Index [] · Supramolecular chemistry is intrinsically a dynamic chemistryin view of the lability of the interactions ... Supramolecular Chemistry: Concepts and Perspectives,VCH Weinheim,

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Index

5 Introduction

7 From Supramolecular Chemistry to Constitutional Dynamic ChemistryJean-Marie Lehn. Nobel Laureate in Chemistry 1987

8 Catenanes, Rotaxanes and Molecular MachinesJean-Pierre Sauvage

10 Fluorous Mixture Synthesis Approaches to Natural Product Stereoisomer LibrariesDennis Curran

12 The Awesome Power of MetathesisAlois Fürstner

14 New Approaches for the Synthesis of Complex PeptidesFernando Albericio

17 Domino and Multiple Pd-Catalyzed Reactions for the Efficient Synthesis of Natural Products and MaterialsLutz F. Tietze

19 DNA Charge Transport for DNA Damage and RepairJacqueline K. Barton

22 Streamlining Synthesis via C-H OxidationM. Christina White

23 Recent Studies in Alkaloid Total SynthesisLarry E. Overman

24 The Catalytic Cycle of Discovery in Total SynthesisPhil S. Baran

26 Palladium -and Nickel- Catalyzed Coupling ReactionsGregory C. Fu

27 New Developments of Organometallic Catalysts in Organic SynthesisJean-Pierre Genet

31 New Applications of Quinones and Quinols in Asymmetric SynthesisM. Carmen Carreño

34 Stereoselective Transformations of AllylaminesSteve G. Davies

36 The Evolution of Lilly Oncology, from Targeted Cytotoxic Agent (Alimta®) to Kinase InhibitorsJoe Shih

39 Lilly Distinguished Career Award. Chemistry 2008

41 Speakers & Chairpersons

PROMOTER/SPONSOR

55

CHEMISTRY: SCIENCE AT THE FRONTIER

Chemistry is, often called the central science,because of its role in connecting “hard” sciencessuch as physics with the “soft” sciences such asbiology or medicine, producing the more excitingadvances in the frontier with other scientificareas. It is in that way chemistry is producingseminal contributions to biomedicine, helping thecreation of new drugs.

Inventing and developing a new drug is a long,complex, costly and risky process that has fewpeers in the industry world. Historically, as itstoday, creation of a new drug rides much–although not only- over the wave of newsynthetic technologies. The new syntheticmethods, by which scientists can createincreasingly complex molecules, are often in thebasis of the new, and more efficient molecularentities recently developed. In addition, presentminiaturization and automation of testingtechniques is producing a parallel effort inimprovement of synthetic methodology.

The Thirteenth Lilly Foundation ScientificSymposium “Chemistry: Science at the Frontier”had tried to mix scientists with different views andcultures in their approach to creation of newmolecules, from the use of parallel fluoroustechniques to obtain libraries of natural products,to organometallic chemistry in all his presentpossibilities, expanding the available syntheticmethods as never seen before; from newapproaches to the synthesis of alkaloids, to thesynthesis of complex peptides; from catalysis intheir last approaches, to enantioselectivesynthesis; from purely medicinal chemistrydirected to precisely chosen targets, to chemicalbiology related to DNA chemistry; fromsupramolecular chemistry developments, to thechemistry of catenanes, rotaxanes and molecularmachines.

In all these lectures an equilibrium was alwaysintended between two philosophies: one takes innature its inspiration, while the other uses newtools and processes which science is putting inour hands, and in our labs. This combination oflectures would make and exciting offer aboutmodern chemistry.

In previous symposia, a mixture of wellestablished masters with young emerging

13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM

Chemistry: Science at theFrontier

13ª FUNDACIÓN LILLY SIMPOSIO CIENTÍFICO

Química,Ciencia en lafrontera

A la química con frecuencia se la denomina “laciencia central”, debido a su papel como puenteentre ciencias "duras" como la física, y ciencias"blandas" como la biología o la medicina,favoreciendo los avances mas interesantes en lafronteras con otras áreas científicas. De estamanera la química está contribuyendo a abrirnuevas perspectivas a la biomedicina, ayudandoa la creación de nuevos fármacos.

La invención y desarrollo de un nuevo fármacoes un proceso largo, complejo, costoso yarriesgado que tiene pocos ejemplos similares enel mundo industrial. Históricamente, como en laactualidad, la creación de un nuevo fármaco hacabalgado sobre todo –aunque no solamente-sobre la onda de las nuevas metodologías desíntesis. Los nuevos métodos de síntesis, através de los cuales los científicos pueden crearmoléculas cada vez más complejas, seencuentran con frecuencia en la base de lasnuevas y cada vez más eficaces entidadesmoleculares desarrolladas. De forma adicional, laactual miniaturización y automatización de lastécnicas de ensayo biológico está produciendoun avance paralelo en la mejora de lametodología de síntesis.

El decimotercero Simposio Científico de laFundación Lilly “Química, Ciencia en la Frontera”ha intentado reunir científicos con diferentespuntos de vista y culturas en la creación denuevas moléculas. Desde el uso de técnicasfluorosas en paralelo para obtener productosnaturales hasta la química organometálica, contodas sus posibilidades actuales, que estáproduciendo la expansión y disponibilidad denuevos métodos sintéticos como nunca se habíavisto anteriormente; desde la catálisis en susúltimas aproximaciones hasta la síntesisenantioselectiva; desde la química médicadirigida con precisión a dianas escogidas hastala biología química relacionada con la químicadel ADN; desde los desarrollos de la químicasupramolecular hasta la química de loscatenanos, rotaxanos y máquinas moleculares.

Hemos pretendido en todas las conferencias elequilibrio entre dos filosofías: una, que toma dela naturaleza su fuente de inspiración, y otra quehace uso de nuevas herramientas que la ciencia

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specialists has been sought by the committee, in theexpectation that this would create an inspiring andunique atmosphere useful to all participants in theSymposium.

Scientific Organizing Committee

va poniendo en nuestras manos y en nuestroslaboratorios. Esperamos que de esta combinaciónde enfoques resulte una oferta atractiva para laquímica moderna.

Como en simposios anteriores, el Comité Científicoha pretendido una mezcla de maestros reconocidoscon jóvenes investigadores, esperando con ellocrear una atmósfera única e inspiradora, para todoslos participantes en el Simposio.

Comité Científico Organizador

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Supramolecular chemistry is actively exploringsystems undergoing self-organization, i.e. systemscapable of spontaneously generating well-definedfunctional supramolecular architectures by self-assembly from their components, on the basis of themolecular information stored in the covalentframework of the components and read out at thesupramolecular level through specific interactionalalgorithms, thus behaving as programmed chemicalsystems.

Supramolecular chemistry is intrinsically a dynamicchemistry in view of the lability of the interactionsconnecting the molecular components of asupramolecular entity and the resulting ability ofsupramolecular species to exchange theirconstituents. The same holds for molecularchemistry when the molecular entity containscovalent bonds that may form and break reversibility,so as to allow a continuous change in constitution byreorganization and exchange of building blocks.These features define a Constitutional DynamicChemistry (CDC) on both the molecular andsupramolecular levels.

CDC introduces a paradigm shift with respect toconstitutionally static chemistry. The latter relies ondesign for the generation of a target entity, whereasCDC takes advantage of dynamic diversity to allowvariation and selection. The implementation ofselection in chemistry introduces a fundamentalchange in outlook. Whereas self-organization bydesign strives to achieve full control over the outputmolecular or supramolecular entity by explicitprogramming, self-organization with selectionoperates on dynamic constitutional diversity inresponse to either internal or external factors toachieve adaptation.

Applications of this approach in biological systemsas well as in materials science will be described.

The merging of the features: - information andprogrammability, - dynamics and reversibility, -constitution and structural diversity, points towardsthe emergence of adaptive chemistry.

References

[11] Lehn, J.-M., Supramolecular Chemistry: Concepts andPerspectives, VCH Weinheim, 1199955..[22] Lehn, J.-M., Dynamic combinatorial chemistry andvirtual combinatorial libraries, Chem. Eur. J., 1199999, 5, 2455.[33] Lehn, J.-M., Programmed chemical systems: Multiplesubprograms and multiple processing/expression ofmolecular information, Chem. Eur. J., 2000000, 6, 2097.[[44]] Lehn, J.-M., Toward complex matter: Supramolecularchemistry and self-organization, Proc. Natl. Acad. Sci. USA,22000022, 99, 4763.[55] Lehn, J.-M., Toward self-organization and complexmatter, Science, 2200022, 295, 2400.[66] Lehn, J.-M., Dynamers : Dynamic molecular andsupramolecular polymers, Prog. Polym. Sci., 2000055, 30, 814.[77] Lehn, J.-M., From supramolecular chemistry towards constitutional dynamic chemistry and adaptivechemistry, Chem. Soc. Rev., 220007, 36, 151.

FromSupramolecularChemistry toConstitutionalDynamicChemistry

Jean-Marie Lehn

ISIS, Université Louis Pasteur, Strasbourg and Collège de France, Paris, France

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The field of catenanes and rotaxanes [1] isparticularly active, mostly in relation to the novelproperties that these compounds may exhibit(electron transfer, controlled motions, mechanicalproperties, etc…). In addition, catenanes representattractive synthetic challenges in molecularchemistry. The creation of such complex functionalmolecules as well as related compounds of therotaxane family demonstrates that syntheticchemistry is now powerful enough to tackle problemswhose complexity is sometimes reminiscent ofbiology, although the elaboration of molecularensembles displaying properties as complex asbiological assemblies is still a long-term challenge.The most efficient strategies for making suchcompounds are based on template effects. The firsttemplated synthesis [2] relied on copper(I). The useof Cu(I) as template allows to entangle two organicfragments around the metal centre beforeincorporating them in the desired catenanebackbone. Organic templates assembled viaformation of aromatic acceptor-donor complexesor/and hydrogen bonds have also been verysuccessful. Nowadays, numerous templatestrategies are available which have led to thepreparation of a myriad of catenanes and rotaxanesincorporating various organic or inorganic fragmentsand displaying a multitude of chemical or physicalfunctions.

A particularly promising area is that of syntheticmolecular machines and motors [3]. In recent years,several spectacular examples of molecular machinesleading to real devices have been proposed, basedeither on interlocking systems or on non interlockingmolecules [4]. In parallel, more and moresophisticated molecular machines have beenreported, frequently based on multicomponentrotaxanes. Particularly noteworthy are the muscle-like compounds reported by two groups [5,6], amolecular elevator [7], illustrating the complexity thatdynamic threaded systems can reach.

One of the prototypical systems is a bistablecatenane whose motions are triggered by anelectrochemical signal. The compound and itsvarious forms are represented in Figure 1 [4a].Copper is particularly well adapted to the design ofmolecular machines since its two oxidation states

have distinct stereo-electronic requirements:whereas copper(I) is fully satisfied in a 4-coordinate(tetrahedral) geometry, copper(II) requires moreligands in its coordination sphere. A5-coordinatesituation is more adapted to the divalent state, asillustrated on Figure 1, Cu(II) being coordinated toboth a 1,10-phenanthroline ligand and a 2,2’,2’’,6’’-terpyridine.

Figure 1. The prototypical bistable copper-complexedcatenane. The compound undergoes a completemetamorphosis by oxidising Cu(I) or reducing Cu(II). Theprocess is quantitative but slow.

In the course of the last 12 years, the responsetimes of the various molecular machines made inStrasbourg have been considerably shortened. Thefastest system is a rotaxane, able to undergo a“pirouetting” motion under the action of the sameredox signal as for the catenane (CuII/CuI) andwhose axis incorporates a non sterically hinderingchelate of the 2,2’-bipyridine type. Now, the motionstake place on the micro- to milli-second timescale [8].

In recent years, our group has also proposedtransition metal-based strategies for making two-dimensional interlocking and threaded arrays [9].Large cyclic assemblies containing several copper(I)centres could be prepared which open the gate tocontrolled dynamic two-dimensional systems andmembrane-like structures consisting of multiplecatenanes and rotaxanes. Two examples arepresented in Figure 2.

Catenanes,Rotaxanes and MolecularMachines

Jean-Pierre Sauvage

Institut de Chimie, Laboratoire de Chimie Organo-Minérale, Université Louis Pasteur CNRS/UMR 7177, Strasbourg, France

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Figure 2. 2-dimensional interlocking arrays built via the copper(I)-template strategy. The "gathering and threading effect "of Cu(I) leads to the quantitative formation of the rotaxane tetramers (A) or (B) from thecorresponding organic fragments and stoichiometricamounts of copper(I) [ref. [9a] and [9b] respectively].

The X-ray structure of a compound similar to (B) wasrecently solved by the group of Kari Rissanen(Finland). It is shown in Figure 3.

Figure 3. X-ray structure of the [2]rotaxane tetramer. Theblack dots of the Scheme (right) represent the 4 copper(I)atoms.

Finally, in the course of the last four years, we havebeen much interested in endocyclic but non stericallyhindering chelates [10]. These compounds are basedon carefully designed 3,3'-biisoquinoline (biiq)derivatives. Some of them have even beenincorporated into macrocyclic compounds. Aparticularly efficient and fast moving molecular"shuttle" based on such a chelate has been madeand investigated as well as three-componentmolecular entanglements constructed by assemblingthree such ligands around an octahedral metalcentre. These biisoquinoline-based compounds areparticularly promising in relation to fast-respondingcontrolled dynamic systems and novel topologies. AnX-ray structure of a biiq-incorporating ring ispresented in Figure 4 as well as that of an iron(II)complex containing three such ligands and thusleading to the formation of a three-componententanglement.

Figure 4. Endo topic but sterically non hindering ligands areused to construct fast moving molecular shuttles and three-component entanglements [9].

To conclude, It is still not sure whether the fields ofcatenanes, rotaxanes and molecular machines will

lead to applications in a short term prospective,although spectacular results have been obtained inthe course of the last few years in relation toinformation storage and processing at the molecularlevel [11]. From a purely scientific viewpoint, the fieldof molecular machines is particularly challenging andmotivating: the fabrication of dynamic molecularsystems, with precisely designed dynamic properties,is still in its infancy and will certainly experience arapid development during the next decades.

References

[1] a) For early work, see: G. Schill, Catenanes, Rotaxanesand Knots, Academic Press, New York and London, 1971;b) C. O. Dietrich-Buchecker, J.-P. Sauvage, Chem. Rev.1987, 87, 795-810; c) D. B. Amabilino, J. F. Stoddart, Chem.Rev. 1995, 95, 2725-2828; d) J.-P. Sauvage, C. Dietrich-Buchecker, Molecular Catenanes, Rotaxanes and Knots,Wiley-VCH, Weinheim, 1999.[2] C.O. Dietrich-Buchecker, J.-P. Sauvage, J.-P. Kintzinger,Tet. Letters, 1983, 24, 5095-5098. C.O. Dietrich-Buchecker,J.-P. Sauvage, J.-M. Kern, J. Am. Chem. Soc., 1984, 106,3043-3044.[3] a) Acc. Chem. Res. 2001, 34, 409-522 (Special Issue onMolecular Machines) and references therein; b) J.-P.Sauvage, Ed., Structure and Bonding – Molecular Machinesand Motors, Springer, Berlin, Heidelberg, 2001; c) V. Balzani,M. Venturi, A. Credi, Molecular Devices and Machines – AJourney Through the Nanoworld, Wiley-VCH, Weinheim,2003; d) E. R. Kay, D. A. Leigh, F. Zerbetto, Angew. Chem.2007, 119, 72-196; Angew. Chem. Int. Ed. 2007, 46, 72-191.[4] a) A. Livoreil, C.O. Dietrich-Buchecker, J.-P. Sauvage, J. Am. Chem. Soc. 1994, 116, 9399-9400; b) N. Koumura,R. W. J. Zijistra, R. A. van Delden, N. Harada, B. L. Feringa,Nature 1999, 401, 152-155; c) C. P. Collier, G. Mattersteig,E. W. Wong, Y. Luo, K. Beverly, J. Sampaio, F. M. Raymo,J. F. Stoddart, J. R. Heath, Science 2000, 289, 1172-1175;d) D. A. Leigh, J. K. Y. Wong, F. Dehez, F. Zerbetto, Nature2003, 424, 174-179; e) B. Korybut-Daszkiewicz, A. Wieçkowska, R. Bilewicz, S. Domagata, K. Wozniak,Angew. Chem. 2004, 116, 1700-1704; Angew. Chem. Int.Ed. 2004, 43, 1668-1672; f) L. Fabbrizzi, F. Foti, S. Patroni,P. Pallavicini, A. Taglietti, Angew. Chem. 2004, 116, 5183-5186; Angew. Chem. Int. Ed. 2004, 43, 5073-5077.[5] a) M. C. Jiménez, C. Dietrich-Buchecker, J.-P. Sauvage,Angew. Chem. Int. Ed. 2000, 39, 3284-3287; b) M. C.Jiménez-Molero, C. Dietrich-Buchecker, J.-P. Sauvage,Chem. Eur. J. 2003, 8, 1456-1466.[6] Y. Liu, A. H. Flood, P. A. Bonvallet, S. A. Vignon, B. H.Northrop, J. O. Jeppesen, T. J. Huang, B. Brough, M. Baller,S. N. Magonov, S. D. Solares, W. A. Goddard, C.-M. Ho, J.F. Stoddart, J. Am. Chem. Soc. 2005, 127, 9745-9759.[7] J. D. Badjic, V. Balzani, A. Credi, S. Serena, J. F.Stoddart, Science 2004, 303, 1845-1849.[8] U. Létinois-Halbes, D. Hanss, J. Beierle, J.-P. Collin, J.-P. Sauvage, Org. Lett. 2005, 7, 5753.[9] a) T. Kraus, M. Budesinsky, J. Cvacka, J.-P. Sauvage,Angew. Chem. Int. Ed. 2006, 45, 258-261. b) J.-P. Collin, J.Frey, V. Heitz, E. Sakellariou, J.-P. Sauvage, C. Tock, NewJ. Chem. 2006, 30, 1386-1389.[10] a) F. Durola, L. Russo, J.-P. Sauvage, K. Rissanen, O.S. Wenger, Chem. Eur. J. 2007, 13, 8749-8753. b) F.Durola, J.-P. Sauvage, Angew. Chem. Int. Ed. 2007, 46,3537-340.[11] J. E. Green, J. W Choi, A. B., Y. Bunimovich, E.Johnston-Halperin, E. DeIonno, Y. Luo, B. A. Sheriff, K. Xu,Y. S. Shin, H.-R. Tseng, J. F. Stoddart, J. R. Heath, Nature,2007, 445, 415-417

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Fluorous MixtureSynthesis ofNatural ProductStereoisomerLibraries

Dennis P. Curran

Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA

Much current work in the field of fluorous chemistryrelies on the use of fluorous stationary phases forseparation. Following the introduction of fluoroustagging in 1996, [1] we soon introduced thetechnique of fluorous solid phase extraction (FSPE)[2]. The FSPE separation (Figure 1) allows the use ofsmaller (and therefore lighter) fluorous tags, and themethod is especially useful for small scale discoverychemistry and library applications in drug discoveryand other areas [3]. A recent review of FSPEfeatures almost one hundred papers that have usedthe technique [4]. Scores of light fluorous reagents,reactants, catalysts, scavengers and protectinggroups are now commercially available from Aldrich,Waco and Fluorous Technologies, Inc.[5]

Figure 1. Fluorous Solid Phase Extraction: Separatestagged compounds (orange fraction) from untagged ones(blue fraction) by a generic filtration-like process.

Our studies on FSPE soon led us to fluorous HPLCexperiments, and this in turn led to the introductionof “fluorous mixture synthesis”,[6] a technique that wehave since used in many new guises. The underlyingconcepts behind fluorous mixture synthesis, Figure2, are those of solution phase mixture synthesis withseparation and identification tagging. Briefly, a seriesof substrates is tagged with a homologous series offluorous tags. The resulting tagged substrates aremixed and then taken through a multistep synthesisto provide a mixture of tagged products. During thismixture synthesis phase, effort is saved proportionalto the number of compounds that are mixed. Finally,the last mixture is demixed by fluorous HPLC toprovide the individual tagged products, which arethen detagged (deprotected) to provide the finaltarget compounds The concepts of solution phasemixture synthesis are general, and Craig Wilcoxintroduced a new class of oligoethylene (OEG)tags[7].

Fiiggurre 22. Concepts of Fluorous Mixture Synthesis:Substrates are tagged and mixed. Mixture synthesis thenprecedes demixing and detagging.

Soon after the introduction fluorous quasiracemicsynthesis [8], we introduced the concept of completestereoisomer libraries [9] (made by fluorous mixturesynthesis), a concept that has been featured in muchof our natural products work since then. We laterunited fluorous and OEG tags in the technique ofdouble mixture synthesis [10]. These techniqueshave gone well beyond “proof-of-principle”; thederived products (see Figure 3) have been used tosolve structure problems and provide importancebiological information[11,12].

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Figure 3. Natural Products Made by FMS or Double Mixture

Synthesis

All these applications are driven by the favorablefeatures of fluorous tagging in reactions,identification and analysis, and separation. Mostrecently, these features have begun to be recognizedby the chemical biology community, and a new waveof fluorous chemistry appears to be on the horizon.

I warmly thank an excellent cadre of collaboratorsand coworkers for their intellectual and experimentalcontributions as well as for their support andfriendship. I thank the Institute of General MedicalSciences of the National Institutes of Health forsustained funding of our work in fluorous chemistryover more than a decade.

References

[11] Studer, A.; Hadida, S.; Ferritto, R.; Kim, S.-Y.; Jeger, P.;Wipf, P.; Curran, D. P. Science 1199997, 275, 823-826.[22] Curran, D. P.; Hadida, S.; He, M. J. Org. Chem. 119977,62, 6714-6715.[33] Curran, D. P. Aldrichim. Acta 2200066,, 39, 3-9.[44] Zhang, W.; Curran, D. P. Tetrahedron 2200006, 62, 11837-11865.[[55]] DPC owns an equity interest in this company.[66] Luo, Z. Y.; Zhang, Q. S.; Oderaotoshi, Y.; Curran, D. P.Science 22000011, 291, 1766-1769.[77] Wilcox, C. S.; Turkyilmaz, S. Tetrahedron Lett. 2200005, 46,1827-1829.[88] Zhang, Q. S.; Curran, D. P. Chem. Eur. J. 200055, 11,4866-4880.[99] Dandapani, S.; Jeske, M.; Curran, D. P. Proc. Nat. Acad.Sci. 220004, 101, 12008-12012.[110] Wilcox, C. S.; Gudipati, V.; Lu, H. J.; Turkyilmaz, S.;Curran, D. P. Angew. Chem. Int. Ed. 2200005, 44, 6938-6940.[1111] Short review: Zhang, W., Arkivoc 2200004, 101-109.[112] (a) Dandapani, S.; Jeske, M.; Curran, D. P. J. Org.Chem. 220005, 70, 9447-9462. (b) Zhang, W.; Luo, Z.; Chen,C. H. T.; Curran, D. P. J. Am. Chem. Soc. 2200002, 124,10443-10450. (c) Fukui, Y.; Brueckner, A. M.; Shin, Y.;Balachandran, R.; Day, B. W.; Curran, D. P. Org. Lett. 2200006,8, 301-304. (d) Curran, D. P.; Zhang, Q. S.; Richard, C.; Lu,H. J.; Gudipati, V.; Wilcox, C. S. J. Am. Chem. Soc. 2200006,128, 9561-9573. (e) Curran, D. P.; Moura-Letts, G.;Pohlman, M. Angew. Chem. Int. Ed. 220066, 45, 2423-2426.(f) Yang, F.; Newsome, J. J.; Curran, D. P. J. Am. Chem.Soc. 220066, 1288, 14200-14205.

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The AwesomePower ofMetathesis

Alois Fürstner

Max-Planck-Institut für Kohlenforschung,Mülheim an der Ruhr, Germany

Although olefin metathesis had already beendiscovered during early studies on Zieglerpolymerization and had found industrial applicationsshortly thereafter, it was not until the 1990th that thistransformation gained real significance for advancedorganic synthesis. The last decade, however, hasseen an explosive growth of interest in metatheticconversions in general, making clear that thisreaction is one of the most fascinating and versatileprocesses in the realm of homogeneous catalysis.

Scheme 1. Basic catalytic cycle of RCM.

Alkene metathesis refers to the redistribution of thealkylidene moieties of a pair of olefins effected bycatalysts that are able to cleave and to form C-C-double bonds under the chosen reaction conditions.This mutual alkylidene exchange occurs via asequence of formal [2+2] ycloadditions/cycloreversions(Chauvin mechanism)[1] involving metal alkylideneand metallacyclobutane species as the catalyticallycompetent intermediates. Among the many possibleuses of metathesis, the ring closing olefin metathesis(RCM) of dienes to cycloalkenes depicted in Scheme1 remains particularly popular.

It was the development of well defined metalalkylidene complexes combining high catalyticactivity with an excellent tolerance towards polarfunctional groups that has triggered this avalanche ofinterest. The most prominent and versatile ones are

molybdenum alkylidenes developed by Schrock[2]

and five coordinate ruthenium carbene complexesintroduced by Grubbs (Scheme 1)[33]. Thesecommercially available complexes define thestandard in the field and have reached an immensepopularity as witnessed by a truly prolific number ofsuccessful applications. They also serve as “leadstructures” for the development of even morepowerful “second generation” catalysts bearing N-heterocyclic carbenes as ancillary ligands. The latter

effect even the formation oftetrasubstituted cycloalkenes and aresufficiently reactive to activate electrondeficient? as well as certain electronrich alkenes that were beyond reach ofthe parent Grubbs catalyst.

RCM is essentially driven by entropy;the ensuing equilibrium is constantlyshifted towards the cycloalkene byloss of ethylene (or another volatileolefin) formed as the by-product (cf.Scheme 1). The inherent competitionbetween cyclization of a given dieneand its polymerization via acyclic dienemetathesis (ADMET) strongly dependson the ring size formed as well as onpre-existing conformational constraintsand can be influenced to some extent

by adjusting the dilution. While five to seven-membered carbo- and heterocycles usually formwithout incident, medium- and large rings are moredelicate and deserve careful consideration duringretrosynthetic planning. It is known that chelation ofthe metal carbene intermediates by the polarsubstitutents in the substrates plays a decisive rolefor productive macrocyclization [[44]; hence, properanalysis of the donor strength of the heteroatoms,their distance and relative orientation towards thealkene groups allows for reliable planning even ofcomplex target molecules of virtually any ring size. Afew recent examples of bioactive compounds formedby RCM-based total synthesis protocols by our groupare shown in Scheme 2 [[5]].

A major advantage of RCM over more conventionalapproaches stems from the exceptionalchemoselectivity of the available metathesis

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catalysts for the activation of olefins in the presenceof most other functional groups. This, in turn, allowsto avoid lengthy protecting group manipulations, thusrendering many metathesis based approachesunprecedentedly short and economic in the overallnumber of steps. As a consequence modernmetathesis chemistry has a profound impact on thelogic of synthesis. Its enormous relevance is furtherincreased by the fact that the modern catalysts arefully operative under aqueous conditions as well asin unconventional media such as ionic liquids orsupercritical CO2.

Despite this highly attractive overall profile and thematurity reached in recent years, several problemsremain yet to be solved. One of the major challengesis the missing control over the geometry of theemerging double bond during RCM-based formationsof macrocycles as well as in many cross metathesisreactions. One way to tackle this problem takesrecourse to ring closing alkyne metathesis (RCAM)followed by semi-reduction of the cycloalkynes thusformed (Scheme 3) [6]. This approach has beensuccessfully implemented into various totalsyntheses, including a fully selective and highyielding route to the promising anti-cancer agentepothilone A [7].

Schheemee 3. Ring Closing Alkyne Metathesis RCAM)/Semi-Reduction – Selected Examples of Natural Productsprepared by this Methodology

References

[11] Y. Chauvin, Angew. Chem. Int. Ed. 2200066, 45, 3740(Nobel lecture).[22] R. R. Schrock, Angew. Chem. Int. Ed. 2200006, 45, 3748(Nobel lecture).[[33]] R. H. Grubbs, Angew. Chem. Int. Ed. 22000066, 45, 3760(Nobel lecture).[44] a) A. Fürstner, K. Langemann, J. Org. Chem. 1999966, 61,3942; b) A. Fürstner, O. R. Thiel, C. W. Lehmann,Organometallics 220022, 21, 331.[55] A. Fürstner, Angew. Chem. Int. Ed. 2200000, 39, 3013.[66] A. Fürstner, G. Seidel, Angew. Chem. Int. Ed. Engl.19998, 37, 1734.[77] A. Fürstner, P. W. Davies, Chem. Commun. 2000055, 2307.

Scheme 2. Natural products prepared by our group via RCM.

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NuevasEstrategias para la Síntesisde PéptidosComplejosNew Approaches for theSynthesis of ComplexPeptides

Fernando Albericio

Institute for Research in Biomedicine, Barcelona Science Park, University of Barcelona, Spain

Abstract

Recent years have witnessed a revival in the field ofpeptides. Success in the field of peptide research ispartly attributable to the fact that it is now possible tosynthesize almost any peptide on both small andlarge scales. In this communication, several topicswill be discussed. First of all, we will present a shortoverview of the use of peptides in medicine. Next,the most used synthetic strategies, which involvesolid-phase, a combination of solid-phase solution,and chemical ligation, will be discussed for thesynthesis of complex peptides from marine origin.

Introducción

Durante los últimos años se ha visto un aumentoimportante en el número de péptidos como APIs(ingredientes farmacéuticos activos). Así, hasta elinicio de los años 90 únicamente estaban en elmercado los análogos de LH-RH (leuprolide,goserelin, gonadorelin…), los análogos desomatostatina y las diferentes calcitoninas. A finalesde los 90 e inicios de los 2000, el mercadoexperimentó un crecimiento reducido, pero a partirdel año 2004 se ha experimentado un crecimientomucho más importante, con nuevas entidadesquímicas (NCE) introducidas. Así, en el año 2004, el volumen de negocio fue de 5.9 billones de US $ y en el 2006 de 7.94 billones de US $, lo querepresenta un crecimiento anual de dos dígitos.

Aunque la oncología continúa siendo la principalindicación terapéutica para los péptidos, los NCErecientemente introducidos han ampliado susindicaciones terapéuticas. Así, tenemos péptidospara inmunología (glatiramer), diabetes (exenatide y pramlintide), afecciones cardiovasculares(bivalirudin, eptifibatide), infecciones (enfuvirtide ythymalfasin), reproducción (atosigan), sistemanervioso central (ziconotide y taltirelin), yenfermedades óseas (teriparatide). Asimismo en elaño 2006, había 136 péptidos en fases clínicas,mientras que en el 2004, eran únicamente 70.

Cuáles son las razones para este renacimiento delos péptidos como fármacos. En primer lugar, unfracaso relativo de las llamadas “small molecules”(pequeñas moléculas), luego una relativa facilidadpara desarrollar los programa de química médica

basados en péptidos (facilidad para alcanzar fasesclínicas, necesidad de menor número deinvestigadores para alcanzar los hitos), todo elloacompañado del enorme impulso que se ha dado alas nuevas formulaciones de “drug delivery”(administración de fármacos).

Otro hecho interesante es la evolución que hasufrido la propia estructura de los péptidos en elmercado o en fase clínicas. En la últimas decadas,eran péptidos basados en secuencias naturales, derelativo bajo peso molecular. En estos momentos,las moléculas son más sofisticadas, con secuenciasmás largas, más estructurados, conteniendoaminoácidos no naturales y partes no peptídicas(ciclos, péptidos pegilados, con ácidos grasos, concarbohidratos, con cadenas múltiples…).

Un factor importante en este “boom” de los péptidoscomo fármacos lo podemos encontrar en eldesarrollo extraordinario que ha sufrido la fase sólidacomo estrategia de síntesis. Así, los nuevossoportes sólidos, grupos protectores y agentes deacoplamiento permiten sintetizar a escala demultiquilogramos casi cualquier estructura. Ennuestra presentación se discutió algunas de lasmetodologías desarrolladas en nuestro laboratorio,tales como la utilización de soportes sólidos depolietilenglicol, reactivos de acoplamiento/protecciónbasados en la hexafluoroacetona (HFA), el p-nitrobenciloxicarbonilo (pNZ) como grupo protectorortogonal, y la síntesis de una molécula complejacomo es la oxatiocoralina.

Resinas de polietilenglicol

Recientemente y en colaboración con Côté [1],hemos desarrollado una resina totalmente de PEG(ChemMatrix). Las propiedades óptimas de PEG sondebidas a las distribuciones vecinal de enlacescarbono-oxígeno en la cadena, las cuales provocanque PEG adopte una estructura helicoidal coninteracciones gauche entre los enlaces polarizados.PEG puede exhibir tres organizaciones helicoidalesdistintas, la primera, enormemente hidrofóbica, lasegunda, de hidrofobicidad intermedia, y la tercera,hidrofílica. La naturaleza amfifílica de PEG hace quela resina solvate bien en disolventes polares y nopolares.

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EEssttrruuccttuurraa QQuuíímmiiccaa ddee rreessiinnaa CChheemmMMaattrriixx. Se ha utilizado la resina ChemMatrix para la síntesis depéptidos complejos y también de pequeñas proteínas (> 60aa) mediante una síntesis secuencial. Como ejemplo,podemos citar la proteína asociada al virus del SIDA.

Química basada en la HFA

La química de la hexafluoroacetona (HFA), que esun reactivo bidentado para la protección y laactivación de los ácidos carboxílicos a-funcionalizadosse ha desarrollado y adaptado a la fase sólida. Laslactonas formadas a partir de a-hidroxiácidosrepresentan ésteres activos, que pueden sufrir unataque nucleófilo y rendir derivados de ácidocarboxílico. Se han utilizado los derivados de HFApara la preparación de aminoácidos no-naturales,que a su vez se han incorporado en péptidos conactividad biológica [3]. Esta química se puede aplicara la síntesis de péptidos con arquitectura compleja,como son lo péptidos siameses que compartenalgún enlace.

Aplicaciones de los sistema de protección/activación de laHFA

pNZ, Grupo Protector Ortogonal.

El grupo p-nitrobenciloxicarbonilo (pNZ) se hautilizado como grupo protector temporal para lafunción a-amino en SPPS. El pNZ, que es ortogonalcon la mayor parte de grupos protectores utilizadosen química de péptidos, se elimina mediantecondiciones neutras en presencia de cantidadescatalíticas de ácido. La utilización del pNZ enquímica Fmoc ha permitido obviar reaccionessecundarias típicas asociadas con la piperidina,tales como la formación de dicetopiperacinas yaspartiimidas. Asímismo, nos ha permitidodesarrollar nuevas estrategias de química ortogonaly convergente, para la síntesis de péptidos queestán en fase clínica como la Kahalalide F. [4]

Mecanismo de eliminación del pNZ

Síntesis de la Oxatiocoralina

La tiocoralina es uno de los nuevos potentes

agentes antitumorales aislados de organismosmarinos el micromonospora sp. Posee variosmotivos communes con una familia de péptidosantibióticos antitumorales, que incluye BE-22179,Triostin A, y Echinomycin. Este grupo de peptidosposeen: a) estructure bicíclica; b) una simetría C2; c) una unidad cromófora de intercalación; d) unaunión ester o tioester en la parte terminal de lacadena peptídica; e) un puente disulfuro o unanálogo en el medio de la cadena peptídica; f) lapresencia de varios N-metil amino ácidos; y g) unaminoácido no natural de configuración D. Así, lafunción amino N-terminal de la tiocoralina estáterminada con ácido 3-hidroxiquináldico, cuya unidadactúa grupo cromóforo intercalador; las dos cadenaspeptídicas son puentes con uniones tioester ydisulfuro de resíduos Cys, siendo los dos queproporcionan el puente disulfuro N-metilado y Dconfiguración asi como los dos resíduos Cys(Me).Todas estas características permiten a esta familiade péptidos capacidad de enlazarse con DNA porbisintercalación, y además alterar el ciclo celularvital. La tiocoralina inhibe la elongación de DNA porDNA a polimerasa a concentraciones que inhiben laprogresión del ciclo celular y la clonogenicidad. Sinembargo, una desventaja para el uso clínico detiocoralina es su baja solubilidad en todos losmedios utilizados para su administración. Unaalternativa consiste en la preparación decompuestos que mantengan una topología similar,presentando distinto patrón de solubilidad. Así, se hasintetizado el derivado oxa de tiocoralina, donde losenlaces tioester se han sustituido por esteres (estodesde el punto de vista de building blocks implica lautilización de resíduos de Ser en lugar de Cys).

Estructura de la Oxatiocoralina

La síntesis se ha llevado a cabo en fase sólidautilizando una resina tipo Wang, cinco diferentesgrupos protectores [Fmoc para la Gly; Fmoc tambiénpara la introducción de la D-Ser, pero se intercambiapor el Boc; Trt para la cadena lateral de la Ser; Allocpara la NMe-Cys(Me); y pNZ para la NMe-Cys(Acm)]; cuatro diferentes métodos deacoplamiento (HATU/DIEA para la incorporaciónsobre los aminoácidos N-metilados; DIPCDI/DMAPpara la esterificación; PyBOP/HOAt/DIEA para lamacrolactamización; EDC·HCl, HOSu para laincorporación del cromóforo). La formación delpuente disulfuro, que se ha realizado en fase sólida,confiere a la molécula una restricciónconformacional que permite evitar totalmente laformación de dicetopiperacinas, que es la principalreacción secundaria que tiene lugar con péptidosN-metilados [55]]. La oxatiocoralina presenta actividadantitumoral en tres líneas celulares.

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Conclusiones

El desarrollo de métodos sintéticos debe serclave en el proceso de descubrimiento de nuevosfármacos. Muchos de ellos estarán inspirados enla naturaleza, puesto que la dificultad sintéticaque presentan muchos de los productos, podráser vencida gracias a las nuevas estrategiassintetizadas. En este sentido, se augura que cadavez más péptidos entrarán en fases clínicas y almercado.

Referencias

[1] García-Martín, F.; Quintanar-Audelo, M.; García-Ramos, Y.; Cruz, L.J.; Gravel, C.; Furic, R.; Côté, S.;Tulla-Puche, J.; Albericio, F. ChemMatrix®, aPolyethylene glycol (PEG)-based Support for the Solid-Phase Synthesis of Complex Peptides. J. Comb. Chem.,8, 213-220 (2006).[2] Frutos, S.; Tulla-Puche, J.; Albericio, F.; Giralt, E.Chemical Synthesis of 19F-labeled HIV-1 ProteaseUsing Fmoc-Chemistry and ChemMatrix Resin. Int. J. Peptide Res. Therapeutics, 13, 221-227 (2007).[3] Spengler, J.; Böttcher, C.; Albericio, F.; Burger, K.Hexafluoroacetone as Protecting and ActivatingReagent: New Routes to Amino, Hydroxy and MercaptoAcids and their Application for Peptide, Glyco- andDepsipeptide Modification. Chem Rev., 106, 4728-4746(2006).[[44]] Gracia, C.; Isidro-Llobet, A.; Cruz, L.J.; Acosta, O.;Álvarez, M.; Cuevas, C.; Giralt, E.; Albericio, F.Convergent Approaches for the Synthesis of theAntitumoral Peptide, Kahalalide F. Investigation ofOrthogonal Protecting Groups. J. Org. Chem., 71, 7196-7204 (2006). [5] Tulla-Puche, J.; Bayó-Puxan, N.; Moreno, J.A.;Francesch, A.M.; Cuevas, C.; Álvarez, M.; Albericio, F.Solid-Phase Synthesis of Oxathiocoraline by a KeyIntermolecular Disulfide Dimer. J. Am. Chem. Soc., 129,5322-5323 (2007).

117


Domino andMultiple Pd-CatalyzedReactions for the Efficient synthesis ofNatural Productsand Materials

Lutz F. Tietze

Institute of Organic and Biomolecular Chemistry,University of Göttingen, Göttingen, Germany

The development of efficient syntheses of bioactivecompounds such as natural products and analogues,drugs, diagnostics, agrochemicals in academia andindustry is a very important issue of modernchemistry [1]. In this respect, complex multistepsyntheses have to be avoided since they are neithereconomically nor ecologically justifiable. Modernsyntheses must deal carefully with our resources andour time, must reduce the amount of waste formed,should use catalytic transformations and finally mustavoid all toxic reagents and solvents. In addition,synthetic methodology must be designed in a waythat it allows access to diversified substance librariesin an automatized way.

A general way to improve synthetic efficiency and inaddition also to give access to a multitude ofdiversified molecules is the development of dominoreactions which allow the formation of complexcompounds starting from simple substrates in asingle transformation consisting of several steps [1].

We have defined domino reactions as processes oftwo or more bond forming reactions under identicalconditions, in which the subsequent transformationstake place at the functionalities obtained in theformer transformations. The quality and importanceof a domino reaction can be correlated to thenumber of bonds generated in such a process andthe increase of complexity, for which we havecreated the expression "bond forming efficiency".Domino reactions can be performed as single-, two-and multicomponent transformations. Thus, most ofthe known multicomponent processes [2] can bedefined as a subgroup of domino reactions.

Domino reactions can be classified according to themechanism of the single steps which may be of thesame or of different kind. As mechanisticaldifferentiation we have included cationic, anionic,radical, pericyclic, transition metal-catalyzed andredox transformations.

A combination of mechanistically different reactionsis the domino-Knoevenagel-hetero-Diels-Alderreaction, which was developed in my group andwhich has emerged as a powerful process which notonly allows the efficient synthesis of complexcompounds such as natural products starting fromsimple substrates but also permits the preparation ofhighly diversified molecules.

It consists of a Knoevenagel condensation [[33] ofgenerally an aldehyde with a 1,3-dicarbonylcompound in the presence of catalytic amounts of aweak base such as ethylene diammonium diacetate(EDDA) or piperidinium acetate. In the reaction a 1-oxa-1,3-butadiene is formed as intermediate whichcan undergo a hetero-Diels-Alder reaction [[4]] eitherwith an enol ether or an alkene.

The procedure has been used by us among othersfor the synthesis of several alkaloids (Scheme 1).

Schheemee 1. Enantiopure alkaloids synthesized by a three orfour component domino-Knoevenagel-hetero-Diels-Alderreaction

Another highly fruitful approach consisting of a Pd-catalyzed nucleophilic substitution of an allyl acetatefollowed by a Pd-catalyzed arylation of an alkenewas used in the synthesis of (–)-cephalotaxine. Thestarting material for this process was obtained via anenantioselective CBS-reduction of the corresponding2 bromocyclopentenone; moreover, the reactionproceeds with high diastereoselectivity forming onlyone diastereomer.

Schheemee 2. Synthesis of (–)-cephalotaxine

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In a similar way steroids such as estradiol and thecontraceptiva desogestrel were synthesized in anenantioselective way using a Pd-catalyzed vinylationand arylation to allow a highly efficient constructionof the tetracyclic core of steroids [[5].. An especiallyeffective procedure is the combination of anenantioselective Wacker-oxidation and a vinylationusing a phenol containing an alkene moiety in thepresence of an alkene with electron withdrawing

groups such as acrylate or methyl vinyl ketone. Inthis process first an intramolecular formation of anether takes place which is followed by anintermolecular C-C-bond formation.

Scheme 3. Synthesis of a-tocopherol

This domino reaction has been used for theenantioselective synthesis of a-tocopherol (Vitamin E)[6] and several other compounds containing achroman moiety [7].

References

[1] (a) L.F. Tietze, G. Brasche, K. Gericke, DominoReactions in Organic Synthesis, Wiley VCH, Weinheim2006; (b) L.F. Tietze, A. Modi, Medicinal Research Reviews2000, 20, 4, 304–322; (c) L.F. Tietze, Chem. Rev. 119966, 96,115–136; (d) L.F. Tietze, U. Beifuss Angew. Chem. 199933,105, 137–170; Angew. Chem. Int. Ed. Engl. 199933, 32,131–163.[2] (a) J. Zhu, Eur. J. Org. Chem. 200033, 1133–1144, citedlit.; (b) A. Dömling, I. Ugi, Angew. Chem. 200000, 112,3300–3344, Angew. Chem. Int. Ed. 200000, 39, 3168–3210;(c) L.F. Tietze, A. Steinmetz, F. Balkenhohl, Bioorganic andMedicinal Chemistry Letters , 1997, 7, 1303–1306.[3] (a) L.F. Tietze, U. Beifuss, In Comprehensive OrganicSynthesis; B.M. Trost, Ed.; Pergamon Press: Oxford, 1199911;Vol. 2, p 341.[4] (a) L.F. Tietze, G. Kettschau, J.A. Gewert, A.Schuffenhauer, Curr. Org. Chem. 1998, 2, 19–62; (b) L.F.Tietze, G. Kettschau, Topics in Current Chemistry 199977,189, 1–120.[5] L.F. Tietze, I. Krimmelbein, Chem. Eur. J. 2000088, 14,1541–1551.[6] L.F. Tietze F. Stecker, J. Zinngrebe, K.M. Sommer,Chem. Eur. J. 2006, 12, 8770–8776.[7] (a) L.F. Tietze, K.F. Wilckens, S. Yilmaz, F. Stecker, J.Zinngrebe, Heterocycles 2006, 70, 309–319; (b) L.F. Tietze,J. Zinngrebe, D.A. Spiegl, F. Stecker, Heterocycles 2000077,74, 473–489.

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DNA ChargeTransportChemistry andBiology

Jacqueline K. Barton

Division of Chemistry and Chemical Engineering.California Institute of Technology. Pasadena, CA, USA

Our laboratory has been interested in exploring boththe fundamentals of how electrons and holes migratethrough the base pair stack as well as the biologicalimplications of this chemistry with respect to howDNA may be damaged and repaired. From ourlaboratory and others it has by now beendemonstrated in a range of different experiments thatdouble helical DNA does indeed mediate the efficienttransport of charge, both electrons and holes, ontimescales as short as picoseconds. [[11]] Moreover,recently our laboratory has focused studies ondetermining how the cell may harnass this chemistryto facilitate redox signaling among proteins bound toDNA, to funnel damage to specific sites and activaterepair of damage to DNA. [2]

The ability of DNA to serve as a medium for thetransport of charge is intrinsic to its p-stackedstructure. The B-DNA double helix is an array ofheterocyclic aromatic base pairs, stacked at adistance of 3.4 Å, wrapped within a negativelycharged sugar phosphate backbone. (Figure 1)

Figure 1. An illustration of the stacked base pairs in DNAlooking across the helix (above) and down the helix axis(below).

It is no surprise that shortly after the double helicalstructure was proposed by Watson and Crick,scientists asked whether inherent in the structure ofstacked base pairs there might be another functionalproperty of DNA. Given the similarity to onedimensional aromatic crystals, it was proposed thatthe DNA p-stack might be a conduit for rapid andefficient charge migration. [3]

This analogy between DNA and solid state p-systemsis useful in considering DNA charge transport: theinteractions between the p-electrons of the DNAbase pairs provide the electronic coupling necessaryfor DNA charge transport to occur. But it is importantto consider also the differences between DNA, a p-stacked macromolecular assembly in solution, andsolid state p-stacks.

In contrast to solid state p-stacks, DNA isconformationally dynamic, a property that is key toall of its biological functions. Conformationalrearrangements of the DNA bases on the ps to mstime scale modulate base stacking interactions,redox potentials, and electronic coupling betweenthe DNA bases. Thus the sequence-dependentdynamical motions of DNA both facilitate and inhibitlong range charge transport through the base pairstack. [[4] Charge transport through the base pairstack is gated by the motions of the DNA bases.

Using electrochemical, biochemical, and biophysicalmeasurements, we have now characterized some ofthe important features of DNA charge transportchemistry. [55]] Importantly, we have found that chargetransport through DNA can occur over very largemolecular distances, > 200 Å. [66,,77] In DNAassemblies containing a pendant photooxidant, wehave shown that hole transport through the DNAduplex can promote oxidative damage to guaninedoublets far from the site of the pendant oxidant.(Figure 2) Moreover this chemistry is independent ofthe oxidant utilized. It is a property of the DNA basepair stack.

Figuuree 2. As schematically illustrated, in a DNA assemblywith tethered photooxidant (red), oxidative damage toguanine doublets (yellow) can be promoted over longdistances through DNA charge transport.

This property is interesting to consider in the contextof reactions within the cell. Indeed, we have alsoshown that DNA hole transport can proceed in thenucleosome core particle to effect damage to DNAfrom a distance. [[88] Hence while DNA may be

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packaged into chromatin, protecting the DNA libraryfrom the onslaught of harmful agents, this chromatinstructure cannot protect the DNA from long rangeoxidative damage through DNA charge transport.Perhaps instead Nature funnels damage to particularsites, protecting others. [2]

It is interesting also to note that we havedemonstrated not only damage to DNA promotedfrom a distance but also the oxidation of DNA-boundproteins from a distance. [9] In particular, p53, acritically important cell cycle regulatory protein,bound to some promoters but not others can beoxidized from a distance leading to its dissociationfrom the DNA. We have proposed that this longrange chemistry may provide a global signaling ofoxidative stress within the cell, yielding thedissociation of p53 from some promoters but notothers so as to activate the cell to respond to theconditions of oxidative stress.

While DNA charge transport can proceed over longmolecular distances, another critical characteristic ofthis chemistry is the exquisite sensitivity toperturbations in the intervening base stack. Singlebase pair mismatches, base lesions, and thestructural changes associated with protein binding alllead to an inhibition of DNA charge transport. [55]]

(Figure 3)

Figure 3. Illustrations of perturbations that inhibit long rangecharge transport through DNA: (left) DNA bulges; (center)DNA mismatches; (right) protein binding that kinks the DNA.

We have demonstrated this sensitivity in not onlythrough experiments monitoring an attenuation inlong range oxidative damage but also in DNAelectrochemistry experiments that monitor theattenuation in redox signal as a function ofintervening perturbations in the base pair stack.[10,11] (Figure 4) This sensitivity in DNA chargetransport to p-stacking perturbations has led to thedevelopment of novel biosensors capable of thedetection of single base mismatches, lesions andDNA-protein interactions.

Given this remarkable sensitivity of DNA chargetransport in detecting DNA lesions, we have alsoasked whether Nature may harnass this chemistryalso in the first steps of DNA repair, where baselesions are first detected. [12,14] Within cells there isan extraordinary repair machinery, the

base excision repair enzymes, which constantlymonitor the genome for base damage, and once

FFiigguurree 44.. DNA-mediated electrochemistry to a redox probe

(blue). This electrochemistry is, however, inhibited by an

intervening mismatch (red).

found, excise the damage, repairing the genome.Interestingly, biquitous to a subset of these baseexcision repair enzymes are 4Fe-4S clusters, acommon redox cofactor in biology. Although theseclusters are not redox-active in the absence of DNA,we have demonstrated using DNA-modifiedelectrodes that, in the presence of DNA, theirpotentials are shifted to a physiologically relevantrange. [[12,,1155] DNA binding thus facilitates oxidationof the clusters in a DNAmediated reaction. We havefurthermore demonstrated that this potential shift isgeneral to a range of DNA repair proteins thatcontain the 4Fe-4S clusters, and we have proposedDNA-mediated signaling among different repair

proteins bound to DNA in detecting base lesions.Essentially analogous to telephone repairmenlooking for a break in the telephone line, proteins cancarry out DNAmediated electron transfer reactionswith one another as long as the intervening DNA isintact; these electron transfers facilitate proteindissociation and a search of the genome. However, ifthere is an intervening lesion, DNA-mediated chargetransport is inhibited, the proteins do not dissociate,and instead remain in the vicinity to repair the lesion.Hence this chemistry provides a means toredistribute the repair proteins where they areneeded in the vicinity of the DNA lesion.

We are now focused on delineating how DNA chargechemistry plays a role in the activity of base excisionrepair proteins as well as asking whether other DNA-binding proteins that contain redox cofactors maysimilarly employ DNA-mediated charge transport forlong range signaling. Certainly this chemistry isunique in that the chemistry can occur with controlover long molecular distances but with a remarkablesensitivity to intervening perturbations. There is

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Figure 5. An illustration of DNA-mediated electron transferbetween two repair proteins (blue and gray).

much to be unraveled still with respect to this richDNA chemistry.

Acknowledgments

I am grateful to the NIH for their support of thisresearch as well as to my coworkers andcollaborators for their ideas and hard work.

References

[1] Topics in Current Chemistry, 236: 67-115, ed. SchusterGB, Springer Verlag (2004).[2] “Biological Contexts for DNA Charge TransportChemistry,” E. J. Merino, A. K. Boal, and J. K. Barton,Current Opinion in Chemical Biology, 12, 229 (2008).[[33]] “Semiconductivity of organic substances. IX. Nucleicacid in the dry state,” D. D. Eley and D. I. Spivey, Trans.Faraday Soc. 58, 411 ((11996622)).[4] “2-Aminopurine: A Probe of Structural Dynamics andCharge Transfer in DNA and DNA:RNA Hybrids,”M. A.O’Neill and J. K. Barton, Journal of the American ChemicalSociety, 124, 13053 (2002).[5] “Sequence-dependent DNA Dynamics: The Regulator ofDNA-mediated Charge Transport,” M. A. O’Neill and J. K.Barton, in Charge Transfer in DNA: From Mechanism toApplication, ed. H.-A. Wagenknecht, Wiley-VCH, 27-75(2005).[6] "Oxidative DNA Damage through Long Range ElectronTransfer," D. B. Hall, R. E. Holmlin, and J. K. Barton,Nature, 382, 731 (1996).[7] “Long-Range Oxidative Damage to DNA: Effects ofDistance and Sequence,”M. E. Nunez, D. B. Hall and J. K.Barton, Chemistry & Biology, 6, 85 (1999).[8] “Evidence for DNA Charge Transport in the Nucleus,”M. E. Nunez, G. P. Holmquist and J. K. Barton,Biochemistry, 40, 12465 (2001).[9] “A Role for DNA-mediated Charge Transport inRegulating p53: Oxidation of the DNA-bound Protein from aDistance,” K. E. Augustyn, E. J. Merino and J. K. Barton,Proceedings of the National Academy of Science, USA,104, 18907 (2007).[10] “Electrochemical DNA Sensors,” T. G. Drummond, M.G. Hill and J. K. Barton, Nature Biotechnology, 21, 1193(2003).[11] “An Electrical Probe of Protein-DNA Interactions onDNA-Modified Surfaces,”E. M. Boon, J. W. Salas, and J. K.Barton, Nature Biotechnology, 20, 282 (2002).[12] “DNA-bound Redox Activity of DNA RepairGlycosylases Containing [4Fe-4S] Clusters,” A. K. Boal, E.Yavin, O. A. Lukianova, V. L. O’Shea, S. S. David, and J. K.Barton, Biochemistry, 44, 8397 (2005).[13] “DNA Repair Glycosylases with a [4Fe-4S] Cluster: ARedox Cofactor for DNA-mediated Charge Transport?,”A. K.Boal, E. Yavin and J. K. Barton, Journal of InorganicBiochemistry, 101, 1913 (2007).[14] “Protein-DNA Charge Transport: Redox Activation of aDNA Repair Protein by Guanine Radical,” E. Yavin, A. K.Boal, E. D. A. Stemp, E. M. Boon, A. L. Livingston, V. L.O’Shea, S. S. David, and J. K. Barton, Proceedings of theNational Academy of Sciences, USA, 102, 3546 (2005).[15] “Direct Electrochemistry of Endonuclease III in thePresence and Absence of DNA,” A. A. Gorodetsky, A. K.Boal and J. K.

222


StreamliningSynthesis viaC—H Oxidation

M. Christina White

Department of Chemistry, Roger Adams Laboratory,University of Illinois, Urbana, IL, USA

Among the frontier challenges in chemistry in the21st century are (1) increasing control of chemicalreactivity and (2) synthesizing complex moleculeswith higher levels of efficiency. Although it has beenwell demonstrated that given ample time andresources, highly complex molecules can besynthesized in the laboratory, too often currentmethods do not allow chemists to match theefficiency achieved in Nature. This is particularlyrelevant for molecules with non-polypropionate-likeoxidation patterns (e.g. Taxol). Traditional organicmethods for installing oxidized functionality relyheavily on acid-base reactions that require extensivefunctional group manipulations (FGMs) includingwasteful protection-deprotection sequences. Due totheir ubiquity in complex molecules and inertness tomost organic transformation, C—H bonds havetypically been ignored in the context of methodsdevelopment for total synthesis. Highly selectiveoxidation methods, similar to those found in Nature,for the direct installation of oxygen, nitrogen andcarbon functionalities into allylic and aliphatic C—Hbonds of complex molecules and their intermediateswill be discussed. Unlike Nature which uses

elaborate enzyme active sites, we rely on the subtleelectronic and steric interactions between C—Hbonds and small molecule transition metalcomplexes to achieve high selectivities. Our currentunderstanding of these interactions gained throughmechanistic studies will be discussed. Novelstrategies for streamlining the process of complexmolecule synthesis enabled by these methods will bepresented. Collectively, we aim to change the waythat complex molecules are constructed byredefining the reactivity principles of C—H bonds incomplex molecule settings.

References

AAliipphhaattiic CC——HH OOxxiidaattionn

[[11]] Chen, M.S.; White, M.C. “A Predictably SelectiveAliphatic C—H Oxidation Reaction for Complex MoleculeSynthesis.” Science, 200077, 318, 783-787.

AAlllyylliic CC—HH OOxxiiddaattiionn

[[22]] Delcamp, J.H.; White, M.C. “Sequential HydrocarbonFunctionalization: Allylic C—H Oxidation/Vinylic C—HArylation.” J. Am. Chem. Soc. 2200006, 128, 15076-15077.[[33]] Fraunhoffer, K.J.; Prabagaran, N.; Sirios, L.E.; White,M.C. “Macrolactonization via Hydrocarbon Oxidation.” J. Am. Chem. Soc. 2000066, 128, 9032-9033.[[44]] Chen, M.S.; Prabagaran, N.; Labenz, N.; White, M.C.“Serial Ligand Catalysis: A Highly Selective Allylic C-HOxidation.” J. Am. Chem. Soc. 22000055, 127, 6970-6971.[[55]] Chen, M.S.; White, M.C. “A Sulfoxide-Promoted,Catalytic Method for the Regioselective Synthesis of AllylicAcetates from Monosubstituted Olefins via C-H Oxidation.”J. Am. Chem. Soc. 2000044, 126, 1346-1347.

AAlllyylliic CC—HH AAmiinnaattiioonn

[[66]] Reed, S.A.; White, M.C. “Catalytic Intermolecular LinearAllylic C—H Amination via Heterobimetallic Catalysis.” J. Am. Chem. Soc., 22000088, 130, 3316-3318.[[77]] Fraunhoffer, K.J.; White, M.C. “syn-1,2-Amino Alcoholsvia Diastereoselective Allylic C—H Amination.” J. Am.Chem. Soc. 2200077, 129, 7274-7276.

SStrreeammliniinng SSyynnthheessiiss Sttraatteggiiees

[[88]] Covell, D.J.; Vermeulen, N.A.; Labenz, N.A.; White, M.C.“Polyol Synthesis via Hydrocarbon Oxidation: De NovoSynthesis of L-Galactose.” Angew. Chem., Int. Ed. Engl.2200006, 45, 8217-8220.[[99]] Fraunhoffer, K. J.; Bachovchin, D.A.; White, M.C.“Hydrocarbon Oxidation vs. C-C Bond Forming Approachesfor Efficient Syntheses of Oxygenated Molecules.” Org. Lett.2200005, 7, 223-226.

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Recent Studiesin Alkaloid TotalSynthesis

Larry E. Overman

Department of Chemistry, 1102 Natural Sciences II,University of California, Irvine, CA, USA

An important objective in chemical synthesis is thedevelopment of new transformations that rapidlyevolve molecular complexity in a stereocontrolledfashion. One approach toward this goal is tocombine two or more distinct reactions into a singletransformation, producing a process often referred toas a sequential, tandem, cascade, or dominoreaction. In this lecture, I discuss the implementationof several cascade processes as the key strategicelement in the total synthesis of heterocyclic naturalproducts. One illustrative example is described inthis brief summary.

A 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole is a central structural feature of theStrychnos alkaloid minfiensine , and akuammilinealkaloids such as vincorine and echitamine (Figure1). Extracts containing akuammiline alkaloids areused throughout the world in the practice oftraditional medicine [1].

Figure 1. Representative alkaloids containing a 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole.

Dihydro-9a,4a-(iminoethano)-9H-carbazoles having a1,2- or 2,3-double bond could serve as versatileplatforms for constructing alkaloids of the typesillustrated in Figure 1. Stitching an ethylideneethanounit between the pyrrolidine nitrogen and C3 of sucha precursor would generate the ring system ofminfiensine, whereas inserting such a unit betweenthe pyrrolidine nitrogen and C2 would generate thering system of vincorine and congeners. A cascadecatalytic-asymmetric Heck–iminium cyclization wasdeveloped that rapidly provides 3,4-dihydro-9a,4a-

(iminoethano)-9H-carbazoles in high enantiomericpurity (Figure 2).

Fiiggurre 22.. Cascade asymmetric Heck /iminium ioncyclizations for forming 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazoles.

The use of this cascade sequence to complete anefficient catalytic asymmetric total synthesis of (+)-minfiensine is dsummarized in Figure 3[[22]]..

Figure 3. Catalytic asymmetric total synthesis of (+)-minfiensine.

References

[1]] Ramirez, A.; Garcia-Rubio, S. Current. Med. Chem.200033, 10, 1891–1915.[2]] Dounay, A. B.; Humphreys, P. G.; Overman, L. E.;Wrobleski, A. D. J. Am. Chem. Soc. 2200088, 130, 5368–5377

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El Ciclo Catalíticodel Descubrimientoen Síntesis TotalThe Catalytic Cycle of Discovery in TotalSynthesis

Phil S. Baran

Chemistry Department, The Scripps Research Institute,La Jolla, California, USA

Abstract

Many would argue that the field of organic synthesishas made such phenomenal advances over the pastfive decades that given unlimited resources, thesynthesis of almost any molecule is now possible. Assuch, total synthesis is becoming increasinglyfocused on preparing natural products in the mostinnovative and efficient manner possible. Selectedstudies from our lab will be presented on the totalsynthesis of complex natural products (see Figurebelow for selected targets).

Desde la penicilina hasta el Taxol, los productosnaturales no tienen competencia en la mejora de lasalud mundial. De hecho, nueve de los veintefármacos más vendidos por la industria farmaceúticaestán inspirados o derivan de productos naturales.Incluso el fármaco más vendido de todos lostiempos, Lipitor, está basado en un producto natural.El arte y ciencia de recrear estas entidades en ellaboratorio, o síntesis total, invariablemente da lugara descubrimientos fundamentales tanto en el ámbitode la química, como en el de la biología o lamedicina. Nuestro grupo de investigación tienecomo objetivo resolver interesantes retos en lasíntesis de productos naturales y en acortar lasdistancias entre el punto de partida y el objetivomediante el descubrimiento de nuevas reaccionesquímicas. De esta forma, estamos más interesadosen hacer contribuciones esenciales para la química.La creación, descubrimiento y diseño de nuevosmétodos que van surgiendo en el camino hasta unproducto natural, es lo que promueve nuestroentusiasmo. A partir de una cuidadosa selección delas dianas y un análisis retrosintético creativo, elesfuerzo de la síntesis total se convierte en unamáquina de descubrir que conduce al campo de laquímica orgánica hacia un nuevo nivel desofisticación y pragmatismo.

En la Figura 1 se muestran recientes síntesistotales, de las cuales todas ellas requieren denuevas estrategias químicas. En un ejemplorepresentativo, la síntesis total de ‘welwitindolinone’y otros alcaloides relacionados llevó a explorar laformación oxidativa del enlace C-C medianteheteroacoplamiento de enolatos. De esta forma seobtienen importantes ventajas en cuestión de

eficiencia (ausencia de grupos protectores,halógenos, grupos funcionales desechables),pragmatismo (secuencias extremadamenteconcisas), estereocontrol (completadistereoselectividad a menudo observada) yconservación del estado de oxidación (el estado deoxidación aumenta de manera lineal en una síntesismediante el uso de funcionalidad innata) cuando laformación oxidativa del enlace C-C se empleaestratégicamente. Tal y como se muestra en laFigura 2, la síntesis total de ‘welwitindolinone A’ haceuso de la formación oxidativa del enace C-C en suetapa clave. Esta síntesis ilustra de manera clara yconcisa las ventajas mencionadas anteriormente, yaque en únicamente ocho pasos de síntesis, reactivossencillos, ausencia de grupos protectores y diez díasde trabajo con un solo estudiante de doctorado, sonsuficientes para construir este complejo productonatural marino de una forma enantioselectiva. Apesar de que la eliminación de grupos protectoresen la síntesis de moléculas complejas ha sidosiempre un objetivo a largo plazo, esta síntesisparece ser el primer ejemplo hasta la fecha enalcanzar esta meta.

En esta presentación, se discutirán los ejemplosmás recientes de síntesis totales alcanzadas conéxito, incluyendo moléculas tales como ‘cortistatin A’,psycotrimine’, ‘axinellamines A y B’ y ‘vinigrol’.

FFiigguurraa 11. Selección de síntesis totales completadas conéxito (2004-2008).

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FFiigguurraa 22. Sencillo ejemplo de síntesis total enantioselectivade productos naturales complejos mediante formaciónoxidativa del enlace C-C.

Referencias

[[11]] Chen, K.; Richter, J. M.; Baran, P. S. 1,3-Diol Synthesisvia Controlled, Radical Mediated C–H Functionalization, J. Am. Chem. Soc., 22000088, in press.[[22]] Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.; Baran, P.S. Synthesis of (+)-Cortistatin A, J. Am. Chem. Soc. 2008,in press.[3] O’Malley, D. P.; Yamaguchi, J.; Young, I. S.; Seiple, I. B.;Baran, P. S. Total Synthesis of (±)-Axinellamines A and B,Angew. Chem. Int. Ed. 2008, 47, 3581 – 3583.[4] Yamaguchi, J.; Seiple, I. B.; Young, I. S.; O’Malley, D. P.;Maue, M.; Baran, P. S. Synthesis of 1,9-Dideoxy-pre-axinellamine, Angew. Chem. Int. Ed. 2008, 47, 3578 – 3580.[5] Maimone, T. J.; Voica, A.-F.; Baran, P. S. A ConciseApproach to Vinigrol, Angew. Chem. Int. Ed. 22000088, 47, 3054– 3056.[6] Burns, N. Z; Baran, P. S. On the Origin of the HaouamineAlkaloids, Angew. Chem. Int. Ed. 2008, 47, 205 – 208.[7] Richter, J. M.; Whitefield, B.; Maimone, T. J.; Lin, D. W.;Castroviejo, P.; Baran, P. S. Scope and Mechanism of theDirect Indole Coupling Adjacent to Carbonyl Compounds:Total Synthesis of Acremoauxin A and Oxazinin 3, J. Am.Chem. Soc. 2007, 129, 12857-12869.[8] Grube, A.; Immel, S.; Baran, P. S.; Köck, M. MassadineChloride: a Biosynthetic Precursor of Massadine andStylissadine, Angew. Chem. Int. Ed. 2007, 46, 6721-6724.[9] Köck, M.; Grube, A.; Seiple, I.; Baran, P. S. The Pursuitof Palau’amine, Angew. Chem. Int. Ed. 2007, 46, 6586-6594[10] Maimone, T. J.; Baran, P. S. Modern SyntheticApproaches to Terpenes, Nature Chem. Bio. 2007, 3, 396 –407.[11] O’Malley, D.P.; Li, K.; Maue, M.; Zografos, A.L.; Baran,P. S. Total Synthesis of Dimeric Pyrrole-Imidazole Alkaloids:Sceptrin, Ageliferin, Nagelamide E, Oxysceptrin, NakamuricAcid, and the Axinellamine Carbon Skeleton, J. Am. Chem.Soc. 2007, 129, 4762 – 4775.[12] Baran, P. S.; Maimone, T. J.; Richter, J. M. TotalSynthesis of Marine Natural Products Without UsingProtecting Groups, Nature 2007, 446, 404-408. [13] Baran, P. S.; Shenvi, R. A. Total Synthesis of(±)–Chartelline C, J. Am. Chem. Soc. 2006, 128, 14028 –14029.[14] Baran, P. S.; DeMartino, M. P. Intermolecular EnolateHeterocoupling, Angew. Chem. Int. Ed. 2006, 45, 7083–7086.[15] Baran, P. S.; Hafensteiner, B. D.; Ambhaikar, N. B.;Guerrero, C. A.; Gallagher, J. Enantioselective TotalSynthesis of Avrainvillamide and the Stephacidins, J. Am.Chem. Soc. 2006, 128, 8678-8693.

226


Palladium -andNickel- CatalyzedCouplingReactions

Gregory C. Fu

Department of Chemistry, Massachusetts Institute ofTechnology, Cambridge, MA, USA

Despite the tremendous accomplishments that havebeen described in the development of palladium-andnickel-catalyzed carbon–carbon bond-formingprocesses, it is nevertheless true that manysignificant opportunities remain. For example, todate the overwhelming majority of studies havefocused on couplings between two sp2-hybridizedreaction sites (e.g., an aryl metal with an aryl halide;Figure 1). Although biaryl and related linkages arecertainly a common feature in many organiccompounds, so, too, are Csp2–Csp3 and Csp3–Csp3

linkages.

Figure 1. Some carbon–carbon bond-forming processes ofinterest.

As of 2001, there were few examples of palladium-ornickel-catalyzed coupling reactions of alkylelectrophiles. Slow oxidative addition of alkylhalides/sulfonates and facile ‚-hydride elimination aretwo likely causes for this paucity of success. Indeed,nearly all of the successful couplings that had beendescribed by 2001 involved specialized electrophilesthat circumvent these impediments by beingactivated toward oxidative addition and by lacking ‚hydrogens (e.g., benzyl halides).

During the past several years, we have pursued thediscovery of palladium-and nickel-based catalysts forcoupling activated and unactivated primary andsecondary alkyl electrophiles that bear ‚ hydrogens.Our recent efforts to develop broadly applicablemethods, including enantioselective processes, willbe discussed.

FFiigguurree 22. Asymmetric Negishi reactions of allylic halides.

FFiigguurree 33. Asymmetric Hiyama reactions of _-halocarbonylcompounds.

FFiigguurree 44. Asymmetric Suzuki reactions of homobenzylichalides.

227


New Developmentsof OrganometallicCatalysts inOrganic Synthesis

Jean Pierre Genet

Laboratoire de Synthèse Sélective Organique et Produits Naturels - UMR 7573, CNRSEcole Nationale Supérieure de Chimie de Paris, Paris, France

Despite the tremendous accomplishments that havebeen described in the development of palladium-andnickel-catalyzed carbon–carbon bond-formingprocesses, it is nevertheless true that manysignificant opportunitieHomogeneous asymmetriccatalysis is undoubtedly a powerful synthetic tool ofthe organic chemist, both on laboratory andproduction scale. Effective homogeneousasymmetric catalysts are organometallic complexesthat consist of one or more chiral ligand coordinatedto a metal center. The choice of the chiral ligand isdecisive both for catalytic activity and for achievinghigh level of chiral induction.

Atropisomeric biaryl diphosphines

Noyori discovered the BINAP ligand in 1980, whichresulted in an extraordinary expansion of the scopeof asymmetric hydrogenation. [1] The elaboration ofnew ligand families such as the MeO-BIPHEP(Roche) or the SEGPHOS (Takasago) is significantof the new current challenges of chemists in the fieldof asymmetric catalysis (Figure 1). Licensing policiescompel companies to synthesize their own originalligand families, displaying high activity and selectivityand the broadest possible scope in terms ofsubstrates. Following our continuous interest inligand design [2] , we have reported the synthesis oftwo original atropisomeric diphosphines SYNPHOS®[3], and DIFLUORPHOS® [4], with stereoelectronically complementary backbones, basedrespectively on bi(benzodioxane) andbi(difluorobenzodioxole) moieties (Figure 1). We alsopropose detailed structural profiling [5] of theseligands and catalytic evaluation in asymmetric Ru-mediated hydrogenation compared to otherleading atropisomeric diphosphines such as BINAPand MeO-BIPHEP.

Figure 1. Rhodium-catalyzed reactions for carbon-carbonbounds formation.

Asymmetric Pauson-Khand reaction

In recent years, a great deal of research has been

devoted to asymmetric catalytic Pauson-Khandreaction (denoted as PKR reaction hereafter), whichis characterized as transition metal mediated [2+2+1]cycloaddition of an alkyne, an alkene and CO. Manyyears ago , Jeong introduced the first rhodiumcatalyzed enantioselective PKR under COatmosphere in the presence of an atropisomericligand.These early results were promising in terms ofenantioselectivity, but they also exhibited somelimitations with certain class of substrates. We havedemonstrated that enantioselectivity and reactionyield were influenced by the electronic density onphosphorus, the dihedral angle of ligands and theelectronic density of the alkyne substrate. Ligandsbearing a narrower dihedral angle than BINAP, suchas SYNPHOS and DIFLUORPHOS, were found toincrease substantially the enantioselectivity of thereaction, compared to BINAP-type ligands.DIFLUORPHOS deshielded phosphine providedbetter enantioselectivity than BINAP, especially withelectron-poor alkyne substrates (Scheme 1).[[66]]

Schheemee 1. Potassium organotrifluoroborates in organicsynthesis

Since the discovery of the Suzuki-Miyaura reaction,organoboranes have emerged as the reagents ofchoice in transition metal-catalyzed reactions. Themain interesting feature of organoboron reagents istheir low toxicity as well as for the by-productgenerated, making these compound environmentallyfriendly compared to other organometallic reagentsand particularly organostannanes.

However many trivalent organoboranes are nothighly stable, particularly alkyl- and alkynylboranes.The lack of stability of organoboranes is due to thevacant orbital on boron, which can be attacked by

228


oxygen or water, resulting in the decomposition ofthe reagent. Efficient preparations of the highlystable potassium aryl, alkenyl and alkynyltrifluoroborates, which does not require the use ofpurified organoboronic acids, are now available [[77]].Five years ago only a limited papers were publishedon these emerging compounds, to day an increasednumber of publications and patents on that topichave been reported in the literature.[7]]

Potassium trifluoro(organo) borates rhodiumcatalyzed reactions

The 1,2- and 1,4- additions of organometallicreagents to unsaturated compounds are some of themost versatile reactions in organic synthesis. Wehave developed an efficient system using rhodiumcatalyst [RhCl(C2H4)]2 3 mol %, P(tBu)3, 3 mol%. Inthe presence of an electron-rich phosphine such asPBu3 and water (toluene/H2O) the reaction proved tobe general, allowing the production of highlyhindered diaryl carbinols and aliphatic aldehydeswere also reactive under these conditions.[8]]

Interestingly, the same catalyst system in theabsence of water allows a direct access to ketonesfrom aldehydes via rhodium-catalyzed cross-couplingreaction with potassium trifluoro (organo) borates [[99aa]].We also have described for the first time astraightforward preparation to congestedbenzophenones frameworks from aryl aldehydes and potassium aryltriffluoroborates. This reactionoccurring under neutral conditions, allows formationof di-,tri- and even tetra-ortho substitutedbenzophenones thanks to the use of stablephosphonium salt of P(t-Bu)3.(Scheme 2) .[[99b]]

Scheme 2.

Asymmetric conjugate addition of potassiumtrifluoro (organo) borates to Michael acceptorsEnones

The asymmetric 1,4-addition of potassiumorganotrifluoroborates turned out to be trickier thanthe racemic version. Most rhodium catalystsdescribed earlier by Batey, Miyaura, Hayashiunderwent poor conversions and/or low enantiomericexcesses. We have reported, after carefuloptimization of the reaction system including ligand,solvent, temperature, that [Rh (cod)2]PF6 associatedto chiral phosphine BINAP, JOSIPHOS and MeO-BIPHEP that the presence of water is also crucial forthis reaction: in its absence, the reaction was veryslow and the asymmetric induction too. On the otherhand, an excess of water slows the reaction downand in pure water no asymmetric induction wasobserved. Indeed, for practical purposes, one shouldtherefore use an excess of water compared to boronreagent (typically 10:1 mixture of toluene/water).Potassium trifluoro (organo) borates react efficiently

and selectively to enones (Scheme 3). [7] Thereaction has been applied to a,b unsaturatedamides, ester and lactones.

SScchheemmee 33

N-protected amidoacrylates

The tandem -1,4 addition enantioselectiveprotonation of N-protected amidoacrylates wouldprovide a new and efficient route to enantiomericallyenriched a-amino acids derivatives. We have shownthat choosing a suitable proton source could controlthe · chiral center. Indeed the conjugate addition ofpotassium aryl and alkenyl-trifluoroborates to N-acylamidoacrylates mediated by a chiral rhodiumcomplex in the presence of achiral phenol derivativesfurnishes a variety of _-amino acid derivatives withgood enantioselectivities up to 89.5% ee using Rh-BINAP catalyst.[[100]] The best proton source wasfound to be inexpensive and non-toxic 2-methoxyphenol or guaiacol. The influence of sterichindrance from methyl to isopropyl and t-butyl esterimproved the enantioselectivity ee up to 95%.[11]

FFiigguurree 22

However lower yields were generally achieved usingt-butyl ester a good compromise is the use ofisopropyl ester.

Reaction pathway of the tandem 1,4enantioselective Rh-catalyzed reaction

Initially we believed that this reaction proceededthrough an oxa p-allyl rhodium intermediate asestablished by Hayashi. Actually, it appears that thepresence of a free N-H bond in a position to theMichael acceptor was essential in order to achievehigh level of enantioselectivity. Deuterium labelingstudies show new interesting aspects of thisrhodium-catalyzed -1,4 addition. The catalyst cycleinvolves (a) transmetallation of the aryl group fromboron to rhodium (b) insertion of the olefin into thearyl-rhodium bond forming a rhodium alkyl species(c) ?-elimination giving a Rh-imino complex (d) 1,3hydrogen shift from rhodium to carbon forming theRh-NP intermediate and (e) its cleavage withguaiacol giving the addition product.

The potential energy profiles have been studied byDFT calculations. The computed sequence of theelementary steps, relative intermediates and

229


transitions states agrees with the previous proposalstep (c) is endothermic with an energy barrier of 27.8kcal/mol (Figure 2).[11]

This step being the rate-determining step. Thus, weanticipated that a more p acceptor than BINAPshould facilitate th _-elimination and improve theselectivity. Having developed DIFLUORPHOS anoriginal atropisomeric ligand with original steric andelectronic properties [4,5]. We were pleased to findthat under optimized conditions both yields andenantioselectivies were significantly increased usingRh- DIFLUORPHOS catalyst (Scheme 4) [11].

Scheme 4. Ruthenium-mediated asymmetric hydrogenationreactions. Chiral Ruthenium catalysts

The first mononuclear hexacoordinate rutheniumcomplex bearing BINAP a ligand has been reportedby Noyori [[11]]. In the last two decades we focusedsome efforts on the design of new, general and mildsyntheses of chiral ruthenium complexes. Ourmethods are based on the easy availability ofRu(COD)(h3-methylallyl)2 from [RuCl2(COD)] n bytreatment with methallyl Grignard [2]. Interestingly, insitu generated catalysts Ru(P*P)X2 have beensynthesized from Ru(COD)(h3-methylallyl)2 and theappropriate chiral diphosphine by treatment with HX(X= Cl, Br, I) at room temperature, giving rise to awide range of chiral catalysts (Scheme 5).In thecourse of collaboration with Firmenich, an industrialproduct-oriented project, a new type of catalyst withhigh reactivity was discovered by treatment of Ru (COD)(h3-methylallyl)2 and various ligands P*P(BINAP, DuPHOS, JOSIPHOS) in weakly coordinatingsolvent (CH2Cl2) with HBF2 (Scheme 5) [13].

Scheme 5

Applications in organic synthesis

3-hydroxy-2-methylpropionic acid methyl ester knownas Roche ester represents a significant buildingblock in organic synthesis and is present in asubstantial number of both naturally occurring andsynthetic biologically relevant molecules.

We found that a generation of cationic chiral Ru-catalyst developed earlier in our group for theparadisone synthesis was highly efficient catalyst.The in situ generated Ru-SYNPHOS catalyst wasprepared by treating a mixture of Ru (COD)(h3-methylallyl)2 and SYNPHOS [3] indichloromethane by addition of 1 or 2eq of HBF4.This cationic Ru-SYNPHOS complex was the bestcatalyst for the hydrogenation reaction providing both

enantiomers of 3-hydroxy-2-methylpropanoic acid t-Butyl with high enantioselectivity (up to 96% ee)

(Scheme 6).. [1133]]

SScchheemmee 66

The Dolabelides contain a 22- or 24- membered ring,including eleven stereogenic centers (Figure 3).Eight of them are hydroxyl or acetyl functions. Thosechallenging molecules and especially their syn andanti 1,3-diol sequences constitute an excellent targetfor our ongoing program on the use of ruthenium-mediated asymmetric hydrogenation for thepreparation of biologically relevant natural products.[[22]]

The synthesis of the C1-C13 fragment of Dolabelideswas performed for the first time using catalyticasymmetric hydrogenation of b-keto esters and b-hydroxy ketones to install the hydroxyl groups atC3, C7, C9 and C11 stereocenters [[1144a]]. This flexiblestrategy is also currently used for the preparation ofDiscodermolide (potent antimitotic agent). Thus, thesynthesis of C1-C7,C9-C14 and C15-C24 key fragmentsof Discodermolide were achieved from a commonintermediate. [1144b]]

FFiguuree 3

330


References

[1] Ohkuma, T.; Kitamura, M.; Noyori, R. AsymmetricHydrogenation in Catalytic Asymmetric Synthesis, 2ndedition, Ojima, I. Ed. Wiley, New York, 200000, 1-110.[2] Genet, J.P. Acc. Chem. Res., 20033, 36, 908-918.[3] (a) Duprat de Paule, S.; Jeulin, S.; Ratovelomanana-Vidal, V.; Genet, J.-P.; Champion, N.; Dellis, P. TetrahedronLett. 2003, 44, 823-826. (b) Duprat de Paule, S.; Jeulin, S.;Ratovelomanana-Vidal, V.; Genêt, J.P.; Champion, N.;Dellis, P. Eur. J. Org. Chem. 22000033, 1931-1941. Bothantipodes of SYNPHOS® and DIFLURPHOS® arecommercially available from Strem Chemicals.[4] Jeulin, S.; Duprat de Paule S.;Vidal V.; Genet J.P.;Champion, N.; Dellis P. Angew. Chem. Int. Ed. 22000044, 43,320-325.[[55]] Jeulin, S.; Duprat de Paule, S.; Ratovelomanana-Vidal,V.; Genet, J.P.; Champion, N.; Dellis P. Proc.Natl.Acd.Sci.USA 2004, 101, 5799–5804.[[66]] Kim,O.E.;Choi,C.;Kim,I.S.;Jeong,N.; Jeulin S.; Vidal V.;Genet, J.P. Adv. Synth. Cat 2007, 349, 1999-2006.[[77]] Darses S.; Genet J.P. Chem.Rev. 22000088, 108, 288-325and references cited therein.[8] (a)Pucheault M.; Darses S.; Genet J.P. Chem.Commun., 2005, 4714-4716;(b) Navarre L., Darses S.,Genet J.P. Adv. Synth. Catal. 2006 348, 317-322.[9] Pucheault M.; Darses S.; Genet, J.P. J. Am. Chem. Soc.2004, 126, 15356-15359 ; b) Chuzel O.; Roesch A.; GenetJ.P.;Darses S. J. Org. Chem. 2008 in press[10] Navarre,L.; Darses, S.; Genet, J.P. Angew. Chem. Int.Ed., 2004, 43, 719-721.[11] Navarre,L.; Martinez,R.; Darses, S.; Genet, J.P. J. Am.Chem. Soc. 22000088, 130,6159-6169.[12] Jeulin S.;Vidal V.; Genet J.P.; Ayad, T, Adv. Synth. Cat,2007, 349,1592-1596[13] Dobbs, D.A.; Vanhessche, K.P.M.; Brazi, E.;Rautenstrauch, V.; Lenoir, J.Y.; Genet, J.P.; Wiles, J.;Bergens, S.H. Angew. Chem. Int. Ed. 2000000, 39, 1992-1995.[14] (a) Dolabelides: Le Roux R.; Desroy N.; Phansavath P.;Genet J.P. Org. Lett. 2008 in press ;(b) Discodermolide :Roche, C.; Le Roux R.; Desroy N.; Phansavath P.; Genet J.P.

331


New Applicationsof Quinones and Quinols inAsymmetricSynthesis

M. Carmen Carreño

Organic Chemistry Department (C-I), Autonoma Universityof Madrid, Cantoblanco, Madrid, Spain

Quinone Diels-Alder reactions have been extensivelyused in organic synthesis for the stereoselectiveconstruction of polycyclic skeletons from whichcomplex natural products were later synthesized [1].Until recently, resolution of racemic adducts was theonly way of access to enantiopure derivatives.Nowadays, some efficient chiral catalysts allow adirect synthesis of the enantiopure adducts [[22]].Applications of quinones in asymmetric synthesishave been rarely based on the use of simplequinonic systems bearing a chiral auxilliary directlylinked to the dienophilic bond.

Enantiopure 2-p-tolylsulfinylquinones turned out tobe powerful dienophiles opening an enantioselectiveaccess to different groups of complex structuresusing an asymmetric Diels-Alder reaction as keystep. The sulfoxide was shown to play severalimportant roles in the reactions of these dienophiles.This group was able to control the regiochemistry ofsulfinylquinone cycloadditions with a range ofsubstituted dienes [3]. High endo and p-facialdiatereoselective reactions were always achieveddue to an efficient differentiation of the diastereotopicfaces of the quinone by the sulfoxide. Moreover,once the adduct was formed, elimination of p-toluenesulfenic acid occurred spontaneouslyallowing to recover the quinone skeleton in a singlestep. As a consequence of this domino process,enantiopure sulfinylquinones could act as homochiralsynthetic equivalents of the unknown triple bondedquinones. The results shown in Scheme 1 illustratethe one-step synthesis of enantiopure 5-methyl-5,8¬dihydro-1,4-naphthoquinone (SS)-4 by reactionbetween (SS)-2-p-tolylsulfinyl-p_benzoquinone 3 andpiperylene. The sulfinyl quinone was readilyaccessible in two steps from 1,4-dimethoxybenzene1 by sequential reaction with n-BuLi and (–)-menthyl-p_toluene sulfinate (SS)-2, followed by oxidativedemethylation of the intermediate diaromaticsulfoxide with CAN4.

Scheme 1

In order to apply this domino sequence to thesynthesis of polycyclic targets, we focused onhelicenes. These are well known representative ofpolycyclic aromatic compounds bearing a series ofortho-condensed aromatic rings that exist in a chiralnon_planar helical disposition due to the sterichindrance of the external rings and their substituents[[55]]. The helical structures can be resolved into theirenantiomers if the interconversion barrier betweenthem is high enough. These artificial moleculespresent excellent properties of huge interest in thefield of new materials, which are inherentlyassociated to their enantiopurity.

The smaller systems, [4]helicenes, haveracemisation barriers which are highly dependent onthe particular structure. Using our asymmetric Diels-Alder reaction we could synthesize 12-alkyl-and 12-methoxy-substituted 7,8-dihydro[4]helicenequinones(P)-9 from (SS)-2-(p-tolylsulfinyl)-1,4-benzoquinone(SS)-3 and 3-vinyl-1,2¬dihydronaphthalenes 7 tofurther evaluate their configurational stability. 6 Thedienes 7 were accessible from 7-methoxy-1-tetralone4 by addition of a Grignard reagent (R1MgBr)followed by sequential aromatization of thedihydroaromatic ring, reductive dearomatization ofthe 2-methoxy substituted ring and transformation ofthe C-2 carbonyl into the enol triflate 6. This keyintermediate was transformed into the vinylsubstituted derivatives 7 by Stille coupling. Uponreaction with an excess of the sulfinylquinone (SS)-3,these dienes gave the dihydro [4]helicenequinones(P)-9 in a one-pot process where the dominoDiels–Alder reaction/pyrolytic sulfoxide eliminationsequence was followed by the oxidation of the B ringof the intermediate (12bR,P)-8 . This aromatizationoccurred in situ by the action of the excess of thequinone which was acting as an oxidant. Theconfigurational stability of these [4]helicenequinoneswas highly dependent on the size of the R1

substituent at C-12 being the tert-butylsubstitutedderivatives the only [4]helicenequinones that wereindefinitely stable at room temperature. The valuesof the racemisation barriers, calculated fromcomputations, confirmed the main role of the stericeffects in the configurational integrity of these helicalquinones.

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Scheme 2

The higher analogues, [5] and [7]helicenequinones,could also be synthesized in enantiomerically pureform from (SS)-3, by applying a similar strategy. Thechoice of the diene allowed the access to thebisquinones. Thus, reaction of vinyldihydrophenantrene 10 with (SS)-3, affordedenantiopure [5]helicenequinone [77]] (P)-11 whichcould be oxidized to the bisquinone (P)-12.

Scheme 3

Using a bisdiene such as 13, a domino processincluding the asymmetric Diels-Alderreaction/pyrolytic elimination of the sulfoxide andaromatization, in the presence of an excess of thequinone, took place twice, leading directly to theenantiopure [7]helicenequinone (M)-14 (Scheme 4).The vinyl and divinyl phenantrene derivatives 10 and13 were available from the correspondingphenantrenone or phenantrenedione, using a Stillecoupling to introduce the vinyl groups on theenoltriflate intermediate.

Scheme 4

Starting from (SS)-2-p-tolylsulfinyl-1,4-naphthoquinones, we could synthesize someangucyclinones,[8] a group of natural tetracyclicquinones showing antibiotic and antitumoralproperties. The tetracyclic skeleton of rubiginone B2

(Scheme 5) was assembled by reaction between 5-methoxy-2-p-tolylsulfinylnaphthoquinone (SS)-15 andthe diene 16, which was used racemic. The

cycloaddition occurred with resolution of the diene ina double asymmetric induction process where thematched pair corresponded to the endo-cycloadditionof (SS)-15 approaching in an anti fashion to the(3R,5R) enantiomer of trans-3-hydroxy-5-methyl-1-vinylciclohexene 16. Aromatization of the newgenerated ring of 17, deprotection of the OTBDMSgroup and photochemical oxidation led to rubiginoneB2. Ochromycinone [[88bb]] and deoxytetrangomycin [8b]

were also synthesized by applying this strategy.

SSchheemee 55

Within the angucyclinone family, some members,such as Rubiginones A2 and C2 (Scheme 6) have anadditional oxygenated function at C-4 of thehydroaroamatic A ring. The Diels-Alder strategybased on the resolution of the diene could not beapplied in this case. We then considered theconstruction of the tetracyclic skeleton starting froman enantiopure vinylcyclohexene such as 25 [9]

which could be synthesized from (SS)-[(p-tolylsulfinyl)methyl]-p-quinol 20. The p-quinols bearing a CH2SOpTol substituent at C-4 ofthe cyclohexadienone moiety had been previouslysynthesized by us [1100]]. A methodologic study hadevidenced that AlMe3 reacted with such p-quinols ina highly chemo-and diastereoselective mannerleading to only one out of the four possiblediastereomers resulting from conjugate addition. Theprocess led to the efficient desimmetrization of theprochiral cyclohexadienone moiety of 20. As shownin Scheme 6, the synthesis of (SS)-20 was achievedin two steps from p-benzoquinone dimethylketal 19,by addition of the lithium anion derived fromenantiopure (SS)-methyl p-tolyl sulfoxide to thecarbonyl group followed by hydrolysis of the ketalgroup. p-Quinol 20 reacted with AlMe3 leading toderivative 21, which has the R configuration at thenew C5 stereogenic center. The sulfoxide of 21 wasoxidized into the sulfone to afford, afterstereoselective reduction of th C=O and protection ofthe secondary carbinol, the _-hydroxy sulfone 22.

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Previously, we had shown that after oxidation of thesulfoxide to a sulfone, compounds such as 21suffered the elimination of methyl p_tolylsulfone by aCs2CO3-promoted retrocondensation, allowing torecover a carbonyl group at C-4 [11]. Thus, ketone23 was obtained in 86% yield, showing that the initial‚_hydroxy sulfoxide can be considered as a chiralprotecting group of a cyclohexanone.

Treatment of 23 with Br2 and Et3N promoted anaddition elimination process leading to anintermediate _-bromo enone, which wasstereoselectively reduced and esterified to 24. Thiswas the immediate precursor of the enantiopure vinylcyclohexene 25, available after a Stille coupling in 78% yield.

Scheme 6

We then proceeded to the construction of thetetracyclic skeleton through the Diels–Alder reactionbetween the enantiopure vinyl cyclohexene 25 and2-(p_tolylsulfinyl)-juglone methyl ether 26, which wasused in racemic form since the role of the sulfoxidein this case was limited to the regiochemical controlof the cycloaddition and to facilitate the recovery ofthe quinone structure from the initial adduct, byspontaneous elimination of p-tolylsulfenic acid(Scheme 6). Rubiginone C2 was finally obtainedupon exposure of 27 to sunlight in the presence ofair under solvent-free conditions. This unprecedentedphotoinduced one-pot transformation implied adomino sequence of three reactions: aromatization ofthe B ring, deprotection of the silyl ether andoxidation of the C-1 position into a carbonyl group.The other natural product, rubiginone A2, resultedfrom rubiginone C2, by methanolysis of the C-4 ester.The 11_methoxy regioisomers of both naturalproducts were synthesized in a similar manner usingracemic 3-p-tolylsulfinyl juglone methyl ether asdienophile [9a]. Other synthetic applications ofsulfoxide bearing p-quinols, focused on naturalpolyoxygenated cyclohexanes and cyclohexenesfrom compounds 22 and 23, easily transfromed intothe natural targets by sterereoselective processesoccurring on the rigid cyclic systems. [12]

Acknowledgments

I am grateful to all my co-workers, especially Drs.Ribagorda and Urbano, for their contribution to thegroup’s research results. Financial support from theMinisterio de Educación y Ciencia (Spain) andComunidad de Madrid is greatly acknowledged.

References

[11] Review: Nicolaou, K. C.; Snyder, S. A. ; Montagnon, T.;Vassilikogiannakis, G.; Angew. Chem. Int. Ed. 22000022, 41,1668-1698.[22] For recent examples see: a) Pingfan Li.; Payette, J. N.;Yamamoto, H. J. Am. Chem. Soc. 2000077, 129, 9536-9537. b)Liu, D., Canales, E., Corey, E. J. J. Am. Chem. Soc. 2200077,129, 1498-1499. c) Jarvo, E. R.; Lawrence, B. M.; JacobsenE. N. Angew. Chem. Int. Ed. 2000055, 44, 6043-6046.[[33]] Carreño, M. C.; García Ruano, J. L.; Toledo, M. A.;Urbano, A.; Remor, C. Z.; Stefani, V.; Fischer, J. J.Org.Chem. 11999966, 61, 503-509.[44] Carreño, M. C.; García Ruano, J. L.; Urbano, A.Synthesis, 11999922, 651-653.[55] Vögtle, F. Fascinating Molecules in Organic Chemistry,Wiley and Sons, New York, 11999922, 156-180.[[66]] a) Carreño, M. C.; Enríquez. A. L.; García-Cerrada, S.;Sanz-Cuesta, M. J.; Urbano, A.; Maseras, F.; Novell-Canals,A. Chem. Eur. J. 22000088, 14, 603-620. b) Carreño, M. C.;García-Cerrada, S.; Sanz-Cuesta, M. J.; Urbano, A. Chem.Commun. 22000011, 1452 – 1453.[77] a) Carreño, M. C.; García-Cerrada, S.; Urbano, A. Chem. Eur. J. 2200003, 9, 4118 –4131. b) Carreño, M. C.;García-Cerrada, S.; Urbano, A. Chem. Commun. 2200022,1412 – 1413; c) Carreño, M. C.; García-Cerrada, S.;Urbano, A. J. Am. Chem. Soc. 2200011, 123, 7929 –7930.[88] a)Carreño, M. C.; Urbano, A. ; Di Vitta, C. Chem. Eur. J.20000, 6, 906 –913. b) Carreño, M. C.; Urbano, A. ; Di Vitta,C. Chem. Commun. 1199999, 817 –818. c) Carreño, M. C.;Fischer, J.; Urbano, A. Angew. Chem. 1199977, 109, 1695 –1697. Angew. Chem. Int. Ed. Engl. 1997, 36, 1621 –1623.[[99]] a) Carreño, M. C.; Ribagorda, M.; Somoza, A.; Urbano,A. Chem. Eur. J. 2200007, 13, 879 – 890. b) Carreño, M. C.;Ribagorda, M.; Somoza, A.; Urbano, A. Angew. Chem.22000022, 114, 2879 –2881. Angew. Chem. Int. Ed. 22000022, 41,2755 –2757.[110] Carreño, M. C.; Pérez González, M.; Ribagorda, M.;Houk, K. N. J. Org. Chem. 1199988, 63, 3687-3693.[1111] a) Carreño, M. C.; Merino, E.; Ribagorda, M.; Somoza,A.; Urbano, A. Org, Lett. 200055, 7, 1419-1422. b) Carreño, M.C.; Pérez González, M.; Ribagorda, M.; Somoza, A.;Urbano, A. Chem. Comm. 200022, 63, 3052-3053.[112] Carreño, M. C.; Merino, E.; Ribagorda, M.; Somoza, A.;Urbano, A. Chem. Eur. J. 220007, 13, 1064-1077.

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StereoselectiveSynthesis ofAmino Diols

Stephen G. Davies

Department of Chemistry, University of Oxford, Oxford, UK

The amino diol motif is a recurring structuralcomponent in a diverse range of biologically activenatural products and synthetic molecules. Theasymmetric synthesis of a range of natural products[1,2] and other highly functionalised moleculararchitectures containing the amino diol unit utilising avariety of synthetic methodology including asymmetricconjugate addition of nitrogen nucleophiles,[[33]] novelcyclisation strategies[[44]] and ammonium-directeddihydroxylation is delineated.[[44]]

The conjugate addition of lithium (S)-N-benzyl-N-(_-methylbenzyl)amide to a _-silyloxy-_-‚ _-unsaturatedester with in situ enolate oxidation with (+)-CSOgives ready access to the corresponding _-hydroxy-_-amino esters as a single diastereoisomer in goodyield. This methodology had been utilised in thesynthesis of a range of natural products includingsphingosine and jaspine B.[2]

We have recently developed a novel iodine-mediated ring-closure/debenzylation protocol of atertiary, unsaturated amine. The utility of thisexquisite transformation has been demonstrated viathe synthesis of polyhydroxylated pyrrolidines. Thus,conjugate addition of lithium (S)-N-benzyl-N-(_-methylbenzyl)amide to a D-ribose-derived _‚ _-unsaturated ester gave the corresponding_-aminoester. Treatment of this_-amino ester with I2 in MeCN

in the presence of NaHCO3 gave a 19:81 mixture ofC(5)-epimeric N-benzyl pyrrolidines with in situ lossof the _-methylbenzyl cation, from which the majordiastereoisomer was isolated in 63% yield in >98%de. In this process, ring-closure to the pyrrolidine andchemoselective N-deprotection had been affected ina single step. Subsequent manipulation of theprimary iodide by displacement with AgOAc, anddeprotection, gave the polyhydroxylated pyrrolidineas a single stereoisomer in good yield.[[44]]

Oxidation of an allylic primary, secondary or tertiaryamine with a peracid is known to occur preferentiallyat the nitrogen atom, giving the corresponding N-oxide. Recent investigations have shown that thein situ protection of the nitrogen atom of an allylicamine by protonation allows chemoselectiveoxidation of the double bond syn to the aminofragment, under hydrogen-bond controlled delivery

by the adjacent ammonium ion. Thus, treatment of 3-N,N-dibenzylamino-cyclohexene withtrichloroacetic acid, followed by subsequent,sequential treatment with mCPBA gives 1,2-anti-2,3-syn-3-amino-1,2-in quantitative yield and >90% de.This metal-free methodology has been successfullyapplied to the synthesis of all four possiblediastereoisomers of 3-amino-cyclohexane-1,2-diol in>98% de.[[5]]

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This work has recently been extended to encompassthe chemo- and stereoselective cyclopropanation ofa range of allylic amines, and a stereodivergentprotocol for the preparation of 2-amino-bicyclo[4.1.0]heptane derivatives has beendeveloped.[6]

References

[1] S. G. Davies and O. Ichihara, Tetrahedron Letters, 1999,40, 9313; S. G. Davies, R. J. Kelly and A. J. Price-Mortimer,Chem. Comm., 2003, 2132; S. G. Davies and O. Ichihara,Tetrahedron Asymmetry, 1996, 7, 1919.[2] E. Abraham, J. I. Candela-Lena, S. G. Davies, M.Georgiou, R. L. Nicholson, P. M. Roberts, A. J. Russell, E.M. Sánchez-Fernández, A. D. Smith and J. E. Thomson,Tetrahedron: Asymmetry, 2007, 18, 2510; E. Abraham, S. G.Davies, N. L. Millican, R. L. Nicholson, P. M. Roberts and A.D. Smith, Org. Biomol. Chem., 2008, 6, 1655; Abraham, E.A. Brock, J. I. Candela-Lena, S. G. Davies, M. Georgiou, R.L. Nicholson, P. M. Roberts, A. J. Russell, E. M. Sánchez-Fernández, P. M. Scott, A. D. Smith and J. E. Thomson,Org. Biomol. Chem., 2008, 6, 1665; E. Abraham, S. G.Davies, P. M. Roberts, A. J. Russell, J. E. Thomson,Tetrahedron: Asymmetry, 2008, 19, 1027.[[33]] S. G. Davies, P. D. Price and A. D. Smith, Tetrahedron:Asymmetry, 2005, 16, 2833; S. G. Davies, N. M. Garrido, D.Kruchinin, O. Ichihara, L. J. Kotchie, P. D. Price, A. J. PriceMortimer, A. J. Russell and A. D. Smith, Tetrahedron:Asymmetry, 2006, 17, 1793.[4] S. G. Davies, R. L. Nicholson, P. D. Price, P. M. Robertsand A. D. Smith, Synlett, 2004, 901.

[5] S. G. Davies, M. J. C. Long and A. D. Smith, Chem.Commun., 2005, 4536.

[6] S. G. Davies, K. B. Ling, P. M. Roberts, A. J. Russell

and J. E. Thomson, Chem. Commun., 2007

336


The Evolution ofLilly Oncology:From TargetedCytotoxic Agents(Alimta®) toKinase Inhibitors

Joe Shih

Discovery Chemistry Research and Technologies, Lilly Research Laboratories, Eli Lilly and Company,Indianapolis, USA

The anticancer drug discovery effort at Lilly can betraced back to the early 1960s and 1970s. Usingcytotoxicity-based cell screen as the primary strategyfor lead identification, the Lilly team then led by Dr.Irving Johnson uncovered potent cytotoxic Vincaalkaloids in the extracts prepared from the leaves ofMadagascar periwinkle (Vinca Rosea Linn G. Don).Through careful chemical structure elucidation andinvestigation of the pharmacological actions of thesecytotoxic alkaloids, Vincristine and Vinblastine weresuccessfully developed as the first class of anti-tubulinchemotherapeutic agents for the treatment of variousleukemia (ALL, ML), Hodgkin/non-Hodgkin lymphomaand germ cell malignancies. Vincas (Vindesine wasdiscovered and added later to the arsenal of Vinca-based chemotherapeutic agents) have since becomewidely used to treat various type of cancers either assingle agent or in combination with otherchemotherapeutic agents.

The success of Vincas stimulated considerableamount of interest at Lilly to continue investigatenovel approaches in discovering effective agents inparticular for the treatment of solid tumors (breast,lung, colon, pancreas and prostate cancers forexample). In early 1980s, the anticancer programunder the direction of Dr. Gerald Grindey decided toshift to the use of solid-tumor human tumor xenograftscreening as way to identify broad-spectrum antitumoragents for difficult to treat human solid tumors.Under this initiative, two novel anti-metabolites,Gemzar (Gemcitabine) and Alimta (Pemetrexed)were discovered and put into clinical development inlate 1980s and 1990s and eventually each receivedUS FDA approval for marketing (Gemzar first in1996for pancreatic cancer and Alimta in 2004 receivedthe first approval for malignant pleural mesothelioma).Gemcitabine is a prodrug that requires enzymaticconversion to its bioactive diphosphate andtriphosphate forms. The diphosphate form ofgemcitabine inhibits the ribonucleotide reductaseand the triphosphate form of gemcitabine can act asa DNA chain terminator once it was incorporated intothe DNA. Gemzar is an effective anticancer agent fortreating various forms of human cancers. In additionas the gold standard for the treatment of pancreaticcancer, Gemzar is also now approved for thetreatment of non-small cell lung cancer (1st line in

combination with cisplatin), bladder cancer,metastatic breast, ovarian and pediatric cancer.

Alimta on the other hand is a novel pyrrole-pyrimidinebased “classical” antifolate. It is derived from thesuccessful 10-year antifolate drug discoverycollaboration program between Lilly and the PrincetonUniversity (key collaborator: Professor Edward Taylorof the Chemistry Department, now retired). Threeclinical candidates (Lometrexol, Alimta and GARFTII)were identified during the decade long collaborationand Alimta was identified through an active SARprogram attempting originally in removing the chiralityat the C-6 asymmetric center (thus simplify theseparation issue of the two diastereomers) of thetetrahydropyridine-pyrimidine region of the GARFT(glycinamide ribonucleotide formyltransferase)inhibitor, Lometrexol. Replacement of thetetrahydropyridine ring with pyrrole led to thediscovery Alimta. Alimta can be effectively preparedby using the palladium-based Sognagesia couplingbetween the 2-pivaloyl-5-iodo-pyrrolopyrimidine andthe 4-ethynyl-diethylbenzoyl-Lglutamate, followed byhydrogenation and removal of the ester and amideprotection groups. While the chemical modification ofLometrexol to Alimta seems straight forward, however,the mode of action of Alimta turned out to be verydifferent and unique from its predecessor, Lometrexol.

Through various careful cell-based cytotoxicityreversal studies and evaluation of polyglutamatedform of Alimta against isolated human folate enzymes,it was concluded that Alimta can potently inhibitseveral key folate enzymes in the folate biochemicalpathway involved in both the purine and thepyrimidine biosynthesis. These enzymes includeGARFT, TS (thymidylate synthase) and DHFR(dihydrofolate reductase). For example, it was foundthat the pentaglutamate derivative of Alimta (Alimta-Glu5) can potently inhibit hTS (IC50= 1.3 nM),dDHFR (IC50= 7.2 nM) and GARFT (IC50= 65 nM).In addition to these three enzymes, Alimtapolyglutamates also inhibit AICARFT(aminoimidazolecarboxamide ribonucleotideformyltransferase, IC50= 260 nM) and C-1tetrahydofolate synthase.[[11]] Alimta was found to bean excellent substrate for the enzymefolylpolyglutamate synthetase (FPGS), through both

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enzyme kinetic and cellular uptake studies it wasfound Alimta can be rapidly (<2h) converted into thepolyglutamated forms (usually up to penta- andhexaglutamates) when incubated in the CCRF-CEMleukemia cells. The excellent polyglutamation profilecoupled with the fact that Alimta can be efficientlytransported into the cells by the active transportsystem, Reduced Folate Carrier (RFC), makesAlimta a very novel classical antifolate that can beeffectively taken up into the tumor cells and affectingthe cellular de novo DNA and RNA synthesis (whichare essential for the rapidly dividing malignantcancerous cells) by simultaneously inhibiting severalkey folate-requiring enzymes of the folate pathway(Figure 1).

Figure 1. Mechanism of action of ALIMTA®

Alimta went into phase I clinical development in theearly 1990s for safety assessment. The 21-dayschedule of Pemetrexed administered at 600 mg/m2on day 1 as a 10-minute intravenous infusion wascarried into phase II trials. As a single agent,interesting activity was observed in mesothelioma,breast, gastrointestinal and NSCLC (non-small celllung cancer), with myelosuppression as the majordose-limiting toxicity. Alimta’s first registration trialwas focused on malignant pleural mesothelioma(MPM) in combination with cisplatin since excitingresponses were observed from the earlier phase IIstudies for Alimta/cisplatin against MPM. With thecritical introduction of daily supplement of oral folicacid (300-1000 ug) and vitamin B12 (1000 ug q9w)to mitigate grade 3 and 4 drug-related toxicities(bone marrow), it was found Alimta plus cisplatin cansignificantly increase the median survival time (MST)(13.3 month vs. 10.0 month) than patients oncisplatin only.[2] The lung functions of the MPMpatients who received Alimta and cisplatin alsoimproved significantly. Alimta was approved by USFDA in February 2004 as the first line therapy (incombination with cisplatin) for malignant pleuralmesothelioma. Alimta was also found to be aneffective antitumor agent for non-small cell lungcancer. It received US FDA approval as a 2nd linetreatment (single agent) on October 2004 forNSCLC. Recently (April 2008), it has also receivedEU EMEA’s approval as a 1st line treatment (in

combination with cisplatin) for NSCLC. Four yearssince the first approval for MPM in 2004, Alimta hasnow emerged as a major targeted-cytotoxic agent forthe management of thoracic cancer with quiteacceptable safety profile and manageable toxicity.

Gemzar and Alimta have now become thecornerstones of the Lilly oncology franchise with totalannual sales of more than 2.3 billion dollars (2007).With this success, the Lilly oncology programcontinues to evolve focusing on bringing more noveland effective agents for the management andtreatment of various forms of cancer. Beginning inthe late 1990s, with the success deciphering ofhuman genome and advancement of molecular andcellular biology in understanding of the control of

cell-signaling pathway, LillyOncology has shifted the focusand strategy once again intothe area of kinase drugdiscovery.

To tackle the challenging taskof targeting kinase genome fordrug discovery, we have builtextensive infrastructures andcapabilities at Lilly ResearchLaboratories for rapidlyidentifying hits and leads forvarious kinase targets. Forexample, we have usedvarious approaches includingtargeted kinase compoundcassette MTS (mediumthroughput screen), PLS

(platform library science), high throughput SBDD(structure-based drug design), bioinformatics, kinasepanel profiling (at Upstate) and phenotypic drugscreening as novel tools for assisting rapididentification and iteration/optimization of novelactives into hits and leads. To illustrate thisintegrated approach for kinase drug discovery, arapid SBDD effort in identifying potent p38a MAPkinase inhibitor for oncology indication is shown.

p38a MAP kinase plays an important role in thesignal transduction pathway and the activation of thiskinase in macrophages and tumors can lead to theproduction of cytokines (TNFa, IL-1b) as well as thestimulation of various angiogenic factors (VEGF,bFGF, EGF, IGF1 and HGF) that could lead toangiogenesis and the development of tumors. Forexample, by using structure-based design approachin carefully analyzing the active site (ATP) of p38aMAP kinase, we have successfully converted arelatively no so potent benzimidazole aryl ketone hit(uM potency identified from c-Raf kinase screen) intoa potent series of triarylimidazole class of p38a MAPkinase inhibitors (LSN 479754, IC50 ~ 5 nM). TheN3 and 2-NH2 groups on the benzimidazole ring canserve each as the hydrogen bond acceptor anddonor interacting pairs with the hinge region amidebonds.

The larger benzimidazole warhead was nicelyaccommodated in the p38a MAP kinase active sitesince it was observed that the hinge of p38a MAPkinase is quite flexible and can move outward

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(compared to other p38a MAK kinase structures withsmaller warhead inhibitor, SB203580 for example) totolerate bigger structure element such asbenzimidazole. The binding mode of the solvedinhibitor/enzyme complex of LSN470754 is exactlyidentical to what was predicted based on the originalSBDD design.

Figure 2. p38aMAP kinase/inhibitor co-crystal structuresGreen: LSN 479754, Yellow: SB203580(Noticed the movement of the hinge region, Met109 Gyl110to accommodate the larger benzimidazole warhead)

Further modification of the LSN 479754 seriesquickly led to the identification of LSN2322600 whichdemonstrated potent effects both in vitro as well asp38a MAP kinase target inhibition in vivo (in eitherperipheral blood monocytes or in B-16F10melanoma, TMED50=3.6 mg/kg). Compound LSN2322600 also demonstrated good antitumor effects(tumor growth delay) in U87MG glioma (incombination with Temodar) or as a single agent inA549 lung xenograft. Excellent anti-inflammatoryeffect in collagen-induced arthritis (CIA) model (rat)was also observed for LSN2322600 (with both pawswelling and histology scores TMED50 = 1.5 mg/kg).The Phase I first human dose of LSN2322600 isscheduled to begin in Q2, 2008.

In conclusion, Lilly Oncology has evolvedsuccessfully in the past 50 years, starting from thenatural products based approach that led to theidentification of novel chemotherapeutic agents suchas Vinca alkaloid (Vincristine, Vinblastine andVindesine). This was then followed by using thesolid-tumor screening in xenografts to identifybroadly active antimetabolite agents (Gemzar andAlimta) for human solid tumors. Gemzar and Alimtaare excellent examples of the power of thisapproach; both drugs have now become one of themost important chemotherapeutic agents/arsenals inmodern day clinical oncology for the front linetreatment and management of various forms ofcancer, including lung, pancreatic, bladder, ovarian,breast and mesothelioma cancer. Lilly Oncology isnow actively involved in the discovery anddevelopment of an array of novel targeted agentsincluding various kinase inhibitors as a way to showour continued commitment in bringing patients andphysician the most effective drugs in the war againstcancer.

References

[[11]] C. Shih, V. J. Chen, L. S. Gossett, S. B. Gates, W. C.MacKellar, L. L. Habeck, K. A. Shackelford, L. G.Mendelsohn, D. J. Soose, V. F. Patel, S. L. Andis, J. R.Bewley, E. A. Rayl, B. A. Morrison, G. P. Beardsley, W.Kohler, R. Ratnam and R. M. Schultz, LY231514, APyrrolo[2,3-d]pyrimidine Based Antifolate That InhibitsMultiple Folate Requiring Enzymes. Cancer Research, 57,1116-1123 (1997)[[22]] H Pass, N. Vogelzang, S. Hahn, M. Carbone. Malignantpleural mesothelioma. Curr Probl Cancer. May-Jun;28(3):93-174 (2004)

--

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As part of the actions of promotion of R&D inBiomedicine in Spain, the Scientific Advisory Councilof the Lilly Foundation proposed the creation of theLilly Distinguished Career Award, deliverable in eachLilly Foundation Scientific Symposium, that seeks torecognize the scientific trajectory of the Spanishscientists, working either in Spain or abroad, that,once fulfilled its career, they have fertilized its area ofknowledge, contributing to increase its scientificlevel, and to generate vocations among itscollaborators.

The concession of these prizes will be made with thecollaboration of the Spanish Scientific Societycorresponding to the area of knowledge of theSymposium, through a protocol agreed by the twoparts.

In the 13th Lilly Foundation Scientific Symposium“Chemistry: Science at the Frontier”, the LillyFoundation with the collaboration of the RoyalSpanish Society of Chemistry, granted the LillyDistinguished Career Award to Prof. José ElgueroBertolini, of the Institute of Medicinal Chemistry(CSIC) of Madrid, for his influence in connection withthe improvement of the level of the Spanish organicchemistry, specially for his contributions inheterociclic, medicinal chemistry and physicalorganic chemistry, as well as for his influence on theyounger generations of scientists.

LillyDistinguishedCareer Award.Chemistry2008

Como parte de las acciones de promoción de laI+D en Biomedicina en España, el ConsejoCientífico Asesor de la Fundación Lilly propuso lacreación del Lilly Distinguished Career Award, quese entregará en cada edición del SimposioCientífico de la Fundación Lilly. El premio pretendereconocer la trayectoria investigadora de loscientíficos españoles que trabajan en España o enel extranjero que, una vez cumplida su carreracientífica, han fertilizado su área de conocimiento,contribuyendo a aumentar su nivel científico, y agenerar vocaciones entre sus colaboradores.

La concesión de estos premios, que constarán deun diploma y un trofeo diseñado al afecto, se harácon la colaboración de la sociedad –o en su casosociedades- científica española correspondiente alárea de conocimiento del Simposio, mediante unprotocolo acordado por las dos partes.

En el 13º Simposio Científico de la Fundación Lilly“Química, Ciencia en la Frontera”, el premio LillyDistinguished Career Award se ha concedido alProf. José Elguero Bertolini, del Instituto deQuímica Médica (CSIC) de Madrid, por suinfluencia en el avance del nivel de la químicaorgánica española, especialmente por suscontribuciones en la química de heterociclos,química médica y química orgánica física, asícomo por su magisterio sobre los investigadoresde las generaciones mas jóvenes.

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JJeeaann--MMaarriiee PP.. LLeehhnn --NNoobbeell LLaauurreeaattee--Professor at the Collège de FranceLaboratoire de Chimie Supramoléculaire, Université Louis Pasteur. Paris, [email protected]

JJeeaann--PPiieerrrree SSaauuvvaaggeeCNRS Director of ResearchInstitut de Chimie, Laboratoire de Chimie Organo-Minérale,Université Louis Pasteur CNRS/UMR 7177 Strasbourg, [email protected]

Phil S. BaranAssociate ProfessorDepartment of Chemistry, The Scripps Research InstituteLa Jolla, California, [email protected]

Dennis CurranDistinguished Service Professor and Bayer Professor of ChemistryDepartment of Chemistry, Chevron Science CenterPittsburgh, [email protected]

Gregory C. FuProfessorMassachusetts Institute of TechnologyCambridge, MA, [email protected]

Alois FürstnerDirectorMax-Planck-Institut für KohlenforschungMülheim an der Ruhr, [email protected]

Jean-Pierre GenetProfessorLaboratoire de Synthèse Sélective Organique et ProduitsNaturels, Ecole Nationale Supérieure de Chimie de ParisParis, [email protected]

Fernando AlbericioFull ProfesorInstitute for Research in Biomedicine, Barcelona SciencePark, University of Barcelona. Barcelona, [email protected]

María del Carmen Carreño García Full ProfessorDepartamento de Química Orgánica, Facultad de Ciencias,Universidad Autónoma de Madrid. Madrid, [email protected]

Stephen G. DaviesProfessorChemistry Research Laboratory, Department of Chemistry,Oxford University. Oxford, [email protected]

Lutz F. TietzeProfessorInstitut für Organische und Biomolekulare Chemie,Universität Göttingen. Göttingen, [email protected]

Jacqueline K. BartonArthur & Marian Hanisch Memorial Professor of ChemistryDivision of Chemistry and Chemical EngineeringCalifornia Institute of Technology. California, [email protected]

Joe ShihDistinguished Lilly ScholarLilly Research Laboratories, Eli Lilly. Indianapolis, [email protected]

M. Christina WhiteAssistant ProfessorDepartment of Chemistry, University of IllinoisUrbana, IL, [email protected]

Larry E. OvermanDistinguished Professor of ChemistryUniversity of California. Irvine, CA, [email protected]

Julio Álvarez-BuillaFull ProfessorOrganic Chemistry Department, Pharmacy School,University of Alcalá de Henares. Madrid, [email protected]

Miguel A.YusFull ProfessorOrganic Chemistry Department, Sciences School, University of Alicante. Alicante, [email protected]

Jesús EzquerraEuropean Discovery Chemist DirectorLilly Research Laboratories. Alcobendas, Madrid, [email protected]

María Ángeles Martínez-GrauLilly Research Laboratories. Alcobendas, Madrid, [email protected]

Rafael SuauFull ProfesorOrganic Chemistry Department, Sciences School, University of Málaga. Málaga, [email protected]

José A. Gutiérrez-FuentesDirector Fundación LillyMadrid, [email protected]

S C I E N T I F I C C O M M I T T E E

Julio Álvarez-Builla

Miguel Yus

Jesús Ezquerra

José A Gutiérrez-Fuentes

Chairpersons& Speakers

Chairmen

Julio Álvarez-BuillaJesús EzquerraMiguel Yus

13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM CHEMISTRY: SCIENCE AT THE FRONTIER

Documents

Index [] · Supramolecular chemistry is intrinsically a dynamic chemistryin view of the lability of the interactions ... Supramolecular Chemistry: Concepts and Perspectives,VCH Weinheim,