resumen ponencias...miguel a yus dep química orgánica, facultad de ciencias, universidad de...

RESUMEN PONENCIAS

Euroforum Infantes. El Escorial, Madrid 15 y 16 de Abril, 2005

new frontiersnuevas fronteras

in organic synthesisen síntesis orgánica

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NEW FRONTIERS IN ORGANIC SYNTHESIS

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Viernes / Friday 15

08:15 Acreditaciones

08:45Opening and Welcome addressesAuthorities

➢ Why this symposium

Session 1Moderador/Chairperson: Jesús Ezquerra

Lilly Research Laboratories. Alcobendas, Madrid, Spain

09:00Manfred T ReetzMax-Planck-Institut fur Kohlenforschung. Mülheim an der Ruhr, Germany

➢ Directed Evolution of Enantioselective Enzymes

10:00Barbara Imperiali

Department of Chemistry, Massachusetts Institute of Technology. USA➢ Chemical Tools for the Study of Complex Biological Systems

11:00 Café

11:30Carlos F Barbas IIIThe Skaggs Institute for Chemical Biology, The Scripps Research Institute, CA, USA

➢ From Catalytic Antibodies to Organocatalysis

12:30James E Audia

Discovery Chemistry Research & Technologies, Lilly Research Laboratories. Indianapolis, USA➢ Pharma Productivity

13:30 Almuerzo

Session 2Moderador/Chairperson: Julio Alvarez Builla

Dpto Química Orgánica, Facultad de Farmacia, Univ Alcalá deHenares, Spain

15:00Tom WeltonDepartment of Chemistry, Imperial College London, South Kensington Campus. London, UK

➢ Ionic liquids as Solvents for Synthesis

16:00William R RoushDepartment of Chemistry, University of Michigan, USA

➢ New synthetic methods of biologically active natural products

17:00Miguel A YusDep Química Orgánica, Facultad de Ciencias, Universidad de Alicante. Alicante, Spain

➢ New methodologies based on an arene-catalyzed lithiation

Chairmen:Julio Álvarez-BuillaFernando Albericio

Jesús EzquerraEUROFORUM INFANTES. EL ESCORIAL, MADRID April 15 & 16th, 2005

Programme

ponencias2 7/7/05 11:58 Página 1

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Sábado/Saturday 16

Session 3Moderador/Chairperson: Rafael Ferrito

Lilly Research Laboratories. Alcobendas, Madrid, Spain

08:45

Takashi TakahashiDept Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute ofTechnology. Tokyo, Japan

➢ Solid- and Solution-Phase Synthesis of Natural Products Libraries

09:40

Claudio Palomo NicolauDpto Química Orgánica, Facultad de Química, Universidad del País Vasco. San Sebastián, Spain

➢ Chiral Auxiliaries-Assisted Reactions:Inspiration for Developing CatalyticEnantioselective Processes

10:35 Café

11:00C Oliver KappeDepartment of Chemistry, University of Graz. Graz, Austria

➢ Microwaves in organic synthesis

11:55

Round table: Retos para la I+D en España: el caso de la Química MédicaModerador/Chairperson: José A Gutiérrez Fuentes

Fundación Lilly, Spain➢ Robert W Armstrong. Lilly Research Laboratories. Indianapolis, USA➢ Miquel A Pericàs. Instituto Catalán de Investigación Química. Tarragona, Spain➢ Carlos Martínez Alonso. Consejo Superior de Investigaciones Científicas, Spain➢ Jorge Martín Juárez. Crystal Pharma / Ragactives, S.A. Valladolid, Spain➢ Nazario Martín. Real Sociedad Española de Química, Spain

13:00

Closure LectureModerador/Chairperson: Julio Alvarez BuillaJavier de MendozaInstitute of Chemical Research of Catalonia (ICIQ). Tarragona, Spain➢ Self-assembly: a bio-inspired approach to chemical complexity

13:50Closure / FarewellJulio Alvarez Builla, Fernando Albericio, Jesús Ezquerra, José A Gutiérrez Fuentes

PROMOTOR PATROCINIO

Fundación Lilly Fundación Lilly

COMITÉ CIENTÍFICO ORGANIZADOR LUGAR DE CELEBRACIÓN

Julio Alvarez Builla Fernando AlbericioJesús Ezquerra José A Gutiérrez Fuentes

Euroforum InfantesSan Lorenzo de El Escorial. Madrid

MODERADORES y CONFERENCIANTES

MT Reetz (G)B Imperiali (USA)

J Audia (USA)C Barbas III (USA)

T Welton (UK)WR Roush (USA)

MA Yus (Sp)

JM Villalgordo (Sp)J Pastor (Sp)R Ferrito (Sp)A Molins (Sp)

T Takahashi (Jp)C Palomo (Sp)CO Kappe (Au)

R Armstrong (USA)MA Pericàs(Sp)C Martínez (Sp)

J Martín Juárez (Sp)J Candil (Sp)N. Martín (Sp)

J de Mendoza (Sp)

18:30

Round table: High Throughput SynthesisModerador/Chairperson: Fernando Albericio

Barcelona Biomedical Research Institute. Univ of Barcelona, Spain➢ José Manuel Villalgordo. VillaPharma Research S.L. Spain (Moléculas pequeñas)➢ Joaquín Pastor. Janssen-Cilag. Spain (Diversidad en síntesis)➢ Rafael Ferrito. Lilly, S.A. Spain (Automatización en síntesis)➢ Antoni Molins. Almirall-Prodesfarma. Soain (Quimioinformática)

Viernes / Friday 15


Inventing and developing a new drug is along, complex, costly and risky processthat has few peers in the industry world.

Historically, as its today, creation of a newdrug rides much –although not only- over thewave of new synthetic technologies. The newsynthetic methods, by which scientists cancreate increasingly complex molecules, areoften in the basis of the new, and more effi-cient molecular entities recently developed. Inaddition, present miniaturization and automa-tion of testing techniques is producing a par-allel effort in improvement of synthetic effi-ciency. Moreover, our increasingly sophisti-cated chemical tools are opening ways tostudy complex biological –and hence pharmacological- process-es in a molecular way. All that approaches are expanding ourknowledge in medicinal chemistry, and in the end are allowingthe development of new and more efficient therapies, whichserve all human beings.

The seventh Lilly Scientific Symposium “New Frontiers inOrganic Synthesis” had tried to mix scientists with differentviews and cultures in their approach to creation of new mole-cules. From the use of enzymes and antibodies as catalysts, theuse of chemical tools to study complex biological systems, to theuse of new technologies as ionic liquids or synthesis withmicrowaves. From the use of new approaches to the synthesis ofnatural products, or the use of parallel synthesis to develop prod-uct libraries, to the use of new lithiation methods or new chiralauxiliaries. From the use of self-assembly to develop complexchemicals, to new concepts on Pharma productivity. In all thoselectures always an equilibrium have been present between twophilosophies: one takes in nature its inspiration, while the otheruses new tools which technology is putting in our hands, and inour labs, to improve our synthetic efficiency. We hope this inti-mate mixture, had created an inspiring atmosphere useful to allparticipants in the Symposium.

_______________________

A paradigm encompassing synthetic strategies, and often incor-porating the use of solid-phase, was reported by Takahashi(Tokyo Institute of Technology). Takahashi’s group prepared alibrary of 122 derivatives of the anti-tumor compoundmacrosphelide A using a method similar to split and mix, inwhich a radio frequency chip is employed to facilitate compound

separation. Furthermore, the group prepareda library based on the anti-tumor antigensphingolipid Lewis X using a solution/solid-phase hybrid strategy. Finally, the grouppresented the automated total synthesis ofTaxol by the robot ChemKonzert.

The use of specially adapted microwaveovens for chemical synthesis was firstreported by Kappe of the University of Graz.This method of transmitting energy can beapplied to reactions in solution or on solid-phase, whether the resin serves as protectinggroup or reagent support. Microwave reac-

tors are highly recommended for heterocycle synthesis and reac-tions involving transition metal catalysts or transpositions, andhave recently been applied in peptide synthesis. Modern auto-mated microwave ovens allow the successive treatment of alarge number of reactions or can be used for work on a medium-scale. This technology improves yields and shortens reactiontimes, in many cases from hours to minutes. Lastly, microwavetechnology can be considered a green method, as it can be usedto drive certain reactions in the absence of solvent.

Another example of green chemistry is the use of ionic liquids insynthesis and catalysis, described by Welton of the ImperialCollege. Owing to their highly reduced vapor pressure, thesesolvents can be used to manipulate chemical reactions by modi-fying factors such as reaction rate and selectivity.

Several new compounds in pharmaceutical development havechiral centers, hence strict synthetic control over stereochemistryis crucial. This area was tackled from different angles byProfessors Reetz, of the Max Planck Institut, Barbas, of theScripps Research Institute, and Palomo, of the Universidad delPais Vasco. While Palomo focused on the use of chiral auxil-iaries, Reetz and Barbas emphasized more bioorganic strategies,including enantioselective enzymes, catalytic antibodies andamino acids such as proline.

Yus, of the University of Alicante, presented novel methodologyfor a series of new arene-catalyzed lithiations. The presentationgiven by Roush from the Scripps Research Institute of Floridabasically encompassed all of the new strategies outlined by the

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Julio Alvarez-Builla G.Department of Organic Chemistry

Universidad de Alcalá, Madrid, [email protected]

Fernando AlbericioDept. Química Orgánica. Facultat de Química.

Universitat de Barcelona Barcelona, Spain. [email protected]

Jesús EzquerraLilly Research Laboratories. Alcobendas. Madrid. Spain


other speakers. His talk highlighted the use of new techniques inthe synthesis of structurally complex, biologically active naturalproducts, such as 13-deoxytedanolide, amphidinol 3 and theamphidinolides C, E and F.

Presentations by Imperiali, of the Massachussets Institute ofTechnology, and Mendoza, of the Institut Català d’InvestigacióQuímica, leaned more towards biochemistry. These talks com-prised the use of chemical probes to study phosphorylation reac-tions, and molecular self-assembly as an alternative method forconstructing supramolecular structures.

Audia, from Lilly Research Laboratories in Indianapolis, summa-rized the challenges currently facing pharmaceutical companies

and proposed solutions to overcome them. According to Audia,these solutions can only stem from an interdisciplinary and mul-tifaceted research philosophy that is well-rooted in knowledge,and in which properties such as activity and ADME-tox are stud-ied at the earliest stages of a compound’s development. In clos-ing his talk, he stressed that the changes occurring in moderndrug development will yield opportunities on personal as well ascommercial levels. Companies, which are now seeking profes-sionals with more interdisciplinary backgrounds, are being forced to externalize operations inorder to gain access to cutting edge technology. Small compa-nies and academic groups must capitalize on this phenomenonif they are to play a more active role in the fascinating worldof drug discovery.

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In 1991, Richard A. Houghten and Kit S.Lam published the first two articles in thefield of combinatorial chemistry, which

takes it name from the corresponding term inmathematics. These authors described theconcurrent synthesis of a multitude, or library,of compounds containing millions of chemi-cal entities (in this case peptides), as well asthe subsequent identification of those com-pounds capable of interacting with predeter-mined molecular targets. One year later,Jonathan A. Ellman published the first synthe-sis of a library of non-peptidic small organic molecules. Thepreparation of these 1,4-benzodiazapenes marked the beginningof a new era in organic synthesis that would eventually find par-allels in genomics, proteomics and metabolomics research. Theaforementioned fields are providing an ever-widening array oftherapeutic targets associated with various terminal diseases forwhich no drugs are currently available. The development of mas-sive-scale biological assays, made possible by automation, hasunderscored the need for high-throughput synthesis (HTS) ofnew chemical entities for screening.

While combinatorial chemistry has undoubtedly revolutionizedsynthetic chemistry, it has also undergone an important evolutionof its own. Combinatorial chemistry was initially envisioned as astrategy to maximize the chemical space covered by the productsof a given synthesis and thereby amplify the probability of gener-ating interesting new chemical entities. Preliminary work in thefield comprised the preparation of libraries of thousands, or evenmillions, of compounds, primarily peptides, oligonucleotides andPNA’s. A library of pentapeptides containing every permutationof the 20 naturally occurring amino acids would contain 3,200,000(205) members. From a synthetic perspective, this library wouldhave to be assembled on solid phase.

The solid-phase strategy developed by R. Bruce Merrifield in the1960’s for peptide synthesis is based on the covalent linkage ofthe carboxylic acid of the first amino acid in a sequence to aninsoluble polymer that acts as a protecting group.

Figure 1. Schematic of solid-phase synthesis.

The resulting C-terminal component is insol-uble in the solvents used for the synthesis.Excess reagents and most byproducts areultimately removed by simple filtration andwashing of the polymer that contains thegrowing peptide chain (Figure 1). This factfacilitates the use of large excesses ofreagents, thus providing near-quantitativeyields for many steps.

Biological screening of libraries of mixturesprepared on solid-phase are performed on the resin itself or oncethe desired compounds have been cleaved from the resin. In thelatter case, deconvolution methods are used to identify activecompounds.

On-resin biological screening requires libraries constructed bythe split and mix method, as this method guarantees that eachpolymer bead contains only one compound. In this technique,also known as one-bead one-compound, the resin beads act asindividual reactors, as illustrated in Figure 2.

Figure 2. Preparation of a library by the split and mix method.

In the split and mix assembly of trimers, a resin is divided intothree portions, each of which is treated with a single monomer:A, B or C. The portions are then mixed and equally split amongthree reactors. Monomer D, E or F, is then added to each of thereactors, which are subsequently remixed, re-split and finallytreated with monomer G, H or I. This process ensures that eachresin bead contains exclusively one compound. The library of27 compounds in this example of split and mix synthesis is pre-pared in only nine reactions, whereas classical methods (i.e.,individual syntheses) would have required 81 (27 x 3) reactions.

Biological screening in solution of the aforementioned com-pounds upon their cleavage from the solid-support impliesdeconvolution, for which many methods exist. Deconvolution

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Fernando AlbericioDept. Química Orgánica. Facultat de Química.

Universitat de Barcelona Barcelona, Spain. [email protected]


of the library described above via positional scanning wouldentail the preparation of nine sub-libraries, shown in Figure 3(where X, Y and Z represent the following three component mix-tures: A + B + C, D + E + F, and G + H + I, respectively). Thesub-libraries are prepared on solid-phase incorporating the cor-responding monomers. The best monomer for the first positionof the trimers is determined by comparing the activity of thenine-component sub-libraries AYZ, BYZ and CYZ, which areidentical in positions two and three (each containing mixtures ofthree monomers) and differ only in their first position. The bestmonomers for the remaining positions are then determined in ananalogous fashion, ultimately providing the structure of the tar-get trimer to be prepared.

Figure 3. Sub-libraries prepared for biological screening in solution.

While the utility of libraries of mixtures of small organic mole-cules has also been demonstrated, their preparation is complicat-ed by differences in reactivity among members of a given classof organic reagents (e.g., acids, aldehydes, alcohols, amines,etc.) It should also be mentioned that screening mixtures of

compounds is less reliable than screening individual compounds.These two facts have limited the use of mixtures of libraries tothe screening of biomolecules (e.g., peptides, oligonucleotides,peptoids) for early stages of drug-discovery programs.

Combinatorial or high-throughput chemistry is now focused onthe rapid and rational generation of libraries of approximately150 compounds, in which each product is prepared on a scale of5-25 mg, characterized by at least HPLC-MS and 1H-NMR, andgreater than 95% pure. These libraries are assembled in parallelon solid-phase or in solution.

As previously mentioned, a polymer-support can act as a protect-ing group for peptide synthesis. Moreover, polymer-supports canbe bound to myriad reagents, and the resulting functionalizedresins can be used in solution-phase synthesis or purification. Inthe former, a reagent immobilized on solid-support is added tothe reaction, and excess reagents or by-products are ultimatelyfiltered off, whereas in the latter, a functionalized polymer, orscavenger resin, is added at the end of a reaction to bind to impu-rities and then removed by filtration. Solid-phase techniquesallow the use and subsequent removal of excess reagents, oftenthe key factor in optimizing the yield of a given reaction.Furthermore, solid-phase reagents facilitate the automation andparallel lay-out of many synthetic processes.

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In enantioselective transition metal cataly-sis, the development of a single highlyeffective chiral catalyst requires the

preparation and testing of a large number ofligands. Success depends on design, which isbased on knowledge of the mechanism, intu-ition and molecular modeling. Often, trial anderror also plays a role. Alternatively, biocata-lysts can be used, but by nature the problemof substrate specificity persists.

A fundamentally different approach to thedevelopment of enantioselective catalysts is described, namelydirected evolution as a method to stepwise increase the enantios-electivity of a given unselective enzyme. The underlying princi-ple -”evolution in the test tube” - does not require any knowledgeof the enzyme structure or of its catalytic mechanism. Propermolecular biological methods for random mutagenesis andexpression of genes coupled with an efficient high-throughputscreening system for the rapid identification of enantioselectivemutants form the basis of our strategy.

Scheme 1. Directed evolution of an enantioselective enzyme.

Rather than relying on strategies based on structure and mecha-nism, the logic behind the principle outlined in Scheme 1 is theevolutionary pressure which is applied by going through severalcycles of mutation/screening. Thus, Darwinism is mimicked. Theinferior mutants are discarded, and the best one “survives”, i.e.,its gene is subjected once more to mutation/screening. Therefore,directed evolution of enantioselective enzymes goes far beyondcombinatorial transition metal catalysis. In each round of muta-

tion, about 2000-5000 mutant enzymes arecreated, which means that efficient high-throughput ee-screening systems arerequired.

We have developed several high-throughputee-assays. Examples include systems basedon UV/Vis, CAE, ESI-MS, IR-thermographyand most recently on NMR. Between 1000and 20000 ee-determinations can be per-formed per day. Other authors such as K.Mikami, R. Kazlauskas, M.G. Finn, C.T.

Seto, M.D. Shair and C. Miokowski have developed alternativeee-screens. No single screening system is universal.

Using our original UV/Vis-based system, which constitutes thefirst high-throughput ee-assay (allowing for 500-900 samples tobe processed per day), we have applied the known methods ofmolecular biology to the directed evolution of enantioselectiveenzymes (specifically lipases) for use as catalysts in thehydrolytic kinetic resolution of ester 1. The original (wild-type)enzyme shows a selectivity factor of only E = 1.1 in slight favorof the S-acid 2 (Scheme 2). The selectivity factor E reflects therelative reaction rate of the S- with respect to the R-substrate.Several S-selective mutants were evolved (E = 25 - 51).Moreover, it was possible to invert the sense of enantioselectiv-ity in favor R (E = 30)

Scheme 2. Kinetic resolution of ester 1 catalyzed by mutant

lipases produced by directed evolution.

Sequencing of the best mutant showed six mutations, most ofthem occurring at remote positions. This surprising result wasexplained by a relay mechanism uncovered by MM/QM studies.One of the major challenges in synthetic organic chemistry con-cerns selective partial oxidation. Therefore, we have initiatedprojects pertaining to monooxygenases and P450-enzymes. Forexample, cyclohexanone monooxygenases can be used as cata-lysts in O2-mediated Baeyer-Villiger reactions, but the degree ofenantioselectivity is poor for many substrates. Directed evolutioncan be used to evolve highly enantioselective catalysts for a num-ber of different substrates.

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Manfred T. ReetzMax-Planck-Institut für Kohlenforschung

Mülheim/Ruhr, Germany. [email protected]


In summary, directed evolution of enantioselective enzymes hasemerged as a powerful new way of generating catalysts for asym-metric transformations. Several other academic and industrialgroups have joined in these efforts, and further interesting per-spectives are becoming visible.

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1) Review: M. T. Reetz, Controlling theEnantioselectivity of Enzymes by DirectedEvolution: Practical and TheoreticalRamifications, Proc. Natl. Acad. Sci. U. S. A.2004, 101, 5716-5722.


The importance of chemical tools forstudying complex biological systemsis constantly expanding with the real-

ization that such approaches can form power-ful partnerships with traditional strategiesbased on genetic and immunologic approach-es. A key advantage to chemical genetics-based methods lies in the unparalleled abilityto control and monitor specific events in liv-ing cells in real time. Recent research hasfocused on the therapeutically important areaof signal transduction. Due to the essentialsignaling role of protein kinase-mediated protein phosphoryla-tion in all cellular processes, this central process has been adopt-ed as a strategic target area for probe development. Caged phosphopeptides and phosphoproteinsCaged compounds include a photolabile protecting group thatmasks an essential functionality.i Thus, a caged biomolecule,such as the phosphopeptide illustrated in Figure 1A, would bebiologically inactive, but rendered active only after unmaskingby photolysis under mild and neutral conditions (Figure 1B).

Figure 1. A. Section of a peptide integrating caged phosphoser-ine. B. Chemical and biological generation of phosphoproteins

The most commonly implemented caging groups in biologicalstudies are based on substituted o-nitrobenzyl systems, which canbe uncaged at wavelengths >350 nm. The “caging“ strategyallows for spatial and temporal control over the release of effec-tor molecules in living systems. Until recently, access to cagedphosphopeptides had been limited due to the absence of efficientsynthetic strategies for the preparation of suitably-protectedamino acid building blocks for the assembly of the caged phos-phorylated peptides. A general approach for the assembly of caged phosphopeptidesinvolves the synthesis of suitably-protected caged phosphoamino

acid building blocks for use in solid phasepeptide synthesis (SPPS). The key step inthe building block synthesis is the phosphity-lation of an appropriately-protected aminoacid precursor followed by mild oxidationwith t-butyl hydroperoxide or mCPBA anddeprotection of the t-butyl ester as illustratedin Figure 2 for the synthesis of caged phos-phoserine. An analogous strategy has alsobeen applied to the synthesis of the othermajor eukaryotic protein phosphorylation tar-gets - threonine and tyrosine.ii

Figure 2. Synthesis of a caged phosphoserine building block forSPPS

The caged phosphoamino acid analogs of serine, threonine andtyrosine have been incorporated into a number of polypeptideswhich were then used to study critical events in cell migrationand cell cycle control.iii More recently, the synthetic strategy out-lined in Figure 2 has been modified for the semi-synthesis of atransfer RNA (tRNA) that is charged with a caged phosphoaminoacid. This tRNA was then used for the in vitro translation of afull-length caged phosphoprotein using the suppressor tRNAmethodology.iv This major development in the semi-synthesis ofcaged phosphoproteins now provides access to a wide variety ofcaged biological molecules for the study of specific phosphopro-tein effectors in signal transduction pathways. Fluorescent probes of protein kinase activityFluorescence-based probes for monitoring protein phosphoryla-tion and the spatial and temporal characteristics of protein kinaseactivities in cells provide the opportunity to understand thedynamics of cellular processes in healthy and transformed cells.The phosphorylation probes developed in the Imperiali groupexploit novel amino acids with either environment-sensitive orchelation-enhanced fluorescent properties. The probes that

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Barbara ImperialiDepartment of Chemistry and Department of

BiologyMassachusetts Institute of Technology,Cambridge, MA USA. [email protected]

i For a review see: Corrie, J. E. T.; Trentham, D. R. In Biological Applications of Photochemical Switches. Morrison, H., Ed. John Wiley & Sons: New York, NY, 1993;Chapter 5.ii Rothman, D. M.; Vázquez, M. E.; Vogel, E. M.; Imperiali, B. J. Org. Chem. 2003, 68, 6795-6798.iii Nguyen, A.; Rothman, D. M.; Stehn, J.; Imperiali, B.; Yaffe, M. B. Nature Biotechnology, 2004, 22, 993-1000.


include environment-sensitive fluorophores, such as the 2-dimethylamino-6-naphthoyl or dimethylamino naphthalimidegroups in the DANAv and 6-DMNvi amino acids respectively, canbe used to monitor phosphorylation-induced binding of peptidesand proteins to partner molecules as exemplified by the bindingof phosphotyrosine-containing peptides to SH2 domains.Alternatively, the chelation-enhanched fluorophore in the Soxamino acid can be used to directly signal phosphorylation via amechanism that exploits the enhanced affinities of phosphorylat-ed peptides including Sox, for divalent magnesium. The Fmoc-Sox is prepared by the asymmetric alkylation of a glycine precur-sor using the Corey modification of the O’Donnell phase-transfercatalyzed reaction, which implements a modified cinchonidiniumalkaloid as the chiral catalyst.vii

Figure 3. Asymmetric Synthesis of Fmoc-Sox

Chemosensor peptides, based on the Sox amino acid approach,have been developed for a number of physiologically importantprotein kinases including Akt, PKC, PKA and Abl.viii The kinasechemosensors are readily phosphorylated by recombinant targetenzymes and undergo a several-fold increase in fluorescence sig-nal upon phosphorylation. More recently, the aforementionedchemosensors have been demonstrated to show significant utilityin unfractionated cell lysates.ix This latter development will beextremely valuable since it will enable the profiling of small mol-ecule inhibitors of protein kinase activities in more native envi-ronments including physiological levels of ATP, which is not fea-sible with most of the assays currently available.

Conclusions

Recent developments in the design, synthesis, and implementati-on of new chemical probes for studying the roles of protein phos-phorylation in cellular processes now provide powerfulapproaches for the study of complex biological systems.

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iv Rothman, D. M.; Petersson, E. J.; Vázquez, M. E.; Brandt, G. S.; Dougherty, D. A.; Imperiali, B. J. Am. Chem. Soc. 2005, 127, 846-847.v Nitz, M.; Mezo, A. R.; Ali, M. H.; Imperiali, B. Chem. Comm. 2002, 1912-1913.vi Vázquez, M. E.; Canosa, J. B. B.; Imperiali, B, J. Am. Chem. Soc. 2005, 127, 1300-1306.vii Corey, E. J. Xu, F.;Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414-12415.viii Shults, M. D.; Imperiali, B. J. Am. Chem. Soc. 2003, 125,14248-14249.ix Shults, M. D.; Janes, K. A.; Lauffenburger, D. A.; Imperiali, B. Nature Methods


One of the ultimate goals in organicchemistry is the catalytic asymmet-ric assembly of simple and readily

available precursor molecules into stereo-chemically complex products. As chemists,we often turn to nature for inspiration con-cerning stereochemically complex, diverse,and functional molecules. Indeed, the direct-ed asymmetric assembly of simple achiralbuilding blocks into stereochemically com-plex molecules like carbohydrates andpolyketides has long been the purview ofnature’s enzymes. Our approach to this problem began in 1997when we embarked upon studies exploring the similaritybetween proline and a novel class of aldolase antibodies we haddeveloped earlier. Recently, these studies have allowed us todescribe the first direct organocatalytic asymmetric ketone andaldehyde additions in aldol, Michael, Mannich, and Diels-Alderreaction manifolds. Significantly, these studies were originallydesigned for antibody catalysis years before. This lecture willsummarize the contributions of this laboratory to creating andconverting enzymatic enamines, and in some cases imines, intoa versatile catalytic asymmetric strategy powered by smallorganic molecules.

In recent years my laboratory has also focused on the develop-ment of diverse strategies for the development of therapeuticsand the validation of molecular targets. Provided time, I willalso introduce the concept of chemically programmed antibodytherapeutics that utilize enamine chemistry to modify the phar-macokinetics and potency of small molecule drugs. The successof the antibody molecule as therapeutic agent is based on at leastthree properties; (i) an Fab moiety that permits antigen bindingwith high specificity and affinity, (ii) an Fc moiety that mediateseffector functions, and (iii) a molecular weight of at least 150 kDthat permits a circulatory half-life of up to 21 days. Althoughconventional therapeutic agents based on small organic mole-cules have been successful in many instances, they are clearlylimited with respect to their short half-life in circulation andtheir inability to mediate effector functions. Proposing that ablend of these features will lead to therapeutic agents with supe-rior properties, we have developed chemically programmed anti-bodies. In vitro and in vivo studies concerning unique antibodyspecificities that provide for the targeting of two angiogenicpathways combined with b roader targeting of tumors them-selves will be presented.

Figure 1. Diverse Range of Asymmetric Aldol Reactions

Catalyzed by Antibodies

Figure 2. Examples of Efficient Organocatalytic

Aldol Reactions

Figure 3. Organocatalytic Mannich Reactions: b-Formyl-Substituted a-Amino Acids from Unmodified

Aldehydes as Donors.

Figure 4. Multicomponent Reactions with Organocatalysis:Amine-Catalyzed Asymmetric Knoevenagel-

Diels-Alder Reactions.

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Carlos F. Barbas, IIIDepartments of Chemistry, Molecular Biology,and The Skaggs Institute for Chemical Biology.The Scripps Research Institute, La Jolla, CA,

USA. [email protected]


Figure 5. Chemically Programmed Antibodies: A NewImmunotherapeutic Approach Powered by Chemistry.

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REFERENCES:

Wagner, J., Lerner, R.A., and Barbas III, C.F., (1995) Efficient Aldolase Catalytic Antibodies that use the Enamine Mechanismof Natural Enzymes. Science, 270:1797-1800.

Hoffmann, T.; Zhong, G.; List, B.; Shabat, D.; Anderson, J.; Gramatikova, S.; Lerner, R.A.; Barbas, C.F. III (1998) AldolaseAntibodies of Remarkable Scope. J. Am. Chem. Soc., 120, 2768-2779.

Shabat,D.; Lode,H.N.; Pertl, U.; Reisfeld, R.A.; Rader, C.; Lerner, R.A.; Barbas, III, C.F. (2001) In vivo activity in a catalyticantibody-prodrug system: antibody catalyzed etoposide prodrug activation for selective chemotherapy. Proc. Natl. Acad. Sci.,USA 98 (13), 7528-7533.

Tanaka, F.; Barbas III, C.F. (2004) Antibody-catalyzed Aldol Reactions. In: Modern Aldol Reactions Volume 1: Enolates,Biocatalysis and Natural Product Synthesis. R. Mahrwald(Ed.). Wiley Publishers,Weinheim, Germany, 273-310.

Sakthivel, K.; Notz, W.; Bui, T.; Barbas III, C.F. (2001) Amino Acid Catalyzed Direct Asymmetric Aldol Reactions: ABioorganic Approach to Catalytic Asymmetric Carbon-Carbon Bond-Forming Reactions, Journal of the American ChemicalSociety; 123, 5260-5267.

Córdova, A.; Watanabe, S.-I.; Tanaka, F.; Notz, W.; Barbas III, C.F. (2002) A Highly Enantioselective Route to EitherEnantiomer of Both a- and b-Amino Acid Derivatives. Journal of the American Chemical Society, 124(9), 1866-1867.

Notz, W.; Tanaka, F.; Watanabe, S.-I.; Chowdari, N.S.; Turner, J.M.; Thayumanavan, R.; Barbas III, C.F. (2003) The DirectOrganocatalytic Asymmetric Mannich Reaction: Unmodified Aldehydes as Nucleophiles. J. Org. Chem., 68(25):9624-34.

Notz, W.; Tanaka, F.; Barbas III, C.F. (2004) Enamine-based organocatalysis with proline and diamines: The development ofDirect Catalytic Asymmetric Aldol, Mannich, Michael, and Diels-Alder Reactions. Acct. Chem. Res., 37(8):580-591.

Ramachary, D.B.; Barbas III, C.F. (2004)


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The pharmaceutical industry is viewed bymany as facing a productivity dilemma.Despite continued increases in research anddevelopment expenditures, no correspondingincreases in new drug approvals haveemerged.

This presentation outlines some of the characteristics of the pro-ductivity question within the pharmaceutical industry and then out-lines some attributes that would characterize a potential solution.

In that context, an outline is provided for thediscovery chemistry research and technologyorganization within Lilly ResearchLaboratories and some of the approaches takenin that group to substantially increase the pro-ductivity of Lilly’s drug discovery efforts.

Central themes for this productivity enhancement include integra-tion of new technologies in the appropriate context for drug dis-covery, shifting from probabilistic toward knowledge based leadgeneration, and aggressive multi-dimensional lead optimization.

James E. Audia, Ph.D.Executive Director DCRT

Lilly Research Laboratories, A Division of EliLilly & Company

Lilly Corporate Center, Indianapolis, IN, USA46285


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A final element of this approach is the strategic utilization of out-sourcing both for the introduction of new capabilities and tech-nologies, but also for expansion of capacity in critical drug dis-covery activities.


ABSTRACT

The application of ionic liquids tosynthesis and catalysis is the focusof increasing activity in both aca-

demic and industrial environments.i This hasresulted in an explosion of interest, with 470papers appearing in the year 2003 with ionicliquid in the title compared to just 80 in 2000.Also in 2003, the first industrial application ofionic liquids, the BASF BASIL® process,ii wasannounced. In my own group, we have used ionic liquids as sol-vents for inorganic,iii organometallic,iv organic,v and transitionmetal catalysedvi transformations. Although much of the activityin the field has concentrated on ionic liquids as ‘green’ replace-ments for environmentally damaging organic solvents, based ontheir low vapour pressures, it is the possibility of using them tochange the outcomes (rates, selectivities etc.) of reactions that isthe most exciting. It is on this latter subject that my research hasbeen concentrated.

The application of ionic liquids as solvents for chemicals synthe-sis is still a young area. At first it was not even clear that ionicliquids would be able to be used in this role. Hence, there hasbeen a phase of development that is best characterised as a scop-ing exercise. Most of these studies have involved taking a well-

known reaction and trying it in a single ionicliquid to see if it “goes”, often without refer-ence to the same reaction in molecular sol-vents. While this approach has fuelled thegrowing interest in ionic liquids it does littleto explain how the use of ionic liquids canaffect the reactions conducted in them, orhow they might best be applied. Quantitativecomparisons of the properties of the ionic liq-uids with other solvents, and between differ-ent ionic liquids, are the only way in whichthis can be achieved. There has been much

speculation that the ionic nature of these liquids has a profoundeffect on processes carried out in them and in some cases tanta-lising initial results have been reported. Also, the much repeatedproposition that ionic liquids are ‘designer solvents’ rests on theassumption that they are sufficiently different to each other towarrant this approach.

The aim of this talk is to introduce ionic liquids as potential reac-tion media for chemicals synthesis. I will show how ionic liquidscan be described using empirical polarity scales, particularly theKamlet-Taft system.vii I will then show examples of where theionic liquids have affected the rates and selectivities of a numberof stoichiometric organic reactions and use this as a basis todetermine in which processes substitution of a molecular solventwith an ionic liquid.

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TomWeltonDepartment of Chemistry. Imperial College

London. London U.K. [email protected]

i “Ionic Liquids in Synthesis”, P. Wasserschied and T. Welton (eds.), VCH Wiley, Weinheim, 2002.ii (a) WO 03/062171 (BASF AG; (b)M. Freemantle, Chem. Eng. News, 2003, 81, 9.iii A.J. Dent, A. Lees, R.J. Lewis and T. Welton, J. Chem. Soc., Dalton Trans., 1996, 2787.iv P.J. Dyson, M.C. Grossel, N. Srinivasan, T. Vine, T. Welton, D.J. Williams, A.J. White and T. Zigras, J. Chem. Soc., Dalton Trans., 1997, 3465.v A. Sethi, T. Welton and J. Wolff, Tetrahedron Lett., 1999, 40, 793.vi F. Mclachlan, C. J. Mathews, P. J. Smith and T. Welton, Organometallics, 2003, 22, 5350.vii L. Crowhurst, P. R. Mawdsley, J. M. Perez-Arlandis, P. A. Salter and T. Welton, Phys. Chem. Chem. Phys., 2003,


Recent studies on the development ofnew synthetic methodology will bepresented, along with applications

towards the total synthesis of stereochemi-cally complex, biologically active natural

products. The specific examples highlight-ed will be selected from our recent effortson the total synthesis of 13-deoxytedano-lide, amphidinol 3, and amphidinolides C, Eand F.

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William R RoushExecutive Director of Medicinal Chemistry, The

Scripps Research Institute. Florida, USA. [email protected]


The arene-catalyzed lithiation1 has beenshown to be a very efficient methodol-ogy for the lithiation of different sub-

strates under very mild reaction conditions.The following four sections will explore recentrepresentative applications of this procedure:

1. Preparation of organolithium com-pounds from non-halogenated materials

Different non-halogenated materials (such asethers, thioethers, alcohols and their O-silylderivatives, sulfonates, sulfates, nitriles, sulfoxides, sulfones,phosphates, esters, amides, carbonates, carbamates or ureas) areeasily transformed into organolithium compounds using anarene-catalyzed lithiation (Scheme 1). In some cases it is neces-sary to perform the reaction in the presence of the electrophile(Barbier conditions) in order to avoid the decomposition of the insitu generated organolithium. The reaction has also been appliedto the deprotection of different protected alcohols and amines(allyl, benzyl, sulfonyl or silyl derivatives).

Scheme 1

2. Ring opening of heterocycles

The arene-catalyzed lithiation has been usedfor the reductive ring opening of differentthree-, four-, five-, six- and seven-memberedsaturated or benzofused oxygen-, sulphur-or nitrogen-containing heterocycles, so aseries of functionalized organolithium com-pounds2 is easily accessible (Scheme 2). Aninteresting application of this methodologyallows the selective functionalization of car-bohydrates (glucose or fructose) and steroids

(estrone or cholestanone) through the corresponding epoxides.

Scheme 2

3. Dilithium synthons

Starting from dichlorinated materials, their arene-catalyzed lithi-ation in the presence of carbonyl compounds (Barbier reactionconditions) affords diols, which are easily transformed into inter-esting heterocyclic units, including perhydrofurofurans, perhy-drofuropyrans, and dioxaspiroalkanes. These cyclic polyethermoieties are extensively represented in naturally occurring com-pounds. The introduction of two different electrophilic fragments

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Miguel YusDepartamento de Química Orgánica, Facultadde Ciencias, and Instituto de Síntesis Orgánica,

Universidad de Alicante, Spain. [email protected]

1 For reviews, see: (a) Yus, M. Chem. Soc. Rev. 1996, 25, 155-161. (b) Ramón, D. J.; Yus, M. Eur. J. Org. Chem. 2000, 225-237. (c) Yus, M. Synlett 2001, 1197-1205. (d)Yus, M.; Ramón, D. J. Lat. J. Chem. 2002, 79-92. (e) Ramón, D. J.; Yus, M. Rev. Cubana Quim. 2002, 14, 75-115. (f) Yus, M. In The Chemistry of OrganolithiumCompounds; Rappoport, Z.; Marek, I., Eds.; J. Wiley & Sons: Chichester, 2004; Chapter 11. For mechanistic studies, see: (g) Yus, M.; Herrera, R. P.; Guijarro, A. TetrahedronLett. 2001, 42, 3455-3458. (h) Yus, M.; Herrera, R. P.; Guijarro, A. Chem. Eur. J. 2002, 8, 2574-2584. (i) Yus, M.; Herrera, R. P.; Guijarro, A. Tetrahedron Lett. 2003, 44,1309-1312. (j) Yus, M.; Herrera, R. P.; Guijarro, A. Tetrahedron Lett. 2003, 44, 1313-1316. (k) Yus, M.; Herrera, R. P.; Guijarro, A. Tetrahedron Lett. 2003, 44, 5025-5027.For a polymer supported arene-catalyzed version of this reaction, see: (l) Gómez, C.; Ruiz, S.; Yus, M. Tetrahedron Lett. 1998, 39, 1397-1400. (m) Gómez, C.; Ruiz, S.;Yus, M. Tetrahedron 1999, 55, 7017-7026. (n) Yus, M.; Candela, P.; Gómez, C. Tetrahedron 2002, 58, 6207-6210. (o) Alonso, F.; Gómez, C.; Candela, P.; Yus, M. Adv. Synth.Catal. 2003, 345, 275-279. (p) Gómez, C.; Candela, P.; Yus, M. Russ. J. Org. Chem. 2004, 40, 795-801. For the last paper from our laboratory, see: (q) Ortiz, R.; Yus, M.Tetrahedron 2005, 61, 1699-1707.2 For reviews, see: For reviews, see: (a) Nájera, C.; Yus, M. Trends Org. Chem. 1991, 2, 155-181. (b) Nájera, C.; Yus, M. Org. Prep. Proc. Int. 1995, 27, 383-457. (c) Nájera,C.; Yus, M. Recent Res. Devel. Org. Chem. 1997, 1, 67-96. (d) Nájera, C.; Yus, M. Curr. Org. Chem. 2003, 7, 867-926. (e) Nájera, C.; Sansano, J. M.; Yus, M. Tetrahedron2003, 59, 9255-9303. (f) Chinchilla, R.; Nájera, C.; Yus, M. Chem. Rev. 2004, 104, 2667-2722. (g) See also the special issue of Tetrahedron Symposium in Print dedicatedto ‘Functionalised Organolithium Compounds’, Tetrahedron 2005, 61, 0000-0000.


is possible starting from the corresponding chloroethers,chlorothioethers or chloro bromo derivatives, simply controllingthe lithiation conditions (by using either the stoichiometric or thecatalytic version of the arene-promoted lithiation) (Scheme 3).

Scheme 3

4. Activation of other metals: Nickel

The NiCl2·2H2O/Li/arene(cat.) combination is an effective mix-ture to carry out hydrogenation processes without using molecu-lar hydrogen. Thus, olefins or alkynes can be either fully hydro-genated to the corresponding alkanes or in the second case par-tially reduced to the corresponding cis-alkenes. Halogen or sul-fonyloxy derivatives give the corresponding alkanes, whereasarenes or heteroarenes can be partially hydrogenated (a Birch-type reaction) using the mentioned combination. Also nitrogen-nitrogen (in hydrazones, azo and azoxy compounds, and azides)or nitrogen-oxygen bonds (in amine N-oxide, nitrones andWeinreib amides) can be cleaved using the same reducion mix-

ture (Scheme 4). When deuterium oxide was included in the nick-el salt instead of water, the corresponding deuteriated productsare obtained. On the other hand, the use of the anhydrous salt inthe same process but employing molecular hydrogen at normalpressure results a reasonable alternative to Raney-Ni. Nickelnanoparticles are involved in all the mentioned processes.

Scheme 4

AcknowledgementsThe chemistry described here has been generously supported bythe Spanish Ministerio de Ciencia y Tecnología, the GeneralitatValenciana and the Universidad de Alicante.

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The level and type of Diversity is affect-ed by the different Drug DiscoveryPhases, and also by the new concepts

of “Front Loading Discovery” and “ParallelMulti-Factorial Optimization” that the Pharmaindustry has incorporated few years ago. Thus,the philosophy behind combinatorial librarydesign has changed drastically since the earlydays of huge chemistry driven libraries, target-ing maximal diversity for general screening.Nowadays, focused libraries, with much moreMedicinal Chemistry input, trying to hit a sin-gle or a family of targets are the main choice. These are result ofmulti-objective designs, which take into consideration drug- orlead-likeness, in silico ADMET profiling, diversity, etc.Nevertheless, the design and production of general screeninglibraries is still a hot field, where Nature is source of inspiration.Thus, there is a revival of natural products derived libraries, orDiversity Oriented Synthetic collections, which incorporate diver-sity features of the natural product space. The use of proprietaryunder-represented scaffolds and advanced building blocks for cor-porate library enrichment exercises should be also taken intoaccount. General concepts regarding “scaffold-derived diversityvs. full combinatorial exploitation of a few” should be kept inmind. A balanced strategy, which incorporates these approaches

into different levels of risk, timing, in-outsource and investment is desirable. One stepfurther, the principal aim of a “Hit to Lead”campaign is to test the potential of a particu-lar hit (or hit series) to reach the lead criteriain terms of activity-selectivity, physicochemi-cal and ADMET properties. Additionally, aconsistent SAR/SPR, and establishment ofcorrelations, which allow in silico predictionsat the level of “early” LO is of high value. We,HTMC and MI at J&J-PRD-Toledo, are cur-rently working in a platform, which targets

the Multi-Factorial Optimization of hit/leads via systematic explo-rations. It is based in the key use of “SAR/SPR” sets of reagents,to sample the Med-Chem Space (Activity vs. Property) in adiverse manner. The results are then capitalized in further iterativefocused design and finally in the implementation of “LocalModels”. The platform has been tested with several applicationsand the preliminary results are promising, so far. This strategy iscomplemented, of course, with key “singleton type” modifica-tions to have more meaningful outputs. These pre-defined sets ofreagents have been optimized chemically with manual HTC pro-tocols, which are now subject of automation, J&J-PRD-Beerse,with the aim of being of general use among medicinal chemistryteams in their discovery programs.

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Joaquin Pastor Ph.D.Head of Syntech Group. Johnson & JohnsonPharmaceutical Research and Development.

Beerse, Belgium. [email protected]


Combinatorial synthesis of naturalproducts is developing to explorethe analogue of lead compounds

for drug discovery and recently to extendthe construction of important chemicalprobes in the fields of chemical genetics,genomics and proteomics. Therefore, it isnecessary to develop more efficient strate-gies for the high-speed synthesis of a nat-ural product like libraries than those tradi-tionally used for the synthesis of a singlefinal product.

Macrosphelides A has received much attention as a lead com-pound for the development of new anti-cancer drugs.1 Hereinwe wish to report a highly convergent synthesis of a libraryof macrosphelide analogues on a solid-support utilizingradiofrequency encoded combinatorial (REC) chemistry by asplit-and-pool method.2 In our strategy (Scheme-1) for thecombinatorial synthesis of macrospelides analogues (128-membered library), we chose a solid-phase synthesis utilizingthe three synthetic building blocks A(four), B(four), andC(eight) as illustrated in scheme 1. The process involves: 1)attachment of the secondary alcohol in block A to a polymer-support, 2) esterification with block B, 3) chemoselectivecarbonylation of the vinyl iodide in A with alcohol C contain-ing a vinyl bromide moiety, 4) carbonylative macrolactoniza-tion of the polymer-supported A,B,C by exploiting the ratherless reactive vinyl bromide, and 5) cleavage from the poly-mer-support.

Scheme 1

One-pot glycosylation, involving sequentialactivation of glycosyl donors in a single ves-sel, is effective not only for the high-speedsynthesis of a single target oligosaccharide,but also for the parallel synthesis ofoligosaccharide libraries. We have investi-gated the branched- and linear-type one-potglycosylation (Scheme-2) based on thechemoselective activation of glycosyldonors attached with different leavinggroups with appropriate activators. 3

Scheme 2As an application, we first investigated one-pot four-step

synthesis of Lewis X sphigolipid (Scheme-3) which is animportant tumor-associated antigen, and is composed of ab(1,3) and b(1,4) linked tetrasaccharide backbone attachedwith a(1,3) linked branching saccharides.

Scheme 3Based on the above methodology, we achieved an automated

parallel solution-phase synthesis of a protected dimericLewis X library by one-pot glycosylation (Scheme-4). 4

Scheme 4

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Takashi TakahashiDepartment of Applied Chemistry, Graduate

School of Science and Engineering,Tokyo Institute of Technology, Tokyo, Japan.

[email protected]


We have been working on the development of laboratoryautomation in order to improve the quality, efficiency andimportance of experimental works in organic synthesis.Recently, we have achieved a total synthesis of Baccatin III,in which the key intermediates were synthesized by perform-ing reactions in ChemKonzert. In our synthetic strategy(Scheme-5), the B-ring is constructed by intramolecularcyanohydrin alkylation of 6 utilizing Microwave synthesizer.The A-ring 4 and the C-ring 5 were prepared from geraniol(1) by Ti-mediated radical cyclization5 of epoxyalkenes 2and 3, respectively. The total 32 steps from geraniol tocyanohydrin 6 carried out by using automated synthesizer.

Scheme-5

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References

1)M. Hayashi, Y.-P. Kim, H. Hiraoka, M. Natori, S. Takamatsu, T. Kawakubo, R. Masuma, K. Komiyama, S. Omura, J.Antibiot. 1995, 48, 1435-1439. 2)Takahashi, T.; Kusaka, S.-I.; Doi, T.; Chem. Int. Ed.


Control of the stereochemistry in achemical transformation is a keyissue in modern organic chemistry,

which has led to the pre-eminence ofasymmetric synthesis. One option for con-trolling stereochemistry ?and thus for pro-ducing one of the stereoisomers over theother possible ones in a predictable fash-ion? is the use of a stoichiometric chiralauxiliary which is covalently attached tothe prochiral substrate before chiralityrelay is performed. The auxiliary isremoved for reuse once the new stere-ogenic center is built with the desired configuration. A moreadvanced and atom economic option for controlling stereo-chemistry relies on the use of a chiral catalyst, typically atransition metal complex, which is reversibly bound to theprochiral substrate in the catalytic cycle.

The understanding of how factors affect the stereochemical out-come of a given transformation and thus the identification of thekey stereocontrolling elements seems more suitable when usingthe former option. As a result, it is not casual that observationsmade in stereoselective processes relying on covalently boundchiral auxiliaries may result extremely useful for the subsequentdesign of parallel processes that rely on chiral catalysis. A para-digmatic case is the development by Evans of amino acid-derivedN-acyl oxazolidinone auxiliaries, wherein the metal-carbonyldouble coordination is a key stereocontrol element, and the sub-sequent widespread use of N-acyl oxazolidinones as achiral tem-plates in catalytic enantioselective processes.

In recent years we have explored the concept of metal- andproton-assisted chelation of the a-hydroxy carbonyl moiety astool for substrate activation and reaction stereocontrol. In thiscontext, several chiral a-hydroxy ketones (enones) have beendeveloped for some fundamental C-C and C-heteroatom form-

ing reactions, which has been subsequent-ly followed by the development of a fam-ily of simple, aquiral a-hydroxy enones astemplates in a range of catalytic enantios-elective transformations.

Chiral Auxiliary-Based Aldol andMannich ReactionsI

Initial studies led to the design of ?’-hydroxy ketone 5, which upon enolizationaffords a highly ordered chelate ready for anefficient chirality transfer event. We suc-

ceeded in the application of this design reagent to aldol andMannich reactions. Significantly, the reagent is readily availablefrom acetylene and (1R)-(+)-camphor, two commodity chemicalsavailable in bulk, and detachment of the camphor unit fro-madducts is straightforward.

Chiral Auxiliary-Based Metal-Free Diels-Alder ReactionII

In subsequent experiments it was found that Brønsted acids arecapable of activating a’-hydroxy enones, presumably through anintermolecular hydrogen bond network. This principle was illus-trated in the context of Diels-Alder reaction by using a new fam-ily of camphor-based chiral enones, which upon catalytic actionof either trifluoroacetic acid or triflic acid lead to cycloadductswith high chemical and stereochemical efficiency.

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Claudio Palomo NicolauDepartamento de Química Orgánica I, Facultad

de Química. Universidad del País VascoSan Sebastián, Spain. qoppanic.ehu.es

I a) Palomo, C.; González, A.; García, J. M.; Landa, C.; Oiarbide, M.; Rodríguez, S.; Linden, A. Angew. Chem. Int. Ed. 1998, 37, 180-182. b) Palomo, C.; Oiarbide, M.;Aizpurua, J. M.; González, A.; García, J. M.; Landa, C.; Odriozola, I.; Linden, A. J. Org. Chem. 1999, 64. 8193-8200. c) Palomo, C.; Oiarbide, M.; Landa, A.; González-Rego, M. C.; García, J. M.; González, A.; Odriozola, J. M.; Martín-Pastor, M.; Linden, A. J. Am. Chem. Soc. 2002, 124, 8637-8643.II Palomo, C.; Oiarbide, M.; García, J. M.; González, A.; Lecumberri, A.; Linden, A. J. Am. Chem. Soc. 2002, 124, 10288-10289.


Catalytic Enantioselective Diels-Alder ReactionIII

Concurrent with these investigations it was also found that achi-ral a’-hydroxy enones upon combination with chiral Lewis acidsprovide a new platform for carrying out highly enantioselectivecatalytic reactions. For example, a’-hydroxy enones react withdienes in the presence of (S,S)-[Cu(tBu-box)](OTf)2 or (S,S)-[Cu(tBu-box)](SbF6)2 (2 to 10 mol %) to afford the correspon-ding Diels-Alder adducts in high yield and selectivity. Isomericratios (regioselectivity, endo/exo or cis/trans) of up to >99:1 andee values of up to >99% are obtained. Significantly, difficultdienes such as isoprene, 2,3-dimethyl butadiene and piperylenebehave satisfactorily. Subsequent oxidative cleavage of the ketolin the resulting cycloadducts by treatment with cerium ammoni-um nitrate (CAN) yields the corresponding enantiopure car-boxylic acids. Alternatively, carbonyl addition and subsequentdiol cleavage with CAN produces the corresponding ketoneadducts.

Catalytic Enantioselective Conjugate Addition ofCarbamatesIV

The catalytic, enantioselective conjugate addition of carbamateshas remained an elusive goal. For instance, the carbamate conju-gate addition to typical bidentate templates such as N-enoyl oxa-zolidinones and related systems under the presence of some rep-resentative metal catalysts is completely unsuccessful. H

ypothetically, the 1,4-metal arrangement resulting from the coor-dination of the a’-hydroxy enone templates with the catalyst is

advantageous over the 1,5-metal binding pattern often operatingin the above bidentate templates. Gratifyingly, it was found thatcarbamates indeed add to these hydroxyenones quite efficiently.

Catalytic Enantioselective Friedel-Crafts ReactionsV

A further demonstration of the potential scope of _’-hydroxy eno-nes is shown in the Friedel-Crafts alkylation of pyrroles andindoles where remarkably high and regular enantioselectivitiesare obtained.

The simple elaboration of adducts provides a route to enantioen-riched aldehydes, carboxylic acids and ketones containing thepyrrole and indole frameworks. Moreover, in these transforma-tions acetone is the only byproduct formed, an additional aspectof the approach that is of practical interest.

It is likely that this 1,4-metal-binding principle can provide simi-lar levels of substrate activation and reaction stereoselectivityunder a proper choice of metal catalyst in a yet uncovered widetype of transformations. Work in that direction is active in ourlaboratory.

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III Palomo, C.; Oiarbide, M.; García, J. M.; González, A.; Arceo, E. J. Am. Chem. Soc. 2003, 125, 13942-13943.IV Palomo, C.; Oiarbide, M.; Halder, R.; Kelso, M.; Gómez-Bengoa, E.; García, J. M. J. Am. Chem. Soc. 2004, 126, 9188-9189.V Palomo, C.; Oiarbide, M.; Kardak, B. G.; García, J. M.; Linden, A. J. Am. Chem. Soc. 2005, 127, ASAP.


High-speed microwave synthesishas attracted a considerableamount of attention in recent

years. Since the first reports on the use ofmicrowave heating to accelerate organicchemical transformations by the groups ofGedye and Giguere/Majetich in 1986,more than 2000 articles have been pub-lished in the area of microwave-assistedorganic synthesis (MAOS). The initialslow uptake of the technology in the late1980s and early 1990s has been attributedto its lack of controllability and repro-ducibility, coupled with a general lack of understanding ofthe basics of microwave dielectric heating. The risks associ-ated with the flammability of organic solvents in amicrowave field and the lack of available systems for ade-quate temperature and pressure controls were major concerns.Although most of the early pioneering experiments in MAOSwere performed in domestic, sometimes modified, kitchenmicrowave ovens, the current trend clearly is to use dedicat-ed instruments for chemical synthesis which have becomeavailable only in the last few years. Since the late 1990s thenumber of publications related to MAOS has thereforeincreased dramatically to a point where it might be assumedthat, in a few years, most chemists will probably usemicrowave energy to heat chemical reactions on a laboratoryscale. Not only is direct microwave heating able to reducechemical reaction times from hours to minutes, but it is alsoknown to reduce side reactions, increase yields and improvereproducibility. Therefore, many academic and industrialresearch groups are already using MAOS as a forefront tech-nology for rapid reaction optimization, for the efficient syn-thesis of new chemical entities, or for discovering and prob-ing new chemical reactivity. A large number of review arti-cles and several books provide extensive coverage of the sub-ject.

Traditionally, organic synthesis is being carried out by conduc-tive heating with an external heat source (i.e. an oil-bath). This isa comparatively slow and inefficient method for transferringenergy into the system since it depends on the thermal conductiv-ity of the various materials that must be penetrated, and results inthe temperature of the reaction vessel being higher than that ofthe reaction mixture. In contrast, microwave irradiation producesefficient internal heating (in core volumetric heating) by directcoupling of microwave energy with the molecules (e.g. solvents,reagents, catalysts) that are present in the reaction mixture. Since

the reaction vessels employed are typicallymade out of (nearly) microwave transparentmaterials such as borosilicate glass, quartzor Teflon, an inverted temperature gradientas compared to conventional thermal heat-ing results (Figure 1). The very efficientinternal heat transfer results in minimizedwall effects (no hot vessel surface) whichmay lead to the observation of so-called spe-cific microwave effects e.g. in the context ofdiminished catalyst deactivation.

Figure 1. Inverted Temperature Gradients in Microwave VersusOil Bath Heating.

Although many of the early pioneering experiments inmicrowave-assisted organic synthesis have been carried out indomestic microwave ovens, the current trend undoubtedly is touse dedicated instruments for chemical synthesis. All of today’scommercially available dedicated microwave reactors for synthe-sis feature built-in magnetic stirrers, direct temperature control ofthe reaction mixture with the aid of fiber-optic probes or IR sen-sors, and software that enables on-line temperature/pressure con-trol by regulation of microwave power output (Figure 2).Currently two different philosophies with respect to microwavereactor design are emerging: multimode and monomode (alsoreferred to as single mode) reactors. In the so-called multimodeinstruments (conceptually similar to a domestic oven), themicrowaves that enter the cavity are being reflected by the wallsand the load over the typically large cavity. In most instrumentsa mode stirrer ensures that the field distribution is as homoge-neous as possible. In the much smaller monomode cavities, only

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C. Oliver KappeInstitute of Chemistry, Karl-Franzens-University

Graz, Austria. [email protected]


one mode is present and the electromagnetic irradiation is direct-ed through an accurately designed rectangular or circular waveguide onto the reaction vessel mounted in a fixed distance fromthe radiation source, creating a standing wave. The key differencebetween the two types of reactor systems is that whereas in mul-timode cavities several reaction vessels can be irradiated simul-taneously in multi-vessel rotors (parallel synthesis), inmonomode systems only one vessel can be irradiated at the time.In the latter case high throughput can be achieved by integratedrobotics that move individual reaction vessels in and out of themicrowave cavity. Importantly, single-mode reactors processingcomparatively small volumes also have a built in cooling featurethat allows for rapid cooling of the reaction mixture by com-pressed air after completion of the irradiation period (see Figure2). The dedicated single-mode instruments available today canprocess volumes ranging from 0.2 to ca 50 mL under sealed ves-sel conditions (250 °C, ca 20 bar), and somewhat higher volumes(ca 150 mL) under open vessel reflux conditions. In the muchlarger multi-mode instruments several liters can be processedunder both open and closed vessel conditions. For both single-and multimode cavities continuous flow reactors are nowadaysavailable that already allow the preparation of kilograms of mate-rials using microwave technolog.

Figure 2. Temperature (T), pressure (p), and power (P) profile

for a 3 mL sample of methanol heated under sealed vessel

microwave irradiation conditions.

This lecture will highlight recent applications of controlledmicrowave heating technology from our laboratory,1 involvingtransition metal-mediated reactions, heterocycle synthesis, theuse of solid-phase synthesis and of polymer-supported reagents.A variety of processing techniques as well as scle-up exampleswill be discussed.

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1 For a review, see: Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.


The chemical properties and behaviourof supramolecular entities are gov-erned exclusively by the information

stored in their molecular architectures. Whentwo or more identical subunits possess geo-metrical and functional complementarity theymay self-assemble to form a supermoleculeheld together by non-covalent contacts, suchas hydrogen bonds or hydrophobic, electro-static and van der Waals interactions. Themost interesting examples of self-comple-mentary dimers in solution occur when themolecular subunits have hemispherical orcurved structures because the resulting assembly possesses adefined cavity which may encapsulate suitable guest molecules.

Cavitand and calixarene dimersSince the advent in 1993 of the so-called tennis ball,1 a molecu-lar capsule held by complementary hydrogen bonds, develop-ments in the field have been impelled towards larger and morestable assemblies, like soft-balls and related cavities.2

Cavitands containing urea moieties reversibly self-assemble intocylindrical capsules allowing pair-wise complexation of suitablepartners, such as a longer and a shorter carboxylic acid dimer, inan arrangement reminiscent of a “Russian doll” (dimers-inside-dimers) (Figure 1).3 On the other hand, dimeric capsules on thiskind endowed with long hydrocarbon chains at the lower rimtend to self-organize into almost giant reverse vesicles in organ-ic solvents. The vesicles are able to encapsulate dyes.

Figure 1. Pair-wise encapsulation of carboxylic acid dimers ina cavitand dimeric capsule.

Cone-shaped calixarenes endowed with ureafunctions at the wider rim have been exten-sively studied as self-assembling subunits,since they are semi-rigid and substantiallypreorganized.4 Extension of this dimeriza-tion process to the wider though more flexi-ble calix[6]arenes resulted in rather stabletriureidocalix [6]arene dimers (Figure 2a).5

Also, the array of urea-urea hydrogen bondsin tetraureidocalix[4]arenes can be furtherstabilized by an outer shell of additionalhydrogen bonds by attachment of peptidefragments to the ureas (Figure 2b).6

Figure 2. Hydrogen-bonded urea dimers of calixarenes:(a) X-ray structure of a triureidocalix[6]arene dimer containing

two water molecules; (b) tetrapeptidylureido calix[4]arenedimer and top-view of an optimized structure showing the sec-

ond shell of hydrogen bonds.

Helical scaffolds based on guanidinium-oxoanion interactions.Chiral bicyclic guanidines have been widely used in our groupfor the molecular recognition of bio-relevant oxo-anions, such asamino acids or nucleotides.7 Oligomeric guanidinium strandsform helical arrangements around suitable partners, such as sul-fates (anion helicates),8 peptides containing complementary

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Javier de MendozaInstitute of Chemical Research of Catalonia

(ICIQ), Tarragona, Spain andDepartamento de Química Orgánica,

Universidad Autónoma de Madrid, [email protected]

1 Wyler, R.; de Mendoza, J.; Rebek, Jr., J. Angew. Chem. Int. Ed. Engl. 1993, 32, 1699-1701.2 (a) Meissner, R. S.; Rebek, Jr., J.; de Mendoza, J. Science 1995, 270, 1485-1488. Reviews: (b) de Mendoza, J. Chem. Eur. J. 1998, 4, 1373-1377. (c) Conn, M. M.; Rebek,Jr., J. Chem. Rev. 1997, 97, 1647-1668. (d) Rebek, Jr., J. Acc. Chem. Res. 1999, 32, 278-286.3 Ebbing, M. H. K.; Villa, M. J.; Valpuesta, J. M.; Prados, P.; de Mendoza, J. Proc. Natl. Acad. Sci. USA 2002, 99, 4962-4966.4 (a) Shimizu, K. D.; Rebek, Jr., J. Proc. Natl. Acad. Sci. USA 1995, 92, 12403-12407. (b) Mogck, O.; Böhmer, V.; Vogt, W. Tetrahedron 1996, 52, 8489-8496.5 González, J. J.; Ferdani, R.; Albertini, E.; Blasco, J. M.; Arduini, A.; Pochini, A.; Prados, P.; de Mendoza, J. Chem. Eur. J. 2000, 6, 73-80.6 Rincón, A. M.; Prados, P.; de Mendoza, J. J. Am. Chem. Soc. 2001, 123, 3493-3498.7 (a) Galán, A.; de Mendoza, J.; Toiron, C.; Bruix, M.; Deslongchamps G.; Rebek, Jr., J. J. Am. Chem. Soc. 1991, 113, 9424-9425. (b) Galán, A.; Andreu, D.; Echavarren,A. M.; Prados, P.; de Mendoza, J. J. Am. Chem. Soc. 1992, 114, 1511-1512. (c) Deslongchamps, G.; Galán, A.; de Mendoza J.; Rebek, Jr., J. Angew. Chem. Int. Ed. Engl.1992, 31, 61-63. (d) Andreu, C.; Galán, A.; Kobiro, K.; de Mendoza, J.; Park, T. K.; Rebek, Jr., J.; Salmerón, A.; Usman, N. J. Am. Chem. Soc., 1994, 116, 5501-5502. (e)Breccia, P.; Van Gool, M.; Pérez-Fernández, R.; Martín- Santamaría, S.; Gago, F.; Prados, P.; de Mendoza, J. J. Am. Chem. Soc. 2003, 125, 8270-8284.8 Sánchez-Quesada, J.; Seel, C.; Prados, P.; de Mendoza, J.; Dalcol, I.; Giralt, E. J. Am. Chem. Soc. 1996, 118, 277-278.


aspartate or glutamate residues,9 or even protein surfaces.10

Recently, these oligomers have been employed as efficient non-peptidic cell penetrating agents, with selectivity for mitochon-dria.11 An example of a carboxylate (A) - guanidinium (B) ABBApolymeric self-assembly will be provided.

Ureido-pyrimidinone scaffolds.Since hydrogen bonds are weak, for robust and extended assem-blies a complex network of donors (D) and acceptors (A) is nec-essary, such as in the four-fold (DDAA-AADD) dimers of 2-ure-ido-4[1H]-pyrimidinones (UPy).12 UPy’s can be used to stronglylink two calix[4]arenes (in 1,3-alt conformation) through a net-work of eight hydrogen bonds. The two dimeric UPy platforms,held together by the calixarenes, display syn-anti isomerism(Figure 3a).13

Attachment of two 2-ureido-4[1H]-pyrimidinones to a centralspacer results in a cyclic array that could formally be describedas a rosette (Figure 3b). However, depending on the nature andsize of the R substituents the dimeric UPy surfaces can rotateabout the spacer-urea bond so as the resulting cyclic oligomers

are non-planar or tubular. The number of subunits in the mainaggregate is strongly dependent on the angle between the twoUPy subunits attached to the central spacer. Thus, for m-disubsti-tuted benzenes (120o) the rosette is hexameric whereas for 1,3-disubstituted adamantane (109.5o) the self-assembly is a pen-tamer.14

Figure 3. Self-assembly based on ureido-pyrimidinone quadru-ple hydrogen-bonds:

(a) 1,3-alt-calixarene dimers, (b) Rosettes and tubes

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9 (a) Peczuh, M. W.; Hamilton, A. D.; Sánchez-Quesada, J.; de Mendoza, J.; Haack, T.; Giralt, E. J. Am. Chem. Soc. 1997, 119, 9327-9328. (b) Haack, T.; Peczuh, M. W.;Salvatella, X.; Sánchez-Quesada, X.; de Mendoza, J.; Hamilton, A. D.; Giralt, E. J. Am. Chem. Soc. 1999, 121, 11813-11820. (c) Salvatella, X.; Peczuh, M. W.; Gairí, M.;Jain, R. K.; Sánchez-Quesada, J.; de Mendoza, J.; Hamilton, A. D.; Giralt, E. Chem Commun. 2000, 1399-1400. (d) Orner, B. P.; Sánchez-Quesada, J.; de Mendoza, J.; Giralt,E.; Hamilton, A. D. Angew. Chem. Int. Ed. 2002, 41, 117-119.10 (a) Breccia, P.; Boggetto, N.; Pérez-Fernández, R.; Van Gool, M.; Takahashi, M.; René, L.; Prados, P.; Badet, B.; Reboud-Ravaux, M.; de Mendoza, J. J. Med. Chem. 2003,46, 5196-5207. (b) Salvatella, X.; Martinell, M.; Gairí, M.; Mateu, M.; Feliz, M.; Hamilton, A. D.; de Mendoza, J.; Giralt, E. Angew. Chem. Int. Ed. 2004, 43, 196-198.11 Fernández-Carneado, J.; Van Gool, M.; Martos, V.; Castel, S.; Prados, P.; de Mendoza, J.; Giralt, E. J. Am. Chem. Soc. 2005, 127, 869-874.12 (a) Sijbesma, R. P.; Beijer, F. H.; Brunsveld, L.; Folmer, B. J. B.; Hirschberg, J. H. K. K.; Lange, R. F. M.; Lowe, J. K. L.; Meijer, E. W. Science 1997, 278, 1601-1604.(b) Beijer, F. H.; Kooijman, H.; Spek, A. L.; Sijbesma, R. P.; Meijer, E. W. Angew. Chem. Int. Ed. 1998, 37, 75-78. (c) Soentjens, S. H. M.; Sijbesma, R. P.; van Genderen,M. H. P.; Meijer, E. W. J. Am. Chem. Soc. 2000, 122, 7487-7493.13 González, J. J.; Prados, P.; de Mendoza, J. Angew. Chem. Int. Ed. 1999, 38, 525-528.14 Keizer, H. M.; González, J. J.; Segura, M.; Prados, P.; Sijbesma, R. P.; Meijer, E. W.; de Mendoza, J. Chem. Eur. J. 2005, 11, in press.


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