SCIENCE & TECHNOLOGY F R O M T H E ACS
76 to 8 6 % enantiomeric excess (ee), depending on conditions. The investiga tors ascribe the asymmetric amplification to differential reactivity or degradation of brucine derivatives. The excesses are not yet high enough in these specific reactions to be commercially useful, but they illus trate the potential for the technology with further optimization.
MEETING
ADVANCING SYNTHETIC ORGANIC CHEMISTRY Scaffold molecules and multicomponent reactions figure prominently S T E P H E N C. S T I N S O N , C & E N N O R T H E A S T NEWS B U R E A U
DVANCES IN SYNTHETIC METHods especially crafted toward combinatorial chem istry, such as new scaffold mol ecules and multicomponent reactions, seemed particularly prominent at Division of Organic Chemistry sym posia at the American Chemical Society national meeting in San Diego earlier this month. And even the more customary types of organic reagents, building blocks, and catalytic processes described in San Diego could play a role in the synthesis of libraries to be screened for new drugs, pes ticides, catalysts, and functional materials. For example, graduate student Antonella Converso of Scripps Research Insti tute described a three-dimensional chiral scaffold molecule. Among multicompo nent reactions, Senior Scientist Vincent J. Huber ofMolecumetics in Bellevue, Wash., reported a solid-state version of the clas sical Passerini three-component reaction. And graduate students Zubin D. Patel and Xin Yao were among those from the research group of chemistry professor Nicos A. Petasis at the University of South ern California (USC) who brought word of the latest progress in Petasis' own threecomponent reaction. Scaffolds are core molecules that hold the groups attached to them in particular orientations in space. Early scaffolds were such nuclei as triazines, which have three positions free for attachment of other groupings. But triazines are planar, 2-D molecules, while biological receptors for drug molecules are 3-D spaces. And tri azines are achiral, which means that other sources of chirality must be attached to explore stereoselective interactions with receptors. Converso—working with organic chem istry professors K. Barry Sharpless and M. G. Finn at Scripps; research associate Kristina Burow, now at the Novartis Insti tute for Functional Genomics, San Diego; and research chemist Andreas L. Marzinzik, now at Novartis Pharma, Basel—
A
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investigated the adduct of 1,5-cyclooctadiene with sulfur dichloride as a chiral scaf fold for combinatorial synthesis. As found by others 30 years ago, the product of that reaction is chiral 2,6-endo-as-aic\uoTO-9thiabicyclo{3.3. l}nonane. The Scripps team finds that this com pound reacts with amines, sulfonamides, alkoxides, halides, and azide, replacing both chlorine atoms. Because of neighboringgroup assistance from sulfur, substitution occurs in 95% yield and with retention of the endo-cis geometry Single enantiomers of the dichloro compound react with reten tion of configuration. The Scripps team members resolve the dichloro, diazido, and diisopropoxy deriv atives by asymmetric high-performance liquid chromatography They also treat the dichloro compound with (-)-brucine to get a 75% diastereoisomeric excess of one iso mer. That mixture reacts with sodium azide to give diazido compounds ranging from
THE MULTICOMPONENT reaction ad apted to the solid state by Huber of Mol ecumetics was discovered in 1921 by medicinal chemistry professor Mario Passerini at the University of Florence, Italy, when he was a research assistant there. In the original reaction, an isonitrile ( R - N = C : ) reacts with an aldehyde or ketone and a carboxylic acid to produce the carboxylate ester of an a-hydroxyamide. Working with Molecumetics Senior Scientists Gangadhar Nagula and Burton A. Goodman and group leader Christo pher Lum, Huber fashions an isonitrile group from the free amino group of L-leucyl-L-valine, attached at its carboxyl end to cross-linked polystyrene resin. Reac tion with cyanomethyl formate converts the amino group to a formamide. Dehy dration of the formamide with phospho rus oxychloride gives the isonitrile group. The Bellevue workers next carry out the Passerini reaction on the isonitrile with protected D-a-aminobutyraldehyde and trifluoroacetic acid. In the classical Passerini, the product would be a trifluo-
MULTICOMPONENTS Methodology for solid-state Passerini reaction developed CH3 HC: H3C Fmoc v
H .C/N.
"\
n,L
CH, ^OCHoCN
H3C
,/N.
0=CH-
Resin
"\ / \
LH,
Resin
CH,
POCL RoN
Resin = functionalized cross-linked polystyrene Fmoc = 9-f luorenylmethyloxycarbonyl R3N = et hyldi iso propylamine D-Abu-al = D-a-aminobutyraldehyde
CH, H
:c=N" Fmoc-D-Abu-al CF3C02H
CH,
H3C
Resin H3U
^Ηβ
CH 3
Fmoc
OH
H
ii "χ
"\
Resin
CH,
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SCIENCE & TECHNOLOGY roacetate ester. Under conditions used at Molecumetics, the ester linkage does not survive, and the product is the amide of the leucine amino group with a-hydroxy^-aminovaleric acid. In further work, the amino group of the valeric acid unit is available for another Passerini reaction. And the α-hydroxyl group can be oxidized to a keto group. Indeed, the Molecumetics team members demonstrate this aspect of their technique by solid-state syn thesis of the pentapeptide natural prod uct poststatin, which contains the nonnatural β-amino-a-ketovaleric acid. The three-component reaction currendy being mined by the Petasis group at USC is that of aldehydes, amines, and boronic acids. In San Diego, Patel described applications to syntheses of amino sugars, while Yao reported on products that mimic peptides. In the amino sugar work with Peta sis and graduate student Ilia A. Zavialov, Patel uses D-arabinose as the aldehyde, as well as diallylamine and βstyreneboronic acid. The amine forms an adduct with the aldehyde carbonyl group, and the adduct adds the β-styrenyl group. A reduction step removes the allyl groups, leaving the free amine. Reductive ozonolysis of the β-styrenyl double bond generates an aldehyde car bonyl, and the final product yielded is D-mannosamine.
CHIRAL SCAFFOLD Ring system offers stereochemical control
ALDEHYDE SYNTHESIS I s o m e r i z a t i o n of a l l y l alcohols . . . CH(CH 3 ) 2
hUCO'
Rh(l]
Asymmetric catalyst
CH(CH 3 ) 2
H3ccr ^ ^
CH=O
87% yield, 82% enantiomeric excess . . . o r h y d r a t i o n of a c e t y l e n e s (CH3]3C — C = CH J ό
M - * Ru(l)
(CH3]3C —CHCHO ό ό
M^
fYl I
III
Ru(l) W P..ill
THO
CH
For the synthesis of peptidomimetics with Petasis, YSLO uses amides of glyoxylic acid (OCHCONHR) as aldehyde starting materials. For example, to make N-benzylglyoxamide starting material, he forms the amide of benzylamine with β,β-dimethykcryHc acid, ( C H ^ C H = C H C 0 2 H , and subjects that to reductive ozonolysis. Alternatively, he forms the diamide of ben zylamine with tartaric acid and cleaves that with periodic acid. IN PEPTIDOMIMETICproduction,iVben
SCL
NaNL
CI
\NH3.H20
5
S
NH ?
I NHo
zylglyoxamide forms an adduct with dibenzylamine, which reacts with β-styreneboronic acid to generate a β-styrylglycinamide. Hydrogénation of that both saturates the carbon-carbon double bond and removes the benzyl groups from the amine. The amine is thus freed up to make a new glyoxamide by the tartaric acid amide method. The new glyoxamide reacts with more dibenzylamine and/>-anisoleboronic acid to give a />-anisylglycyl homophenylalanine. Hydrogénation again generates a free amino group for yet further addition of amino acid units. The Petasis group is concerned with generating new aldehyde groups to graft
onto their amino acid chains, sometimes using periodic acid as a reagent. But the use of stoichiometric periodic acid as an oxidizing agent has been criticized because of the cost. However, chemists from DSM Fine Chemicals in Linz, Austria, came to San Diego to show how their company's iodine recycling technology makes commercial periodate oxidations feasible. Project Manager Peter Poechlauer described work with scientists Jose Padron and Sabine Boutemmy and technician Lizette Schmieder to develop a chromium(VI)-catalyzed oxidation of primary alcohols by periodate. Periodate is reduced to iodate, which the company recovers as periodate. As Poechlauer put it: "The method is suitable for the oxidation of some classes of alcohols that are difficult to oxidize selectively by other methods. Especially, alcohol groups in polyfunctional compounds can be selectively oxidized without the necessity of prior protection of additional functional groups." In particular, he said, 'A variety of amino alcohols can be oxidized to the corresponding amino acids without protecting the amino function." As a model reaction, Poechlauer described the optimization of the oxidation of 3-heptyn-l-ol to the acid. But, he added, "by a proper choice of the reaction conditions, oxidation of primary alcohols can be directed toward either the carboxylic acid or the aldehyde as the main product." In addition to the DSM work on oxidation of primary alcohols to aldehydes, other chemists came to San Diego to present aldehyde syntheses based on oxidation of primary alcohols, isomerization of allyl alcohols, or hydration of acetylenes. For example, graduate student J. Jacob R. Strouse of New Mexico State University, Las Cruces, described rhenium-mediated oxidation of primary alcohols by dimethyl sulfoxide (DMSO). And graduate student Minghua Liu told of applying polymer-supported rhenium to the same reaction. Other workers on the Las Cruces team are chemistry and biochemistry professor Jeffrey B. Arterburn, inorganic chemistry professor Michael D.Johnson, and graduate student Marc C. Perry Strouse uses an oxorhenium complex with a small amount of 4-ter£-butylcate-
ACS meeting attendees learned of new applications of multicomponent reactions and of scaffold molecules. 36
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SCIENCE & TECHNOLOGY chol to catalyze oxidation of lauryl alcohol to lauraldehyde in 87% yield and oïpnitrobenzyl alcohol to the aldehyde in 97% yield. The system oxidizes secondary alcohols to ketones. Secondary alcohols react preferentially with respect to primary alcohols. So oxidation of 2,2,4-trimethyl-l,3pentanediol yields 88% of 3-oxo-2,2,4trimethylpentanol. For the polymer-supported version, the rhenium complex is bound to a catechol in the form of 3,4-dihydroxyphenylethylamine, which in turn is linked to carboxylated cross-linked polystyrene by an amide bond. Liu finds the same pattern of reactivity of primary and secondary alcohols as for the homogeneous version. In addition, he removes the catalyst from the reaction mixture by filtration of the resin. In the isomerization of allylic alcohols to aldehydes, postdoctoral fellow Ken Tanaka of Massachusetts Institute of Technology described catalysis by a rhodium(I)
chelate with an asymmetric ferrocenephosphine ligand. Working with organic chemistry professor Gregory C. Fu, M I T graduate students Shuang Qiao and Michael M. Lo, and visiting graduate student MamoruTobisu from Osaka University Tanaka treats Z-3-(4-methoxyphenyl)4-methyl-2-penten-l-ol with the rhodium chelate. The product is 87% of (5)-3-(4methoxyphenyl)-4-methylpentanal in 82% ee. Also, associate professor Douglas Grotjahn of San Diego State University reported hydration of terminal acetylenes to aldehydes, catalyzed by a ruthenocene-phosphinoimidazole complex. Working with inorganic chemistry professor Arnold L. Rheingold and graduate student Christopher D. Incarvito, both at the University of Delaware, Grotjahn converts tert-butyiacetylene to 3,3-dimethylbutanal in 91% yield and propargyl tetrahydropyranyl ether to 86% of 3-tetrahydropyranyl-
THREE COMPONENTS Boronic acids make sugars .
+ (Η2 = C = CHCH ) NH
1 JL
2
°
2 2
+ C6H5CH = C H — B(0H) 2
OH D-Arabinose OH
N(CH 2 CH=:CH 2 ) 2
OH
NHBoc
UH]
HO^TY^^C6H5 OH OH CH 2 0H —1-^
H0"" - B(0H],
(C6H5CH2)2NH
N(CH 2 C 6 H 5 ) 2 H
*
W
H
^ OCHo
Boc = ferf-butoxycarbonyl CAHC
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oxypropanal. And only vanishingly small amounts of ketone by-products are produced. Beyond fashioning scaffolds for erection of library molecules and setting the stage for multicomponent reactions, chemists reported on new reactions, reagents, and catalysts in San Diego. Two such reactions are potentially commercial epoxidation of olefins and conversion of epoxides to derivatives. Graduate student Benjamin S. Lane of Texas A&M University brought word of an inexpensive, catalytic, environmentally friendly epoxidation of olefins that is capable of being scaled up to commercial volumes {J.Am. Chem. Soc, 123,2933 (2001)}. And researcher Angela Dibenedetto of the University of Bari, Italy, described conversion of epoxides to carbonates using carbon dioxide rather than phosgene. Working with Texas A & M organic chemistry professor Kevin Burgess, Lane found that the best conditions for olefin epoxidation are slow addition of 10 equivalents of sodium bicarbonate-buffered 30% hydrogen peroxide to a dimethylformamide or tert-buty\ alcohol solution of the olefin containing 1 mole-% of manganese sulfate catalyst. A 92% yield results from toww-stilbene despite known solubility problems. T h e cyclobutane ring of α-pinene, the aldehyde group of citral, and the terminal double bond of linalool go unmolested. Dibenedetto collaborated with chem istry professor Michèle Aresta at Bari to perfect the niobium(V) oxide-catalyzed carbonation of epoxides. In addition to achiral epoxides like those made at Texas A&M, the Bari workers get retention of configuration when converting enantiomeric epoxides to carbonates. Dibenedetto and Aresta convert (R)-(-)styrene oxide to 80% yield of 4-phenyll,3-dioxolan-2-one in 100% ee and (R)propylene oxide to 77% of 4-methyl-l,3dioxolan-2-one in greater than 99% ee at 135 °C and 725 psi of carbon dioxide pressure. Among reagents featured in San Diego was bismuth(III) nitrate with clay or silica gel. Postdoctoral fellow Susanta Samajdar presented progress with nitration, deprotection, and oxidation in the group of molecular pathology professor Bimal K. Banik at the University of Texas, Houston. Working with Banik and molecular pathology professor Frederick F. Becker, Samajdar finds that a nitrate-clay slurry in tetrahydrofuran (THF) nitrates highly reactive aromatic compounds regioselectively in 10 to 15 minutes at room temperHTTP://PUBS.ACS.ORG/CEN
ature, without the need for strong acids or acetic anhydride. Naphthalene gives 100% of 1-nitro compound; anisole, 9 1 % of p-mtro compound; and 2-naphthol, 76% of 1,6-dinitro compound. Phenol gives 89% of mixed o- and/?-nitrophenols, while estrone gives 9 4 % of 1- and 3-nitro derivatives. A nitrate-silica gel slurry in refluxing T H F reconverts oximes and hydrazones to their ketones. Acetophenone oxime yields 89% of ketone after five hours, while the hydrazone gives 92% after 50 minutes. A nitrate-clay slurry in T H F also oxidizes secondary alcohols to ketones in two to seven minutes at room temperature. α-Phenethyl alcohol yields 89% of ace tophenone in two minutes, while 2-heptanol yields 91% of ketone in five minutes. AN OFFBEAT oxidizing agent for second ary alcohols is chromium dioxide. Usually used to coat magnetic tapes, chromium dioxide also can give 90% yields of ketones in refluxing benzene. According to organic chemistry professor Edward J. Parish and graduate student Ding Lu ofAuburn Uni versity, 3-a- and 3 ^ - c h o l e s t a n o l give cholestanone. Cholesterol also gives ketone, but with the 5,6-double bond moved to the 4,5-position. Among new catalysts to get attention in San Diego were DuPont's Nafion and an asymmetric nonmetallic catalyst for 1,3dipolar additions. Nafion is a perfluorinated resin decorated with pendant perfluorinated oxypropoxyethanesulfonic acid groups. The tetrafluoroethanesulfonic acid function is a strong acid similar to trifluoromethanesulfonic acid. USC postdoctoral fellow Thomas Matthew described Nafion's use in medi ating sulfonylation of aromatics to form sulfoxides. Working with organic chem istry professors George A. Olah and G. K. Surya Prakash, Matthew treats excess pxylene with benzenesulfonic or/)-toluenesulfonic acid and Nafion to get about 80% yield of 3,6-dimethyldiphenyl sulfone or 3,6,4-trimethyldiphenyl sulfone. Benzene and toluene give much lower yields of sulfones, and methanesulfonic acid gives only 30% in the sulfonation of/?-xylene to methyl 2,5-dimethylphenyl sulfone. The aromatic sulfonylation done by the USC group was one of many advances reported in San Diego. In addition in other reactions and reagents, attendees learned of new applications of multicomponent reactions and scaffold molecules, all of which may find use in the discovery and commercial production of drugs, pesti cides, and other active compounds. • HTTP://PUBS.ACS.ORG/CEN
CATALYZERS The Scripps team includes Janda (seated) and (from left) Ashley, Paul Wentworth Jr.p and Anita D. Wentworth.
ALTERNATE ROUTE FOR ENEDIYNE CYCLIZATION Catalyst for Bergman cyclization suggests a novel mechanism of anticancer action STU B0RMAN P C&EN WASHINGTON
T
HE DISCOVERY OF A CATALYTIC
antibody that accelerates the cyclization of enediyne com pounds to form an unexpected product has led to a controver sial new proposal for the mechanism by which enediyne antibiotic and anticancer agents damage DNA. The discovery extends the potential applicability of antibody catalysis to a new class of substrates and reactions that have not previously been included in the cat alytic antibody repertoire. Enediynes are organic compounds that contain an enediyne group—a pair of dou ble-bonded carbon atoms flanked by two sets of triple-bonded carbons. Enediyne natural products such as esperamicin, dynemicin, calicheamicin, and neocarzinostatin chromophore have been inten sively studied by numerous research groups because of their potent biological activity and intriguing mode of action. The mechanism has been thought to involve cleavage of D N A by a powerful diradical intermediate that forms in the initial step of a reaction in which enediynes are converted into cyclic aromatic com pounds. This is called the Bergman cycliza
tion reaction, after its discoverer, chem istry professor Robert G. Bergman of the University of California, Berkeley. The mode of action of enediynes has been thought to involve cleavage of D N A mol ecules by the highly reactive diradical intermediate generated in the reaction. In an effort to find catalysts with the ability to activate enediyne drugs in vivo, a research group has now designed and syn thesized a catalytic antibody that acceler ates the Bergman cyclization of an enediynol substrate. The work was carried out by assistant professor Paul'Wfentworth Jr., President Richard A. Lerner, professor Kim DJanda, and coworkers Lyn H. Jones, Curtis W Harwig, Anton Simeonov, Anita D. Wentworth, Sandrine Py, and Jon A. Ashley of Scripps Research Institute [J. Am. Chem. Soc, 123,3607 (2001)}. The Scripps researchers found, surpris ingly that the antibody-catalyzed Bergman cyclization of the enediynol produces a quinone product in aqueous buffer, instead of the aromatic compound they had expected to see. Such a finding is not entirely unprecedented. Two groups had earlier found examples of the chemical con version of enediynes to quinones. And proC&EN
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