids) that can serve as asymmetric auxiliaries or catalysts or as building blocks for new drugs.

Chemists attach asymmetric auxiliary molecules covalently to substrates to induce asymmetry in a reaction that comes next. Following that, chemists can cleave the bond to the asymmetric auxiliary. Nonproteinogenic amino acids such as l-tert-leucine (2-amino-3,3-dimethyl- butanoic acid) and l-neopentylglycine (2-amino-4,4-dimethylpentanoic acid) are favored as asymmetric auxiliaries because these bulky molecules communicate chirality to the reaction site. And as components of drugs, they may be poor substrates for enzymes that might break down the drug.

Schwarm points to the Degussa-Hüls method to make l-neopentylglycine as one of many technologies that the company has for amino acid manufacture. In this case, the company subjects a precursor alpha-keto acid, 4,4-dimethyl-2-oxopentanoic acid, to the action of leucine dehydrogenase.

That enzyme uses the reduced form of a cofactor, nicotinamide adenine dinucleotide (NAD), to deliver an amino group from an ammonium ion to the alpha-carbon atom of the alpha-keto acid. In a concurrent process, formate dehydrogenase oxidizes formate ions in the reaction mixture to regenerate reduced NAD. The company makes the alpah-keto acid by condensation of commercially available 3,3-dimethylbutyraldehyde with hydantoin. Hydrolysis of the intermediate alkylidenehydantoin yields the alpha-keto acid.

Schwarm described another approach in the Degussa-Hüls method for l-homoserine [(S)-2amino-4-hydroxybutanoic acid]. The starting material is l-methionine, in which the company has a large position. The conversion has been done on a small scale by methylation of the methylthio sulfur to a sulfonium salt, which reacts with hydroxide to give the homoserine and dimethyl sulfide.

Schwarm pointed out that the dimethyl sulfide makes that route impractical on a large scale. Instead, he said, the company uses "a proprietary route that is based in principle on well-known reactions." A possibility is reaction of methionine with cyanogen chloride. In that case, the leaving group would be methyl thiocyanate, which may be more amenable to treatment afterward. Degussa-Hüls also makes many amino acids from diethyl acetamidomalonate. Alkylation of the central carbon followed by hydrolysis and decarboxylation yields the N-acetyl amino acid with the desired side chain. Incubation of the amino acid with a lipase results in kinetic resolution to the d- and l-amino acids by enantioselective cleavage of the acetyl group from one isomer.

Schwarm said the technology for making acetamidomalonate is also proprietary. The method most used in the past has been reaction of malonic ester with sodium nitrite and acetic acid, which gives the oximino ester. Reduction of that by dissolved metal in acetic anhydride produces the acetamido ester. Degussa-Hüls instead could have perfected a hydrogenation. The company manufactures malonic ester by reaction of ethyl chloroacetate with carbon monoxide.

Also on the subject of amino acids, Degussa-Hüls has worked with organic chemistry professor Stanley M. Roberts of the University of Liverpool in England on asymmetric epoxidation of olefins using synthetic polypeptides as catalysts [Tetrahedron Lett., 40, 5417 (1999)]. There have been problems with the use of poly(l-leucine) and hydrogen peroxide, activated by urea, because there is a competing uncatalyzed nonenantioselective epoxidation that goes on at the same time and degrades the enantiomeric excess (ee). Roberts recently has worked with Karl-Heinz Drauz, vice president and head of research and development at Degussa Hüls, on an alternate route that uses sodium percarbonate in dimethoxyethane. Under those conditions, the undesirable uncatalyzed epoxidation is suppressed. Thus chalcone is converted to (1R)-benzoyl-(2R)-phenyloxirane in quantitative yield and 96% ee.

Yet another firm that deals partly with single-isomer amino acids is Pharm-Eco Laboratories, Lexington, Mass. Chief Scientist Laxma Reddy described some of the company's drug discovery techniques at the Synthetic Organic Chemical Manufacturers Association's Enabling Technologies Symposium at the Informex custom chemicals exposition in New Orleans in February.

Pharm-Eco uses one-pot reactions of several reagents to synthesize libraries of compounds for combinatorial chemistry. For example, the Passerini reaction combines an isocyanide, a carboxylic acid, and an aldehyde or ketone to produce an alpha-hydroxy acid amide. The Ugi reaction combines an isocyanide, a carboxylic acid, an aldehyde, and an amine to yield an N-acyl amino acid amide. By varying the substituents on the four ingredients of the Ugi reaction, Pharm-Eco can vary the combination of substituents on the basic backbone. For example, Reddy showed how phenyl isocyanide, benzoic acid, isobutyraldehyde, and an amine synthesized by Pharm-Eco chemists could react to give a structure resembling those of certain human immunodeficiency virus (HIV, the virus that causes AIDS) protease inhibitors.

The amine Pharm-Eco uses is (1,3S)-diamino-4-phenyl-(2R)-butanol. The company makes that amine from l-phenylalanine by reaction with nitromethane to form a nitro ketone, which is reduced to the amino alcohol. In addition to amine building blocks, Pharm-Eco also makes isocyanides from amines as combinatorial building blocks.

Elsewhere in industrial chirotechnology, Synthon Corp. , newly moved from Lansing, Mich., to Monmouth Junction, N.J., has received a patent (U.S. 6,040,464) for conversion of its flagship four-carbon (3S)-hydroxybutyrolactone to three-carbon compounds with a (2S) configuration.

Synthon founder and Chief Scientific Officer Rawle I. Hollingsworth developed a process to make the lactone from treatment of lactose, a by-product of cheese making in Michigan, with sodium hydroxide and hydrogen peroxide. Of the raw material, Hollingsworth said jokingly, "In Michigan, lactose is so cheap that they use it to salt the roads in winter." Because chiral drug molecules often have their chirality in such three-carbon sequences, the Synthon technology is important to the industry. In addition, Hollingsworth, who is also a professor of organic chemistry at Michigan State University, has succeeded in producing the (3R)-lactone from l-arabinose, so three-carbon derivatives of (2R) configuration also are available.

Arabinose is available inexpensively in the pulp of beets and of certain woods. Of carbohydrates, Hollingsworth said, "The upside is that carbohydrates are the cheapest source of chirality. The downside is that it's all the same kind: secondary alcohols." Hollingsworth's inventiveness has thus delivered useful chirality at low cost.

In his newest technology, Hollingsworth treats the lactone with ammonia to form the (3S,4)-dihydroxy amide, which he protects as the acetonide. Reaction of protected amide with sodium hypochlorite leads to the aminopropanediol acetonide by Hoffmann rearrangement. Boiling the acetonide with hydrochloric acid cleaves the acetonide to free up the amino diol. Reaction of the acetonide with hydrochloric acid and sodium nitrite in the cold gives the chloropropanediol, and with hydrobromic acid and sodium nitrite gives the bromo diol. Treatment of the bromo diol with potassium hydroxide leads to (R)-glycidol.

Hollingsworth hit on his process for the single-isomer hydroxy lactones as a part of his research at Michigan State. Elsewhere, other academic chemists also are prospecting in enantioselective technology that might be licensed to industry. For example, organic chemistry professor David W. C. MacMillan at the University of California, Berkeley, has invented an all-organic catalyst for asymmetric Diels-Alder reactions [ J. Am. Chem. Soc.,122, 4243 (2000) ]. The virtue of such a catalyst is that there is no metal that must be separated from the product or treated as waste.

The MacMillan catalyst has attracted the attention of Symyx Technologies, Santa Clara, Calif., which has negotiated an option with Berkeley to take an exclusive license on the patent. Symyx uses proprietary instruments, software, and methods in high-throughput synthesis and screening for combinatorial discovery of such products as catalysts, polymers, and electronic materials. Of the MacMillan catalyst, Isy Goldwasser, president and chief operating officer, says, "At this early stage, we're excited by this chemistry. We think the combination of this chemistry and our combinatorial methods shows great promise." The catalyst is 1,2,2-trimethyl-(4R)- or (4S)-benzylimidazolidin-5-one. Working with graduate students Kateri A. Ahrendt and Christopher J. Borths, MacMillan makes the catalyst by reaction of either d- or l-phenylalanine with methylamine and acetone. Thus the catalyst is available in two isomers to mediate the Diels-Alder reaction in either sense.

The Berkeley workers suggest the reaction proceeds through a catalytic cycle in which the imino nitrogen of the imidazolidinone ring forms an iminium salt adduct with a dienophilic aldehyde. The iminium cation serves as an electron-attracting Lewis acid activator, a function that is usually served by a transition-metal ion. After the Diels-Alder reaction, the product iminium salt transfers the catalyst molecule to an unreacted aldehyde molecule.

In one example, 1,3-cyclohexadiene reacts with acrolein mediated by the (R)-catalyst to yield 99% of (S)-bicyclo[2.2.2]oct-5-en-2-carboxaldehyde, of which 93% is the endo aldehyde, in 94% ee. The situation is more complex with such dienophiles as crotonaldehyde or cinnamaldehyde because then there is exo-endo isomerism of methyl and phenyl groups as well as of carboxaldehyde groups.

Asymmetric catalytic activation of carbon-hydrogen bonds is the subject of technology invented by organic chemistry professor Huw M. L. Davies at the State University of New York, Buffalo. Working with graduate student Tore Hansen and inorganic chemistry professor Melvyn Rowen Churchill, Davies uses a catalyst of rhodium coordinated by (S)-N-laurylproline to mediate reactions of aryldiazoacetate esters and either alkanes or tetrahydrofuran [J. Am. Chem. Soc., 122, 3063 (2000)]. For example, reaction of methyl diazophenylacetate and cyclohexane gives 80% yield of methyl (R)-cyclohexylphenylacetate in 92% ee. Tetrahydrofuran yields 90% of methyl phenyl(2-tetrahydrofuryl)acetate in 97% ee. In other enantioselective aldehyde chemistry with industrial implications, organic chemistry professor Erick M. Carreira of the Swiss Federal Institute of Technology, Zurich, uses (+)-N-methylephedrine to catalyze addition of terminal acetylenes to aldehydes [ J. Am. Chem. Soc., 122, 1806 (2000) ].

The nonstereoselective version of this chemistry is practiced by Air Products & Chemicals at its Calvert City, Ky., plant. For example, base-mediated reaction of acetylene with acetone yields first 3-methyl-1-butyn-3-ol, then 2,5-dimethyl-3-hexyne-2,5-diol. Similarly, 2-ethylhexanal gives 4-ethyl-1-octyn-3-ol, butyraldehyde gives 1-hexyn-3-ol, and methyl ethyl ketone gives 3-methyl-1-pentyn-3-ol.

In Carreira's work with graduate student Roger Fässler and postdoctoral fellow Doug E. Frantz, commercially available 3-methyl-1-butyn-3-ol and isobutyraldehyde, mediated by (+)-N-methylephedrine, triethylamine, and zinc trifluoromethanesulfonate, give 97% of 2,6-dimethyl-3-heptyne-(2,5R)-diol in 98% ee. An attractive feature of the method is that it forms a carbon-carbon bond and establishes an asymmetric center in the same process.Yet another advance that bears watching for its industrial implications is the free-radical cyclization mediated by a carbohydrate chiral auxiliary that graduate student Jennifer S. Cottone described to the American Chemical Society national meeting in San Francisco in March. Working with organic chemistry professor Eric J. Enholm at the University of Florida, Cottone synthesized the ester of o-(alpha-bromoethyl)cinnamic acid with 2-O-benzyl-(+)-isosorbide. Treatment of that ester with tributyltin hydride yielded 83% of (1S)-indanacetate ester in greater than 99% ee. Cottone and Enholm achieved similar good results with a (+)-xylose acetonide. This advance is noteworthy because it extends enantioselective chemistry of free-radical reactions. And the work makes use of inexpensive carbohydrates as the auxiliaries.

T  he Florida work is reminiscent of that of organic chemistry professor Yian Shi at Colorado State University. Shi has fashioned a ketone from fructose acetonide and used that as a catalyst ligand for epoxidation of olefins by potassium monopersulfate. Catalytica Pharmaceuticals , Greenville, N.C., has licensed the technology.

Even more than carbohydrates, diamines have been very successful as asymmetric catalyst ligands. Notably, (-)-sparteine, threo-diphenylethylenediamine, and trans-1,2-diaminocyclohexane serve in numerous enantioselective catalyst systems.

But as organic chemistry professor Marisa C. Kozlowski of the University of Pennsylvania has shown, the actual number of such diamines is few. Aided by graduate student Xiaolin Li and undergraduate Laurie B. Schenkel, Kozlowski has set out to increase their number [ Org. Lett., 2, 875 (2000)].

In particular, computer calculations indicate that derivatives of cis-decahydro-1,5-naphthyridine have chiral cavities that might serve to chelate metal ions and induce asymmetry in reactions. The Penn team has tested the N,N'-dimethyl derivative, but enantiomeric excesses are only about 40% to date. They are moving on to more promising substituted decahydronaphthyridines.

Also of possible industrial importance is an asymmetric Friedel-Crafts reaction devised by chemists at Tokyo Institute of Technology. In one example, applied chemistry professor Koichi Mikami used titanium isopropoxide chelated by (R)-1,1'-bi-6-bromo-2-naphthol to catalyze addition of trifluoroacetaldehyde to anisole, yielding 89% of (R)-1-(4-anisyl)-2,2,2-trifluoroethanol in 90% ee [ J. Org. Chem.,65, 1597 (2000) ]. This reaction, devised in work with graduate student Akihiro Ishii and postdoctoral fellow Vadim A. Soloshonok, both elaborates the carbon skeleton of a fluorinated compound and creates an asymmetric center in the same step. Work of organic chemistry professor Scott G. Nelson and graduate student Keith L. Spencer at the University of Pittsburgh makes single isomers of highly reactive beta-lactones accessible as drug intermediates. One such compound is beta-cyclohexyl-beta-propiolactone, which Nelson makes by reaction of cyclohexanecarboxaldehyde with acetyl bromide, mediated by ethyldiisopropylamine and an aluminum salt [ J. Org. Chem., 65, 1227 (2000) ]. The tertiary amine converts acetyl bromide to the ketene, which undergoes cycloaddition with the aldehyde. Treatment of the racemic lactone with a lipase and benzyl alcohol in diisopropyl ether solvent results in 44% yield (out of a possible 50%) of unreacted (S)-lactone and 48% yield of benzyl (R)-3-hydroxy-3-cyclohexylpropanoate. Another type of intermediate that is more widely available is the glycal, owing to an advance by organic chemistry professor Jeffrey Schwartz at Princeton University. Glycals are aldohexose sugar derivatives with a highly reactive double bond between carbons 1 and 2. Glycals are valued for syntheses of oligosaccharides.

In the past, chemists mostly had to install the double bond, then labor to apply the desired protecting groups to the hydroxyls. Schwartz approaches the problem by protecting the sugar, installing the double bond as the last step.

Working with graduate students Cullen L. Cavallaro and Roxanne P. Spencer, Schwartz synthesizes 1-bromo or 1-chloro hexoses and treats those with bis(cyclopentadienyl)titanium chloride [ J. Org. Chem., 64, 3987 (1999) ]. In one example, 3,4,6-tri-O-benzylglucopyranosyl chloride reacts to form tri-O-benzylglucal--the glucal corresponding to glucose--in 94% yield. The titanium(III) derivative is made by reaction of commercially available bis(cyclopentadienyl)titanium dichloride with aluminum foil or zinc dust. Schwartz says chlorides are not as reactive as bromides and sometimes take several hours to react. But the savings in comparison with bromides may justify use of chlorides on a large scale.

Yet another example of asymmetric synthesis is that of asymmetric aminohydroxylation of olefins by organic chemistry professor K. Barry Sharpless of Scripps Research Institute, La Jolla, Calif. The aminohydroxylation is the reaction of the olefin with a sodium N-chloro amide and water, mediated by potassium osmate and the 1,4-phthalazine diether of either hydroquinine or hydroquinidine.

The newest extension of this chemistry, achieved with postdoctoral fellows Lukas Goossen, Hong Liu, and Ruprecht Dress, is to amino heterocycles as nitrogen donors [Angew. Chem. Int. Ed., 38, 1080 (1999)]. The significance of this extension is that heterocyclic molecules are more likely than others to have pharmacological activity. In one example, 2-aminopyrimidine reacts with tert-butyl hypochlorite and sodium hydroxide to give the sodium salt of N-chloro-2-aminopyrimidine. That salt, in turn, undergoes the asymmetric aminohydroxylation with trans-stilbene, using the hydroquinine form of the catalyst, to yield 45% of (R,S)-1,2-diphenyl-2-(2-pyrimidylamino)ethanol in 97% ee. For large-scale uses, 2-aminopyrimidine is commercially available from SKW Trostberg , Germany.

So as chemists travel to Boston for Chiral USA 2000 next week, it will be in an atmosphere of vigorous innovation in enantioselective chemistry. Synthon's Hollingsworth will speak about the newest developments in single-isomer intermediates derived from inexpensive carbohydrates. And attendees will be able to confer firsthand with MacMillan of UC Berkeley, who will speak about his no-metal approach to Lewis acid type catalysts. And those chemists are only two of the 18 academic and industrial chemists who will describe the latest in chirotechnology.
 
 

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Expositions and symposia highlight chiral chemistry The following conferences and expositions are scheduled for the coming year:  May 15-16, Chiral USA 2000. Boston. Contact Scientific Update, Wyvern Cottage, High St., Mayfield, East Sussex TN20 6AE, England, U.K.; phone 44 1435 873062, fax 44 1435 872734, e-mail: sciup@scientificupdate.co.uk.  June 7-8, ChemSpec Europe.Lyon, France. Contact DMG Business Media, 2 Queensway, Redhill, Surrey RH1 1QS, England, U.K.; phone 44 1737 855292, fax 44 1737 855469, e-mail: krivett@dmg.co.uk.  June 7-8, BACS Speciality Chemicals Conference. Lyon, France. Contact British Association for Chemical Specialities, The Gatehouse, Whitecross, Lancaster LA1 4XQ, England, U.K.; phone 44 1524 849606, fax 44 1524 849194, e-mail: cowan@bacsnet.org.  July 10-12, 3rd International Conference on Organic Process Research & Development USA 2000. Montreal. Contact Scientific Update.  July 13-14, Outsource USA 2000.Montreal. Contact Scientific Update. September 24-28, Chirality 2000, Chamonix, France http://www.ens-lyon.fr/STIM/iscd.html  Oct. 2-4, ChiraSource 2000. Lisbon, Portugal. Contact Catalyst Group, P.O. Box 637, Spring House, PA 19477; phone (215) 628-4447, fax (215) 628-2267, e-mail: cnf@catalystgrp.com.  Nov. 7-9, Conference on Pharmaceutical Ingredients. Milan, Italy. Contact Miller Freeman, P.O. Box 200, 3600 AE Maarssen, the Netherlands; phone 31 346 559444, fax 31 346 573811, e-mail: bvanleur@ unmf.com; or T&G Food Ingredient Services, 4220 Commercial Way, Glenview, IL 60025; phone (847) 635-9960, fax (847) 635-6801, e-mail:tgingred@ aol.com.

 
 
 

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