literature highlights in combinatorial science

Literature Highlightsin Combinatorial Science

Editor: A. Ganesan, Southampton, UK

Dear readers,

The journal QSAR and Combinatorial Science has an extensive section featuring abstracts ofQSAR-related publications edited by Ferenc Darvas. This is a great resource for quicklyscanning the literature and keeping up with latest developments. It is my intention to provide asimilar service for combinatorial science.For this first issue, I have personally abstracted combinatorial chemistry papers from thefollowing journals, primarily in the period of publication October-November 2004: Angew.Chem. Int. Ed., Bioorg. Med. Chem., Bioorg. Med. Chem. Lett., Chem. Commun., Chem. Eur. J.,Eur. J. Org. Chem., J. Am. Chem. Soc., J. Comb. Chem., J. Med. Chem., J. Org. Chem., Org.Biomol. Chem., Org. Lett., Synlett, Synthesis, Tetrahedron, Tetrahedron Lett. It has not been myintention to be comprehensive, and to some extent, the articles chosen reflect my own interests.I hope these are catholic enough that everyone will find value in the abstracts. To aid quickbrowsing, I have used a figure for each abstract, followed by a brief paragraph of text. These aremeant to whet your appetite, rather than give full details. For more information, please read theoriginal paper.As this is the first edition, I am sure this feature will continue to grow and evolve with time. Iwill be most grateful for any comments or suggestions for improvement. Meanwhile, happyreading!

A. GanesanSchool of ChemistryUniversity of Southampton, UK

QSAR Comb. Sci. 24 (2005) � 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 189

NEW

Highlights

1/2005

Title: Efficient synthesis of highly substituted diaryl etherson solid supports using the Ullmann reaction.

Authors: Knepper, K.; Lormann, M. E. P.; Br�se, S.*Friedrich-Wilhelms-Universit�t, GermanySource: J. Comb. Chem. 2004, 6, 460 – 463.

Significance: First solid-phase examples of Ullmann cou-pling with the triazene linker. Biaryl ether can be alternative-ly cleaved to the diazonium salt using TFA/CH2Cl2 in step 2.

2/2005

Title: Preparation of poly(ethylene glycol)sulfonamide:synthesis of N-supported b-aminoesters via the aza-Baylis-Hillman reaction.

Authors: Ribiere, P.; Enjalbal, C.; Aubagnac, J.-L.; Yadav-Bhatnager, N.; Martinez, J.; Lamaty, F.*

CNRS-Universites Montpellier, France.Source: J. Comb. Chem. 2004, 6, 464 – 467.

Significance: Aza-Baylis-Hillman reaction carried out witha soluble polymer equivalent of SES-sulfonamide. This ena-bled large reagent excesses to be used, and the product sepa-rated by filtration.

3/2005

Title: Two- and three dimensional combinatorial chemistryfrom multicomponent Grignard reagents.

Authors: B�low, A.; Sinning, S.; Wiborg, O.; Bols, M.*University of Aarhus, DenmarkSource: J. Comb. Chem. 2004, 6, 509 – 519.

Significance: A 125 member library prepared as 15 subli-braries of 25 compounds, each compound being representedthree times. Library screened for inhibition of uptake onmonoamine transporters.

4/2005

Title: Synthesis of substituted thienopyrimidine-4-ones.Authors: Ivachtchenko, A.*; Kovalenko, S.; Tkachenko, O.

V.; Parkhomenko, O.Chemical Diversity, USA.Source: J. Comb. Chem. 2004, 6, 573 – 583.

Significance: 3-Aminothiophene-2-carboxylate was usedto prepare large numbers (> 3,000) of fused heterocycles bysolution-phase parallel synthesis.

5/2005

Title: Automated flow-through synthesis of heterocyclicthioethers.

Authors: Jçnsson, D.; Warrington, B. H.; Ladlow, M.*GlaxoSmithKline, UK.Source: J. Comb. Chem. 2004, 6, 584 – 595.

Significance: Sulfur nucleophiles deprotonated by guani-dine resin, and released upon alkylation. Automated flow-through procedure developed to facilitate array synthesiswith resin regeneration. Method demonstrated by alkylationof four nucleophiles with 11 alkyl halides.

6/2005

Title: Relationship of stereochemical and skeletal diversityof small molecules to cellular measurement space.

Authors: Kim, Y.; Arai, M. A.; Arai, T.; Lamenzo, J. A.;Dean, E. F., III.; Patterson, N.; Clemons, P. A.;* Schreiber,S. L.*

Harvard University, USASource: J. Am. Chem. Soc. 2004, 126, 14740 – 14745.

Significance: Solid-phase synthesis employed with a set ofcarbohydrate scaffolds (one example shown) to produce a122-member library of monocyclic compounds. These werealso converted to a second library of macrobicyles by ring-closing metathesis. The two libraries were screened in 40 cell-

190 � 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim QSAR Comb. Sci. 24 (2005)

based assays. In the monocyclic library, carbohydrate ringstereochemistry was the dominant factor in determining ac-tivity, whereas macrocycle stereochemistry was important inthe bicycles, particularly in the selecvctivity of response seenwith active compounds.

7/2005

Title: A synthesis strategy yielding diverse small moleculescombinatorially.

Authors: Burke, M. D.; Berger, E. M.; Schreiber, S. L.*Harvard University, USASource: J. Am. Chem. Soc. 2004, 126, 14095 – 14104.

Significance: By split-pool synthesis using Still�s haloareneencoding technique, a library of 1260 furans was assembledon beads. The furans differed in two diversity elements, R1

and R2, while two sigma elements, s1 and s2, determine theproduct formed by the Achmatowicz reaction. Thus, the strat-egy enables access to a variety of skeletal types under a singlereaction condition, by variation of the sigma elements.

8/2005/

Title: Accelerated luminophore discovery through combi-natorial synthesis.

Authors: Lowry, M. S.; Hudson, W. R.; Pascal, R. A., Jr.;Bernhard, S.*

Princeton University, USASource: J. Am. Chem. Soc. 2004, 126, 14129 – 14135.

Significance: One hundred iridium(III) and ten rutheniu-m(II) complexes were prepared by parallel synthesis. The lu-minescent properties of the complexes could be determineddirectly from the crude reaction products without prior purifi-cation, and found to agree well with theorietical predictions.

9/2005

Title: Phagemid encoded small molecules for highthroughput screening of chemical libraries.

Authors: Yin, J.; Liu, F.; Schinke, M.; Daly, C.; Walsh,C. T.*

Harvard University, USASource: J. Am. Chem. Soc. 2004, 126, 13570 – 13571.

Significance: Small molecules were conjugated to coen-zyme A, and transferred to peptidyl carrier protein (PCP)displayed on M13 phage. The method uses Sfp phosphopanto-theinyl transferase, an enzyme with high substrate promiscui-ty, to attach the small molecule covalently to a serine residuein PCP. The resulting phage were screened for binding to tar-get proteins, and a single round of selection was often suffi-cient to yield 2000-fold enrichment of ligands with nanomolaraffinity.

10/2005

Title: In situ click chemistry: enzyme inhibitors made totheir own specifications.

Authors: Manetsch, R.; Krasinski, A.; Radic, Z.; Raushel,J.; Taylor, P.; Sharpless, K. B.; Kolb, H. C.*

Scripps Institute, USASource: J. Am. Chem. Soc. 2004, 126, 12809 – 12818.

Significance: Click chemistry was used to identify new in-hibitors of electric eel acetylcholinesterase. Fifty-two binarymixtures of azides and alkynes (one example is shown) wereincubated with the enzyme, potentially giving rise to 104products. The multicomponent mixtures were analyzed byLC-MS, and four potent inhibitors were discovered.

11/2005

Title: (1) Polymer supported palladium N-heterocyclic car-bene complexes: long lived recyclable catalysts for cross cou-pling reactions.

Authors: Steel, P. G.;* Teasdale, C. W. T.University of Durham, UKSource: Tetrahedron Lett. 2004, 45, 8977 – 8980.

12/2005

Title: (2) Environmentally benign synthesis of H-phos-phinic acids using a water-tolerant, recyclable polymer-sup-ported catalyst.

Authors: Deprele, S.; Montchamp, J.-L.Texas Christian University, USASource: Org. Lett. 2004, 6, 3805 – 3808.

13/2005

Title: (3) PS-PEG resin-supported palladium-MOP com-plexes. Application in asymmetric p-allylic reduction.

Authors: Hocke, H.; Uozomi, Y.*Institute for Molecular Science, JapanSource: Tetrahedron 2004, 60, 9297-9236.


Significance: (1) A polymer-supported palladium complexwith N-heterocyclic carbene ligands was prepared. In Suzukiand Heck cross-coupling reactions, the catalyst could be re-cyled more than 14 times without a drop in isolated productyield of more than 5%. (2) A polymer-supported moistureand airstable Pd complex was prepared from polystyrene res-in. The complex is an efficient catalyst for olefin hydrophos-phinylation, and can be recycled. (3) An asymmetric bi-naphthyl ligand was immobilized. The reagent was applied inasymmetric reduction of p-allyl Pd complexes in up to 80%ee with six recycles.

14/2005

Title: Chromium-mediated aldol and homoaldol reactionson solid support directed towards an iterative polyol strategy.

Authors: Wessjohann, L.;* Wild, H.; Schrekker, H. S.Leibniz-Institute of Plant Biochemistry, GermanySource: Tetrahedron Lett. 2004, 45, 9073 – 9078.

Significance: The chromium-mediated aldol reaction wasinvestigated on solid-phase. Either the bromide or aldehydewas immobilized, and a variety of resins/linkers were tried.Nevertheless, yields for the coupling reaction were modest.Possible reasons include the poor penetration of the chromi-um species into the polystyrene resin, and the sensitivity ofthe reaction to steric effects.

15/2005

Title: Preparation of quinolines from resin-bound estersusing titanium reagents.

Authors: Macleod, C.; Austin, C. A.; Hamprecht, D. W.;Hartley, R. C.*

University of Glasgow, UKSource: Tetrahedron Lett. 2004, 45, 8879 – 8882.

Significance: Titanium alkylidenes were prepared from or-tho-amino homobenzylic thioacetals, with the nitrogen pro-tected by the TMS and Boc groups. The titanium alkylidenereacted with resin-bound esters to give enol esters. Resincleavage gave ketones that cyclized to the dihydroquinoline,which was then oxidized with MnO2.

16/2005

Title: Thiol-mediated free radical cyclisations of isocya-nides on solid support.

Authors: Lamberto, M.; Corbett, D. F.; Kilburn, J. D.*University of Southampton, UKSource: Tetrahedron Lett. 2004, 45, 8541 – 8543.

Significance: Immobilized isocyanatoacetate was alkylatedwith allyl halides. Ethanethiol in the presence of AIBN theninitiated a radical cyclisation onto the isonitrile, followed byintramolecular cyclization onto an alkene. The method is suit-able for the solid-phase synthesis of substituted pyrogluta-mates.

17/2005

Title: (1) Solid-phase synthesis of isoquinolinones usingBischler-Napieralski cyclization.

Authors: Chern, M.-S.; Li, W.-R.*National Central University, TaiwanSource: Tetrahedron Lett. 2004, 45, 8323 – 8326.

18/2005

Title: (2) Traceless solid-phase synthesis of carbolinones.Authors: Chern, M.-S.; Shih, Y.-K.; Dewang, P. M.; Li, W.-

R.*Source: J. Comb. Chem. 2004, 6, 855 – 858.

Significance: (1) A set of phenethylamines was immobi-lized using the p-nitrophenyl carbonate linker. Compoundswith R4 ¼H could be further functionalized by alkylation onsolid-phase, while tyrosine-like building blocks with R4 ¼ es-ter were reduced to the alcohol, converted to the mesylated


and displaced by thiol nucleophiles. The final step was a cy-clative cleavage under Bischler-Napieralski conditions to pro-vide the isoquinolinones.

(2) Similar chemistry was employed with tryptamine andtryptophan derivatives to access the carbolinone skeleton af-ter Bischler-Napieralski reaction.

19/2005

Title: Solid-phase synthesis of 5-aminotetrazoles.Authors: Yu, Y.; Ostresh, J. M.; Houghten, R. A.*Torrey Pines Institute, USASource: Tetrahedron Lett. 2004, 45, 7787 – 7789.

Significance: An aldehyde resin was reductively alkylatedwith amines, followed by reaction with isothiocyanates togive the unsymmetrical thiourea precursor. Under activationby mercury (II), the thiourea reacted with azide anion andsubsequent cyclization produced the aminotetrazole.

20/2005

Title: A new approach for the solid-phase synthesis of pyr-rolo[2,1-c][1,4]benzodiazepines involving reductive cleavage.

Authors: Kamal, A.;* Reddy, K. L.; Devaiah, V.; Shankar-aiah, N.; Reddy, Y. N.

Indian Institute of Chemical Technology, IndiaSource: Tetrahedron Lett. 2004, 45, 7667 – 7669.

Significance: Precursors bearing an azidobenzamide moi-ety were readily prepared from a thiol linker. Treatment withtriphenylphosphine generated an iminophosphorane, whichunderwent Staudinger reaction with the aldehyde producedby DIBAL reduction to give the target compounds.

21/2005

Title: Development of a new traceless aniline linker forcombinatorial solid-phase parallel synthesis of rod-shaped liq-uid crystals with an azomethine linkage.

Authors: Hioki, H.; Fukutaka, M.; Takahashi, H.; Koda-ma, M.; Kubo, K.; Ideta, K.; Mori, A.*

Kyushu University, JapanSource: Tetrahedron Lett. 2004, 45, 7591 – 7594.

Significance: An amine linker was prepared starting fromaminomethyl SynPhase lanterns. This was condensed withmethyl 4-formyl benzoate, and the carboxylate further deriv-atized. Imine exchange with amines then resulted in releaseof the imine product, and a 28-member library was prepared.

22/2005

Title: (1) A novel solid-phase equivalent to the triflategroup and its application to traceless linking and cross-cou-pling-release strategies.

Authors: Cammidge, A. N.;* Ngaini, Z.University of East Anglia, UKSource: Chem. Commun. 2004, 1914 – 1915.

23/2005

Title: (2) A �Triflate-like� Tetrafluoroarylsulfonate Linkerfor Multifunctional Solid-phase Organic Synthesis.

Authors: J. D. Revell, A. Ganesan*University of Southampton, UKSource: Chem. Commun. 2004, 1916 – 1917.

Significance: A new �triflate�-like linker that is readily andinexpensively prepared from pentafluorobenzoic acid is de-scribed. Immobilized phenols are cleaved by Pd(0) to givethe arylpalladium intermediate, which can be hydrogenatedin a �traceless� fashion or used in cross-couplings e.g. Suzuki,Heck, Negishi. The method was applied to a solid-phase syn-thesis of the angiotensin receptor antagonist Valsartan.

24/2005

Title: Microarrays of tagged combinatorial triazine libra-ries in the discovery of small-molecule ligands of human IgG.

Authors: Uttamchandani, M.; Walsh, D. P.; Khersonsky,S. M.; Huang, X.; Yao, S. Q.;* Chang, Y.-T.*

National University of Singapore, Singapore and NewYork University, USA

Source: J. Comb. Chem. 2004, 6, 862 – 868.

Significance: A library of 2688 triazines was immobilizedas a microarray, and screened for binding to fluorescently la-belled human IgG. From the screening, four micromolar bind-ers were identified.


25/2005

Title: Combining Biginelli multicomponent and clickchemistry: Generation of 6-(1,2,3-triazol-1-yl)-dihydropyrimi-done libraries.

Authors: Khanetskyy, B.; Dallinger, D.; Kappe, C. O.*University Graz, AustriaSource: J. Comb. Chem. 2004, 6, 884 – 892.

Significance: This paper combines two powerful reactions,the Biginelli condensation and �click chemistry�. Dihydropyri-midines bearing a methyl group were prepared by the 3-com-ponent Biginelli condensation. A microwave assisted proce-dure was developed for bromination of the methyl group, anddisplacement by azide. The azides then underwent copper-catalyzed dipolar cycloaddition to the triazoles.

26/2005

Title: Traceless solid-phase synthesis of nitrogen-contain-ing heterocycles and their biological evaluations as inhibitorsof neuronal sodium channels.

Authors: Kong, K.-H.; Chen, Y.; Ma, X.; Chui, W. K.;Lam, Y.*

National University of Singapore, SingaporeSource: J. Comb. Chem. 2004, 6, 928 – 933.

Significance: Immobilized sulfone anions were reactedwith epoxides to give g-hydroxy sulfones, which were oxidisedto the y-ketosulfones. The latter underwent cleavage to vari-ous nitrogen heterocycles. For example, reaction with o-phe-nylenediamine gave benzodiazepines, one of which was a sub-millimolar inhibitor of neuronal sodium channels.

27/2005

Title: Solution-phase parallel synthesis of an N-alkylateddihydropteridinone library from fluorous amino acids.

Authors: Nagashima, T.; Zhang, W.*Fluorous Technologies, USASource: J. Comb. Chem. 2004, 6, 942 – 949.

Significance: Amino acid esters were prepared with a fluo-rous tag. A five-step procedure then led to the parallel syn-thesis of a dihydropteridine scaffold, with three diversity posi-tions. The fluorous tag facilitated purification of intermedi-ates and the final product.

28/2005

Title: Polystyrene-supported a-seleno carbanions: Effi-cient reagents for highly stereocontrolled syntheses of vinyl-phosphonates and vinylsulfones.

Authors: Xu, W. M.; Tang, E.; Huang, X.*Chinese Academy of Sciences, ChinaSource: Synthesis 2004, 2094 – 2098.

Significance: A polymer-supported selenide was alkylated.Hydrogen peroxide oxidative elimination provided the re-leased products, while the oxidized resin can be reduced andrecycled.

29/2005

Title: Efficient solid-phase synthesis of disubstituted 1,3-dihydro-imidazol-2-ones.

Authors: Rosse, G.;* Strickler, J.; Patek, M.Aventis, USASource: Synlett 2004, 2167 – 2168.

Significance: A bromoacetal linker was used in the syn-thesis of imidazolones. The bromide was displaced by primaryamines, and the intermediate reacted with isocyanates. Acidiccleavage produced an N-acyliminium ion that underwent cyc-lization to the heterocycle.

30/2005

Title: Solid phase synthesis of triazadibenzoazulenone.Authors: Saha, B.; Srivastava, G. K.; Kundu, B.*Central Drug Research Institute, IndiaSource: Synlett 2004, 2242 – 2244.

Significance: Immobilized phenylene diamine derivativeswere condensed with o-nitrobenzaldehydes. Subbsequent re-duction of the nitro group and acidic cleavage resulted in cyc-lization to the unusual triazadibenzoazulenone scaffold ingood yields.


31/2005

Title: Facile synthesis of @-tide b-strand peptidomimetics:improved assembly in solution and on solid phase.

Authors: Phillips, S. T.; Piersanti, G.; R�th, M.; Guberna-tor, N.; van Lengerich, B.; Bartlett, P. A.*

University of California-Berkeley, USA.Source: Org. Lett. 2004, 6, 4483 – 4485.

Significance: The Bartlett group has previously reportedon the �@-tide b-strand� peptidomimetic scaffold. This paperdescribes the synthesis of Fmoc protected monomers, thatcan be homologated using standard Fmoc solid-phase syn-thesis conditions. Oligomers containing up to 13 -@tide unitswere prepared.

32/2005

Title: Polymer-supported Mukaiyama reagent: a usefulcoupling reagent for the synthesis of esters and amides.

Authors: Crosignani, S.; Gonzalez, J.; Swinnen, D.*Serono, SwitzerlandSource: Org. Lett. 2004, 6, 4579 – 4582.

Significance: A straightforward and reliable preparationof a polymer-supported version of Mukaiyama�s reagent. Theresin was used to activate carboxylic acids for conversion toesters and amides.

33/2005

Title: N-H insertion reactions of Boc-amino acid amides:solution- and solid-phase synthesis of pyrazinones and pyra-zines.

Authors: Matsushita, H.; Lee, S.-H.; Yoshida, K.; Clap-ham, B.; Koch, G.; Zimmermann, J.; Janda, K. D.*

Scripps Institute, USASource: Org. Lett. 2004, 6, 4627 – 4629.

Significance: A set of a-diazo-b-keto esters was preparedon solid-phase. Rhodium-catalyzed carbenoid generation andinsertion into the N�H bonds of amino acid amides followedby acidic cleavage of the Boc group and cyclization yieldedthe pyrazinone scaffold, which can be further modified beforecleavage.

34/2005

Title: Stereochemical control of the Passerini reaction.Authors: Andreana, P. R.; Liu, C. C.; Schreiber, S. L.*Source: Org. Lett. 2004, 6, 4231 – 4233.

Significance: Despite the popularity of the Passerini andUgi multicomponent reactions, stereoselective versions arerare. Schreiber demonstrates that Cu-pybox ligands are effec-tive catalysts for enantioselective Passerini reactions, provid-ed the aldehyde is capable of bidentate chelation. In the ex-ample shown, an ensuing Diels-Alder reaction results in a tri-cyclic skeleton.

35/2005

Title: Solid-phase combinatorial synthesis of peptide-bi-phenyl hybrids as calpain inhibitors.

Authors: Montero, A.; Albericio, F.;* Royo, M.;* Herra-don, B.

University of Barcelona, SpainSource: Org. Lett. 2004, 6, 4089 – 4092.

Significance: Reaction of a biphenyl anhydride with an im-mobilized peptide enabled the incorporation of a biphenyl-peptide hybride. Further elaboration of the free acid led tonanomolar inhibitors of calpain.

36/2005

Title: High-load, soluble oligomeric carbodiimide: syn-thesis and application in coupling reactions.

Authors: Zhang, M.; Vedantham, P.; Flynn, D. L.;* Han-son, P. R.*

University of Kansas, USASource: J. Org. Chem. 2004, 69, 8340 – 8344.

Significance: A soluble oligomeric carbodiimide was pre-pared by ring opening metathesis polymerization. The re-agent is an effective carboxylic acid activator, and its usedemonstrated for the synthesis of amides, esters, and anhy-drides.


37/2005

Title: Combinatorial approach to the asymmetric hydroge-nation of b-acylamino acrylates: use of mixtures of chiralmonodentate P-ligands.

Authors: Reetz, M. T.;* Li, X.Max-Planck Institut, Mulheim, GermanySource: Tetrahedron, 2004, 60, 9709 – 9714.

Significance: A set of chiral monodentate phosphites andphosphonites was evaluated in the Rh(I) catalyzed hydroge-nation of b-acetamidoacrylates. In each experiment, two li-gands was employed, leading to the simultaneous formationof homo- and hetero-combinations. Cases where the hetero-combination gives higher ee than the homo-combinationwere identified, and R1 ¼ me and R2 ¼ cyclohexyl was foundto be particularly effective.


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