Joe Shih

Tags: DNA, DNA charge transport, LILLY FOUNDATION, molecular chemistry, Charge Transport, the reaction, base excision repair, Jean-Marie Lehn, reaction, Supramolecular Chemistry, Scheme, Molecular Machines, catalyst system, asymmetric hydrogenation, Ru-catalyst, asymmetric induction, DNA mismatches, DNA lesions, Oxidative DNA Damage, DNA charge, DNA library, DNA repair proteins, chiral center, conjugate addition, supramolecular, Materials Lutz F. Tietze, Constitutional Dynamic Chemistry, natural products, Total Synthesis, Efficient Synthesis of Natural Products, volumen de negocio, Asymmetric Synthesis, enantioselective synthesis, organometallic chemistry, acyclic diene metathesis, ica, Nobel Laureate in Chemistry, synthetic methods, Dynamic combinatorial chemistry, Dennis Curran, Science at the Frontier, Dellis P. Angew
Content: Index 5 Introduction 7 From Supramolecular Chemistry to Constitutional Dynamic Chemistry Jean-Marie Lehn. Nobel Laureate in Chemistry 1987 8 Catenanes, Rotaxanes and Molecular Machines Jean-Pierre Sauvage 10 Fluorous Mixture Synthesis Approaches to Natural Product Stereoisomer Libraries Dennis Curran 12 The Awesome Power of Metathesis Alois Fьrstner 14 New Approaches for the Synthesis of Complex Peptides Fernando Albericio 17 Domino and Multiple Pd-Catalyzed Reactions for the Efficient Synthesis of Natural Products and Materials Lutz F. Tietze 19 DNA Charge Transport for DNA Damage and Repair Jacqueline K. Barton 22 Streamlining Synthesis via C-H Oxidation M. Christina White 23 Recent Studies in Alkaloid Total Synthesis Larry E. Overman 24 The Catalytic Cycle of Discovery in Total Synthesis Phil S. Baran 26 Palladium -and Nickel- Catalyzed Coupling Reactions Gregory C. Fu 27 New Developments of Organometallic Catalysts in Organic Synthesis Jean-Pierre Genet 31 New Applications of Quinones and Quinols in Asymmetric Synthesis M. Carmen Carreсo 34 Stereoselective Transformations of Allylamines Steve G. Davies 36 The Evolution of Lilly Oncology, from Targeted Cytotoxic Agent (Alimta®) to Kinase Inhibitors Joe Shih 39 Lilly Distinguished Career Award. Chemistry 2008 41 Speakers & Chairpersons PROMOTER/SPONSOR 3
13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM Chemistry: Science at the Frontier
13Є FUNDACIУN LILLY SIMPOSIO CIENTНFICO Quнmica, Ciencia en la frontera
Chemistry is, often called the central science, because of its role in connecting "hard" sciences such as physics with the "soft" sciences such as biology or medicine, producing the more exciting advances in the frontier with other scientific areas. It is in that way chemistry is producing seminal contributions to biomedicine, helping the creation of new drugs. Inventing and developing a new drug is a long, complex, costly and risky process that has few peers in the industry world. Historically, as its today, creation of a new drug rides much ­although not only- over the wave of new synthetic technologies. The new synthetic methods, by which scientists can create increasingly complex molecules, are often in the basis of the new, and more efficient molecular entities recently developed. In addition, present miniaturization and automation of testing techniques is producing a parallel effort in improvement of synthetic methodology. The Thirteenth Lilly Foundation Scientific Symposium "Chemistry: Science at the Frontier" had tried to mix scientists with different views and cultures in their approach to creation of new molecules, from the use of parallel fluorous techniques to obtain libraries of natural products, to organometallic chemistry in all his present possibilities, expanding the available synthetic methods as never seen before; from new approaches to the synthesis of alkaloids, to the synthesis of complex peptides; from catalysis in their last approaches, to enantioselective synthesis; from purely medicinal chemistry directed to precisely chosen targets, to chemical biology related to DNA chemistry; from supramolecular chemistry developments, to the chemistry of catenanes, rotaxanes and molecular machines. In all these lectures an equilibrium was always intended between two philosophies: one takes in nature its inspiration, while the other uses new tools and processes which science is putting in our hands, and in our labs. This combination of lectures would make and exciting offer about modern chemistry. In previous symposia, a mixture of well established masters with young emerging
A la quнmica con frecuencia se la denomina "la ciencia central", debido a su papel como puente entre ciencias "duras" como la fнsica, y ciencias "blandas" como la biologнa o la medicina, favoreciendo los avances mas interesantes en la fronteras con otras бreas cientнficas. De esta manera la quнmica estб contribuyendo a abrir nuevas perspectivas a la biomedicina, ayudando a la creaciуn de nuevos fбrmacos. La invenciуn y desarrollo de un nuevo fбrmaco es un proceso largo, complejo, costoso y arriesgado que tiene pocos ejemplos similares en el mundo industrial. Histуricamente, como en la actualidad, la creaciуn de un nuevo fбrmaco ha cabalgado sobre todo ­aunque no solamentesobre la onda de las nuevas metodologнas de sнntesis. Los nuevos mйtodos de sнntesis, a travйs de los cuales los cientнficos pueden crear molйculas cada vez mбs complejas, se encuentran con frecuencia en la base de las nuevas y cada vez mбs eficaces entidades moleculares desarrolladas. De forma adicional, la actual miniaturizaciуn y automatizaciуn de las tйcnicas de ensayo biolуgico estб produciendo un avance paralelo en la mejora de la metodologнa de sнntesis. El decimotercero Simposio Cientнfico de la Fundaciуn Lilly "Quнmica, Ciencia en la Frontera" ha intentado reunir cientнficos con diferentes puntos de vista y culturas en la creaciуn de nuevas molйculas. Desde el uso de tйcnicas fluorosas en paralelo para obtener productos naturales hasta la quнmica organometбlica, con todas sus posibilidades actuales, que estб produciendo la expansiуn y disponibilidad de nuevos mйtodos sintйticos como nunca se habнa visto anteriormente; desde la catбlisis en sus ъltimas aproximaciones hasta la sнntesis enantioselectiva; desde la quнmica mйdica dirigida con precisiуn a dianas escogidas hasta la biologнa quнmica relacionada con la quнmica del ADN; desde los desarrollos de la quнmica supramolecular hasta la quнmica de los catenanos, rotaxanos y mбquinas moleculares. Hemos pretendido en todas las conferencias el equilibrio entre dos filosofнas: una, que toma de la naturaleza su fuente de inspiraciуn, y otra que hace uso de nuevas herramientas que la ciencia
5 CHEMISTRY: SCIENCE AT THE FRONTIER
specialists has been sought by the committee, in the expectation that this would create an inspiring and unique atmosphere useful to all participants in the Symposium. Scientific Organizing Committee
va poniendo en nuestras manos y en nuestros laboratorios. Esperamos que de esta combinaciуn de enfoques resulte una oferta atractiva para la quнmica moderna. Como en simposios anteriores, el Comitй Cientнfico ha pretendido una mezcla de maestros reconocidos con jуvenes investigadores, esperando con ello crear una atmуsfera ъnica e inspiradora, para todos los participantes en el Simposio.
Comitй Cientнfico Organizador
6 13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM
From Supramolecular Chemistry to Constitutional Dynamic Chemistry
Jean-Marie Lehn ISIS, Universitй Louis Pasteur, Strasbourg and Collиge de France, Paris, France
Supramolecular chemistry is actively exploring systems undergoing self-organization, i.e. systems capable of spontaneously generating well-defined functional supramolecular architectures by selfassembly from their components, on the basis of the molecular information stored in the covalent framework of the components and read out at the supramolecular level through specific interactional algorithms, thus behaving as programmed chemical systems. Supramolecular chemistry is intrinsically a dynamic chemistry in view of the lability of the interactions connecting the molecular components of a supramolecular entity and the resulting ability of supramolecular species to exchange their constituents. The same holds for molecular chemistry when the molecular entity contains covalent bonds that may form and break reversibility, so as to allow a continuous change in constitution by reorganization and exchange of building blocks. These features define a Constitutional Dynamic Chemistry (CDC) on both the molecular and supramolecular levels. CDC introduces a paradigm shift with respect to constitutionally static chemistry. The latter relies on design for the generation of a target entity, whereas CDC takes advantage of dynamic diversity to allow variation and selection. The implementation of selection in chemistry introduces a fundamental change in outlook. Whereas self-organization by design strives to achieve full control over the output molecular or supramolecular entity by explicit programming, self-organization with selection operates on dynamic constitutional diversity in response to either internal or external factors to achieve adaptation. Applications of this approach in biological systems as well as in materials science will be described. The merging of the features: - information and programmability, - dynamics and reversibility, constitution and structural diversity, points towards the emergence of adaptive chemistry.
References [1] Lehn, J.-M., Supramolecular Chemistry: Concepts and Perspectives, VCH Weinheim, 1995. [2] Lehn, J.-M., Dynamic combinatorial chemistry and virtual combinatorial libraries, Chem. Eur. J., 1999, 5, 2455. [3] Lehn, J.-M., Programmed chemical systems: Multiple subprograms and multiple processing/expression of molecular information, Chem. Eur. J., 2000, 6, 2097. [4] Lehn, J.-M., Toward complex matter: Supramolecular chemistry and self-organization, Proc. Natl. Acad. Sci. USA, 2002, 99, 4763. [5] Lehn, J.-M., Toward self-organization and complex matter, Science, 2002, 295, 2400. [6] Lehn, J.-M., Dynamers : Dynamic molecular and supramolecular polymers, Prog. Polym. Sci., 2005, 30, 814. [7] Lehn, J.-M., From supramolecular chemistry towards constitutional dynamic chemistry and adaptive chemistry, Chem. Soc. Rev., 2007, 36, 151.
7 CHEMISTRY: SCIENCE AT THE FRONTIER
Jean-Pierre Sauvage Institut de Chimie, Laboratoire de Chimie Organo-Minйrale, Universitй Louis Pasteur CNRS/UMR 7177, Strasbourg, France
Catenanes, Rotaxanes and Molecular Machines
The field of catenanes and rotaxanes [1] is particularly active, mostly in relation to the novel properties that these compounds may exhibit (electron transfer, controlled motions, mechanical properties, etc...). In addition, catenanes represent attractive synthetic challenges in molecular chemistry. The creation of such complex functional molecules as well as related compounds of the rotaxane Family Demonstrates that synthetic chemistry is now powerful enough to tackle problems whose complexity is sometimes reminiscent of biology, although the elaboration of molecular ensembles displaying properties as complex as biological assemblies is still a long-term challenge. The most efficient strategies for making such compounds are based on template effects. The first templated synthesis [2] relied on copper(I). The use of Cu(I) as template allows to entangle two organic fragments around the metal centre before incorporating them in the desired catenane backbone. Organic templates assembled via formation of aromatic acceptor-donor complexes or/and hydrogen bonds have also been very successful. Nowadays, numerous template strategies are available which have led to the preparation of a myriad of catenanes and rotaxanes incorporating various organic or inorganic fragments and displaying a multitude of chemical or physical functions. A particularly promising area is that of synthetic molecular machines and motors [3]. In recent years, several spectacular examples of molecular machines leading to real devices have been proposed, based either on interlocking systems or on non interlocking molecules [4]. In parallel, more and more sophisticated molecular machines have been reported, frequently based on multicomponent rotaxanes. Particularly noteworthy are the musclelike compounds reported by two groups [5,6], a molecular elevator [7], illustrating the complexity that dynamic threaded systems can reach. One of the prototypical systems is a bistable catenane whose motions are triggered by an electrochemical signal. The compound and its various forms are represented in Figure 1 [4a]. Copper is particularly well adapted to the design of molecular 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 more ligands in its coordination sphere. A5-coordinate situation is more adapted to the divalent state, as illustrated on Figure 1, Cu(II) being coordinated to both a 1,10-phenanthroline ligand and a 2,2',2'',6''terpyridine. Figure 1. The prototypical bistable copper-complexed catenane. The compound undergoes a complete metamorphosis by oxidising Cu(I) or reducing Cu(II). The process is quantitative but slow. In the course of the last 12 years, the response times of the various molecular machines made in Strasbourg have been considerably shortened. The fastest system is a rotaxane, able to undergo a "pirouetting" motion under the action of the same redox signal as for the catenane (CuII/CuI) and whose axis incorporates a non sterically hindering chelate of the 2,2'-bipyridine type. Now, the motions take place on the micro- to milli-second timescale [8]. In recent years, our group has also proposed transition metal-based strategies for making twodimensional interlocking and threaded arrays [9]. Large cyclic assemblies containing several copper(I) centres could be prepared which open the gate to controlled dynamic two-dimensional systems and membrane-like structures consisting of multiple catenanes and rotaxanes. Two examples are presented in Figure 2.
8 13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM
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 the corresponding organic fragments and stoichiometric amounts of copper(I) [ref. [9a] and [9b] respectively]. The X-ray structure of a compound similar to (B) was recently solved by the group of Kari Rissanen (Finland). It is shown in Figure 3. Figure 3. X-ray structure of the [2]rotaxane tetramer. The black dots of the Scheme (right) represent the 4 copper(I) atoms. Finally, in the course of the last four years, we have been much interested in endocyclic but non sterically hindering chelates [10]. These compounds are based on carefully designed 3,3'-biisoquinoline (biiq) derivatives. Some of them have even been incorporated into macrocyclic compounds. A particularly efficient and fast moving molecular "shuttle" based on such a chelate has been made and investigated as well as three-component molecular entanglements constructed by assembling three such ligands around an octahedral metal centre. These biisoquinoline-based compounds are particularly promising in relation to fast-responding controlled dynamic systems and novel topologies. An X-ray structure of a biiq-incorporating ring is presented in Figure 4 as well as that of an iron(II) complex containing three such ligands and thus leading to the formation of a three-component entanglement.
lead to applications in a short term prospective, although spectacular results have been obtained in the course of the last few years in relation to information storage and processing at the molecular level [11]. From a purely scientific viewpoint, the field of molecular machines is particularly challenging and motivating: the fabrication of dynamic molecular systems, with precisely designed dynamic properties, is still in its infancy and will certainly experience a rapid development during the next decades. References [1] a) For early work, see: G. Schill, Catenanes, Rotaxanes and 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. DietrichBuchecker, 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 on Molecular Machines) and references therein; b) J.-P. Sauvage, Ed., Structure and Bonding ­ Molecular Machines and Motors, Springer, Berlin, Heidelberg, 2001; c) V. Balzani, M. Venturi, A. Credi, Molecular Devices and Machines ­ A Journey 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, Nature 2003, 424, 174-179; e) B. Korybut-Daszkiewicz, A. Wieзkowska, 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, 51835186; Angew. Chem. Int. Ed. 2004, 43, 5073-5077. [5] a) M. C. Jimйnez, C. Dietrich-Buchecker, J.-P. Sauvage, Angew. Chem. Int. Ed. 2000, 39, 3284-3287; b) M. C. Jimйnez-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. Lйtinois-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, New J. 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
Figure 4. Endo topic but sterically non hindering ligands are used to construct fast moving molecular shuttles and threecomponent entanglements [9]. To conclude, It is still not sure whether the fields of catenanes, rotaxanes and molecular machines will
9 CHEMISTRY: SCIENCE AT THE FRONTIER
Fluorous Mixture Synthesis of Natural Product Stereoisomer Libraries
Dennis P. Curran Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA
Much current work in the field of fluorous chemistry relies on the use of fluorous stationary phases for separation. Following the introduction of fluorous tagging in 1996, [1] we soon introduced the technique of fluorous solid phase extraction (FSPE) [2]. The FSPE separation (Figure 1) allows the use of smaller (and therefore lighter) fluorous tags, and the method is especially useful for small scale discovery chemistry and library applications in drug discovery and other areas [3]. A recent review of FSPE features almost one hundred papers that have used the technique [4]. Scores of light fluorous reagents, reactants, catalysts, scavengers and protecting groups are now commercially available from Aldrich, Waco and Fluorous Technologies, Inc.[5]
Our studies on FSPE soon led us to fluorous HPLC experiments, and this in turn led to the introduction of "fluorous mixture synthesis",[6] a technique that we have since used in many new guises. The underlying concepts behind fluorous mixture synthesis, Figure 2, are those of solution phase mixture synthesis with separation and identification tagging. Briefly, a series of substrates is tagged with a homologous series of fluorous tags. The resulting tagged substrates are mixed and then taken through a multistep synthesis to provide a mixture of tagged products. During this mixture synthesis phase, effort is saved proportional to the number of compounds that are mixed. Finally, the last mixture is demixed by fluorous HPLC to provide the individual tagged products, which are then detagged (deprotected) to provide the final target compounds The concepts of solution phase mixture synthesis are general, and Craig Wilcox introduced a new class of oligoethylene (OEG) tags[7].
Figure 1. Fluorous Solid Phase Extraction: Separates tagged compounds (orange fraction) from untagged ones (blue fraction) by a generic filtration-like process.
Figure 2. Concepts of Fluorous Mixture Synthesis: Substrates are tagged and mixed. Mixture synthesis then precedes demixing and detagging. Soon after the introduction fluorous quasiracemic synthesis [8], we introduced the concept of complete stereoisomer libraries [9] (made by fluorous mixture synthesis), a concept that has been featured in much of our natural products work since then. We later united fluorous and OEG tags in the technique of double mixture synthesis [10]. These techniques have gone well beyond "proof-of-principle"; the derived products (see Figure 3) have been used to solve structure problems and provide importance biological information[11,12].
10 13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM
Figure 3. Natural Products Made by FMS or Double Mixture Synthesis All these applications are driven by the favorable features of fluorous tagging in reactions, identification and analysis, and separation. Most recently, these features have begun to be recognized by the chemical biology community, and a new wave of fluorous chemistry appears to be on the horizon. I warmly thank an excellent cadre of collaborators and coworkers for their intellectual and experimental contributions as well as for their support and friendship. I thank the Institute of General Medical Sciences of the National Institutes of Health for sustained funding of our work in fluorous chemistry over more than a decade.
References [1] Studer, A.; Hadida, S.; Ferritto, R.; Kim, S.-Y.; Jeger, P.; Wipf, P.; Curran, D. P. Science 1997, 275, 823-826. [2] Curran, D. P.; Hadida, S.; He, M. J. Org. Chem. 1997, 62, 6714-6715. [3] Curran, D. P. Aldrichim. Acta 2006, 39, 3-9. [4] Zhang, W.; Curran, D. P. Tetrahedron 2006, 62, 1183711865. [5] DPC owns an equity interest in this company. [6] Luo, Z. Y.; Zhang, Q. S.; Oderaotoshi, Y.; Curran, D. P. Science 2001, 291, 1766-1769. [7] Wilcox, C. S.; Turkyilmaz, S. Tetrahedron Lett. 2005, 46, 1827-1829. [8] Zhang, Q. S.; Curran, D. P. Chem. Eur. J. 2005, 11, 4866-4880. [9] Dandapani, S.; Jeske, M.; Curran, D. P. Proc. Nat. Acad. Sci. 2004, 101, 12008-12012. [10] Wilcox, C. S.; Gudipati, V.; Lu, H. J.; Turkyilmaz, S.; Curran, D. P. Angew. Chem. Int. Ed. 2005, 44, 6938-6940. [11] Short review: Zhang, W., Arkivoc 2004, 101-109. [12] (a) Dandapani, S.; Jeske, M.; Curran, D. P. J. Org. Chem. 2005, 70, 9447-9462. (b) Zhang, W.; Luo, Z.; Chen, C. H. T.; Curran, D. P. J. Am. Chem. Soc. 2002, 124, 10443-10450. (c) Fukui, Y.; Brueckner, A. M.; Shin, Y.; Balachandran, R.; Day, B. W.; Curran, D. P. Org. Lett. 2006, 8, 301-304. (d) Curran, D. P.; Zhang, Q. S.; Richard, C.; Lu, H. J.; Gudipati, V.; Wilcox, C. S. J. Am. Chem. Soc. 2006, 128, 9561-9573. (e) Curran, D. P.; Moura-Letts, G.; Pohlman, M. Angew. Chem. Int. Ed. 2006, 45, 2423-2426. (f) Yang, F.; Newsome, J. J.; Curran, D. P. J. Am. Chem. Soc. 2006, 128, 14200-14205.
11 CHEMISTRY: SCIENCE AT THE FRONTIER
Alois Fьrstner Max-Planck-Institut fьr Kohlenforschung, Mьlheim an der Ruhr, Germany
The Awesome Power of Metathesis
Although olefin metathesis had already been discovered during early studies on Ziegler polymerization and had found industrial applications shortly thereafter, it was not until the 1990th that this transformation gained real significance for advanced organic synthesis. The last decade, however, has seen an explosive growth of interest in metathetic conversions in general, making clear that this reaction is one of the most fascinating and versatile processes in the realm of homogeneous catalysis. Scheme 1. Basic catalytic cycle of RCM. Alkene metathesis refers to the redistribution of the alkylidene moieties of a pair of olefins effected by catalysts that are able to cleave and to form C-Cdouble bonds under the chosen reaction conditions. This mutual alkylidene exchange occurs via a sequence of formal [2+2] ycloadditions/cycloreversions (Chauvin mechanism)[1] involving metal alkylidene and metallacyclobutane species as the catalytically competent intermediates. Among the many possible uses of metathesis, the ring closing olefin metathesis (RCM) of dienes to cycloalkenes depicted in Scheme 1 remains particularly popular. It was the development of well defined metal alkylidene complexes combining high catalytic activity with an excellent tolerance towards polar functional groups that has triggered this avalanche of interest. The most prominent and versatile ones are
molybdenum alkylidenes developed by Schrock[2] and five coordinate ruthenium carbene complexes introduced by Grubbs (Scheme 1)[3]. These commercially available complexes define the standard in the field and have reached an immense popularity as witnessed by a truly prolific number of successful applications. They also serve as "lead structures" for the development of even more powerful "second generation" catalysts bearing Nheterocyclic carbenes as ancillary ligands. The latter effect even the formation of tetrasubstituted cycloalkenes and are sufficiently reactive to activate electron deficient? as well as certain electron rich alkenes that were beyond reach of the parent Grubbs catalyst. RCM is essentially driven by entropy; the ensuing equilibrium is constantly shifted towards the cycloalkene by loss of ethylene (or another volatile olefin) formed as the by-product (cf. Scheme 1). The inherent competition between cyclization of a given diene and its polymerization via acyclic diene metathesis (ADMET) strongly depends on the ring size formed as well as on pre-existing conformational constraints and can be influenced to some extent by adjusting the dilution. While five to sevenmembered carbo- and heterocycles usually form without incident, medium- and large rings are more delicate and deserve careful consideration during retrosynthetic planning. It is known that chelation of the metal carbene intermediates by the polar substitutents in the substrates plays a decisive role for productive macrocyclization [4]; hence, proper analysis of the donor strength of the heteroatoms, their distance and relative orientation towards the alkene groups allows for reliable planning even of complex target molecules of virtually any ring size. A few recent examples of bioactive compounds formed by RCM-based total synthesis protocols by our group are shown in Scheme 2 [5]. A major advantage of RCM over more conventional approaches stems from the exceptional chemoselectivity of the available metathesis
12 13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM
catalysts for the activation of olefins in the presence of most other functional groups. This, in turn, allows to avoid lengthy protecting group manipulations, thus rendering many metathesis based approaches unprecedentedly short and economic in the overall number of steps. As a consequence modern metathesis chemistry has a profound impact on the logic of synthesis. Its enormous relevance is further increased by the fact that the modern catalysts are fully operative under aqueous conditions as well as in unconventional media such as ionic liquids or supercritical CO2. Despite this highly attractive overall profile and the maturity reached in recent years, several problems remain yet to be solved. One of the major challenges is the missing control over the geometry of the emerging double bond during RCM-based formations of macrocycles as well as in many cross metathesis reactions. One way to tackle this problem takes recourse to ring closing alkyne metathesis (RCAM) followed by semi-reduction of the cycloalkynes thus formed (Scheme 3) [6]. This approach has been successfully implemented into various total syntheses, including a fully selective and high yielding route to the promising anti-cancer agent epothilone A [7].
Scheme 3. Ring Closing Alkyne Metathesis RCAM)/SemiReduction ­ Selected Examples of Natural Products prepared by this Methodology References [1] Y. Chauvin, Angew. Chem. Int. Ed. 2006, 45, 3740 (Nobel Lecture). [2] R. R. Schrock, Angew. Chem. Int. Ed. 2006, 45, 3748 (Nobel lecture). [3] R. H. Grubbs, Angew. Chem. Int. Ed. 2006, 45, 3760 (Nobel lecture). [4] a) A. Fьrstner, K. Langemann, J. Org. Chem. 1996, 61, 3942; b) A. Fьrstner, O. R. Thiel, C. W. Lehmann, Organometallics 2002, 21, 331. [5] A. Fьrstner, Angew. Chem. Int. Ed. 2000, 39, 3013. [6] A. Fьrstner, G. Seidel, Angew. Chem. Int. Ed. Engl. 1998, 37, 1734. [7] A. Fьrstner, P. W. Davies, Chem. Commun. 2005, 2307.
Scheme 2. Natural products prepared by our group via RCM. 13 CHEMISTRY: SCIENCE AT THE FRONTIER
Nuevas Estrategias para la Sнntesis de Pйptidos Complejos New Approaches for the Synthesis of Complex Peptides
Fernando Albericio Institute for Research in Biomedicine, Barcelona Science Park, University of Barcelona, Spain
Abstract Recent years have witnessed a revival in the field of peptides. Success in the field of peptide research is partly attributable to the fact that it is now possible to synthesize almost any peptide on both small and large scales. In this communication, several topics will be discussed. First of all, we will present a short overview of the use of peptides in medicine. Next, the most used synthetic strategies, which involve solid-phase, a combination of solid-phase solution, and chemical ligation, will be discussed for the synthesis of complex peptides from marine origin. In t r o d u c ci у n Durante los ъltimos aсos se ha visto un aumento importante en el nъmero de pйptidos como APIs (ingredientes farmacйuticos activos). Asн, hasta el inicio de los aсos 90 ъnicamente estaban en el mercado los anбlogos de LH-RH (leuprolide, goserelin, gonadorelin...), los anбlogos de somatostatina y las diferentes calcitoninas. A finales de los 90 e inicios de los 2000, el mercado experimentу un crecimiento reducido, pero a partir del aсo 2004 se ha experimentado un crecimiento mucho mбs importante, con nuevas entidades quнmicas (NCE) introducidas. Asн, en el aсo 2004, el volumen de negocio fue de 5.9 billones de US $ y en el 2006 de 7.94 billones de US $, lo que representa un crecimiento anual de dos dнgitos. Aunque la oncologнa continъa siendo la principal indicaciуn terapйutica para los pйptidos, los NCE recientemente introducidos han ampliado sus indicaciones terapйuticas. Asн, tenemos pйptidos para inmunologнa (glatiramer), diabetes (exenatide y pramlintide), afecciones cardiovasculares (bivalirudin, eptifibatide), infecciones (enfuvirtide y thymalfasin), reproducciуn (atosigan), sistema nervioso central (ziconotide y taltirelin), y enfermedades уseas (teriparatide). Asimismo en el aсo 2006, habнa 136 pйptidos en fases clнnicas, mientras que en el 2004, eran ъnicamente 70. Cuбles son las razones para este renacimiento de los pйptidos como fбrmacos. En primer lugar, un fracaso relativo de las llamadas "small molecules" (pequeсas molйculas), luego una relativa facilidad para desarrollar los programa de quнmica mйdica
basados en pйptidos (facilidad para alcanzar fases clнnicas, necesidad de menor nъmero de investigadores para alcanzar los hitos), todo ello acompaсado del enorme impulso que se ha dado a las nuevas formulaciones de "drug delivery" (administraciуn de fбrmacos). Otro hecho interesante es la evoluciуn que ha sufrido la propia estructura de los pйptidos en el mercado o en fase clнnicas. En la ъltimas decadas, eran pйptidos basados en secuencias naturales, de relativo bajo peso molecular. En estos momentos, las molйculas son mбs sofisticadas, con secuencias mбs largas, mбs estructurados, conteniendo aminoбcidos no naturales y partes no peptнdicas (ciclos, pйptidos pegilados, con бcidos grasos, con carbohidratos, con cadenas mъltiples...). Un factor importante en este "boom" de los pйptidos como fбrmacos lo podemos encontrar en el desarrollo extraordinario que ha sufrido la fase sуlida como estrategia de sнntesis. Asн, los nuevos soportes sуlidos, grupos protectores y agentes de acoplamiento permiten sintetizar a escala de multiquilogramos casi cualquier estructura. En nuestra presentaciуn se discutiу algunas de las metodologнas desarrolladas en nuestro laboratorio, tales como la utilizaciуn de soportes sуlidos de polietilenglicol, reactivos de acoplamiento/protecciуn basados en la hexafluoroacetona (HFA), el p-nitrobenciloxicarbonilo (pNZ) como grupo protector ortogonal, y la sнntesis de una molйcula compleja como es la oxatiocoralina. Resinas de polietilenglicol Recientemente y en colaboraciуn con Cфtй [1], hemos desarrollado una resina totalmente de PEG (ChemMatrix). Las propiedades уptimas de PEG son debidas a las distribuciones vecinal de enlaces carbono-oxнgeno en la cadena, las cuales provocan que PEG adopte una estructura helicoidal con interacciones gauche entre los enlaces polarizados. PEG puede exhibir tres organizaciones helicoidales distintas, la primera, enormemente hidrofуbica, la segunda, de hidrofobicidad intermedia, y la tercera, hidrofнlica. La naturaleza amfifнlica de PEG hace que la resina solvate bien en disolventes polares y no polares.
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Estructura Quнmica de resina ChemMatrix. Se ha utilizado la resina ChemMatrix para la sнntesis de pйptidos complejos y tambiйn de pequeсas proteнnas (> 60 aa) mediante una sнntesis secuencial. Como ejemplo, podemos citar la proteнna asociada al virus del SIDA. Quнmica basada en la HFA La quнmica de la hexafluoroacetona (HFA), que es un reactivo bidentado para la protecciуn y la activaciуn de los бcidos carboxнlicos a-funcionalizados se ha desarrollado y adaptado a la fase sуlida. Las lactonas formadas a partir de a-hidroxiбcidos representan йsteres activos, que pueden sufrir un ataque nucleуfilo y rendir derivados de бcido carboxнlico. Se han utilizado los derivados de HFA para la preparaciуn de aminoбcidos no-naturales, que a su vez se han incorporado en pйptidos con actividad biolуgica [3]. Esta quнmica se puede aplicar a la sнntesis de pйptidos con arquitectura compleja, como son lo pйptidos siameses que comparten algъn enlace.
agentes antitumorales aislados de organismos marinos el micromonospora sp. Posee varios motivos communes con una familia de pйptidos antibiуticos antitumorales, que incluye BE-22179, Triostin A, y Echinomycin. Este grupo de peptidos poseen: a) estructure bicнclica; b) una simetrнa C2; c) una unidad cromуfora de intercalaciуn; d) una uniуn ester o tioester en la parte terminal de la cadena peptнdica; e) un puente disulfuro o un anбlogo en el medio de la cadena peptнdica; f) la presencia de varios N-metil amino бcidos; y g) un aminoбcido no natural de configuraciуn D. Asн, la funciуn amino N-terminal de la tiocoralina estб terminada con бcido 3-hidroxiquinбldico, cuya unidad actъa grupo cromуforo intercalador; las dos cadenas peptнdicas son puentes con uniones tioester y disulfuro de resнduos Cys, siendo los dos que proporcionan el puente disulfuro N-metilado y D configuraciуn asi como los dos resнduos Cys(Me). Todas estas caracterнsticas permiten a esta familia de pйptidos capacidad de enlazarse con DNA por bisintercalaciуn, y ademбs alterar el ciclo celular vital. La tiocoralina inhibe la elongaciуn de DNA por DNA a polimerasa a concentraciones que inhiben la progresiуn del ciclo celular y la clonogenicidad. Sin embargo, una desventaja para el uso clнnico de tiocoralina es su baja solubilidad en todos los medios utilizados para su administraciуn. Una alternativa consiste en la preparaciуn de compuestos que mantengan una topologнa similar, presentando distinto patrуn de solubilidad. Asн, se ha sintetizado el derivado oxa de tiocoralina, donde los enlaces tioester se han sustituido por esteres (esto desde el punto de vista de building blocks implica la utilizaciуn de resнduos de Ser en lugar de Cys).
Aplicaciones de los sistema de protecciуn/activaciуn de la HFA pNZ, Grupo Protector Ortogonal. El grupo p-nitrobenciloxicarbonilo (pNZ) se ha utilizado como grupo protector temporal para la funciуn a-amino en SPPS. El pNZ, que es ortogonal con la mayor parte de grupos protectores utilizados en quнmica de pйptidos, se elimina mediante condiciones neutras en presencia de cantidades catalнticas de бcido. La utilizaciуn del pNZ en quнmica Fmoc ha permitido obviar reacciones secundarias tнpicas asociadas con la piperidina, tales como la formaciуn de dicetopiperacinas y aspartiimidas. Asнmismo, nos ha permitido desarrollar nuevas estrategias de quнmica ortogonal y convergente, para la sнntesis de pйptidos que estбn en fase clнnica como la Kahalalide F. [4] Mecanismo de eliminaciуn del pNZ Sнntesis de la Oxatiocoralina La tiocoralina es uno de los nuevos potentes
Estructura de la Oxatiocoralina La sнntesis se ha llevado a cabo en fase sуlida utilizando una resina tipo Wang, cinco diferentes grupos protectores [Fmoc para la Gly; Fmoc tambiйn para la introducciуn de la D-Ser, pero se intercambia por el Boc; Trt para la cadena lateral de la Ser; Alloc para la NMe-Cys(Me); y pNZ para la NMeCys(Acm)]; cuatro diferentes mйtodos de acoplamiento (HATU/DIEA para la incorporaciуn sobre los aminoбcidos N-metilados; DIPCDI/DMAP para la esterificaciуn; PyBOP/HOAt/DIEA para la macrolactamizaciуn; EDC·HCl, HOSu para la incorporaciуn del cromуforo). La formaciуn del puente disulfuro, que se ha realizado en fase sуlida, confiere a la molйcula una restricciуn conformacional que permite evitar totalmente la formaciуn de dicetopiperacinas, que es la principal reacciуn secundaria que tiene lugar con pйptidos N-metilados [5]. La oxatiocoralina presenta actividad antitumoral en tres lнneas celulares.
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Conclusiones El desarrollo de mйtodos sintйticos debe ser clave en el proceso de descubrimiento de nuevos fбrmacos. Muchos de ellos estarбn inspirados en la naturaleza, puesto que la dificultad sintйtica que presentan muchos de los productos, podrб ser vencida gracias a las nuevas estrategias sintetizadas. En este sentido, se augura que cada vez mбs pйptidos entrarбn en fases clнnicas y al mercado. Ref er en ci as [1] Garcнa-Martнn, F.; Quintanar-Audelo, M.; GarcнaRamos, Y.; Cruz, L.J.; Gravel, C.; Furic, R.; Cфtй, S.; Tulla-Puche, J.; Albericio, F. ChemMatrix®, a Polyethylene glycol (PEG)-based Support for the SolidPhase 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 Protease Using Fmoc-Chemistry and ChemMatrix Resin. Int. J. Peptide Res. Therapeutics, 13, 221-227 (2007). [3] Spengler, J.; Bцttcher, C.; Albericio, F.; Burger, K. Hexafluoroacetone as Protecting and Activating Reagent: New Routes to Amino, Hydroxy and Mercapto Acids and their Application for Peptide, Glyco- and Depsipeptide Modification. Chem Rev., 106, 4728-4746 (2006). [4] Gracia, C.; Isidro-Llobet, A.; Cruz, L.J.; Acosta, O.; Бlvarez, M.; Cuevas, C.; Giralt, E.; Albericio, F. Convergent Approaches for the Synthesis of the Antitumoral Peptide, Kahalalide F. Investigation of Orthogonal Protecting Groups. J. Org. Chem., 71, 71967204 (2006). [5] Tulla-Puche, J.; Bayу-Puxan, N.; Moreno, J.A.; Francesch, A.M.; Cuevas, C.; Бlvarez, M.; Albericio, F. Solid-Phase Synthesis of Oxathiocoraline by a Key Intermolecular Disulfide Dimer. J. Am. Chem. Soc., 129, 5322-5323 (2007). 16 13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM
Domino and Multiple Pd-Catalyzed Reactions for the Efficient synthesis of Natural Products and Materials
Lutz F. Tietze Institute of Organic and Biomolecular Chemistry, University of Gцttingen, Gцttingen, Germany
The development of efficient syntheses of bioactive compounds such as natural products and analogues, drugs, diagnostics, agrochemicals in academia and industry is a very important issue of modern chemistry [1]. In this respect, complex multistep syntheses have to be avoided since they are neither economically nor ecologically justifiable. Modern syntheses must deal carefully with our resources and our time, must reduce the amount of waste formed, should use catalytic transformations and finally must avoid all toxic reagents and solvents. In addition, synthetic methodology must be designed in a way that it allows access to diversified substance libraries in an automatized way. A general way to improve synthetic efficiency and in addition also to give access to a multitude of diversified molecules is the development of domino reactions which allow the formation of complex compounds starting from simple substrates in a single transformation consisting of several steps [1]. We have defined domino reactions as processes of two or more bond forming reactions under identical conditions, in which the subsequent transformations take place at the functionalities obtained in the former transformations. The quality and importance of a domino reaction can be correlated to the number of bonds generated in such a process and the increase of complexity, for which we have created the expression "bond forming efficiency". Domino reactions can be performed as single-, twoand multicomponent transformations. Thus, most of the known multicomponent processes [2] can be defined as a subgroup of domino reactions. Domino reactions can be classified according to the mechanism of the single steps which may be of the same or of different kind. As mechanistical differentiation we have included cationic, anionic, radical, pericyclic, transition metal-catalyzed and redox transformations. A combination of mechanistically different reactions is the domino-Knoevenagel-hetero-Diels-Alder reaction, which was developed in my group and which has emerged as a powerful process which not only allows the efficient synthesis of complex compounds such as natural products starting from simple substrates but also permits the preparation of highly diversified molecules.
It consists of a Knoevenagel condensation [3] of generally an aldehyde with a 1,3-dicarbonyl compound in the presence of catalytic amounts of a weak base such as ethylene diammonium diacetate (EDDA) or piperidinium acetate. In the reaction a 1oxa-1,3-butadiene is formed as intermediate which can undergo a hetero-Diels-Alder reaction [4] either with an enol ether or an alkene. The procedure has been used by us among others for the synthesis of several alkaloids (Scheme 1). Scheme 1. Enantiopure alkaloids synthesized by a three or four component domino-Knoevenagel-hetero-Diels-Alder reaction Another highly fruitful approach consisting of a Pdcatalyzed nucleophilic substitution of an allyl acetate followed by a Pd-catalyzed arylation of an alkene was used in the synthesis of (­)-cephalotaxine. The starting material for this process was obtained via an enantioselective CBS-reduction of the corresponding 2 bromocyclopentenone; moreover, the reaction proceeds with high diastereoselectivity forming only one diastereomer. Scheme 2. Synthesis of (­)-cephalotaxine
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In a similar way steroids such as estradiol and the contraceptiva desogestrel were synthesized in an enantioselective way using a Pd-catalyzed vinylation and arylation to allow a highly efficient construction of the tetracyclic core of steroids [5]. An especially effective procedure is the combination of an enantioselective Wacker-oxidation and a vinylation using a phenol containing an alkene moiety in the presence of an alkene with electron withdrawing groups such as acrylate or methyl vinyl ketone. In this process first an intramolecular formation of an ether takes place which is followed by an intermolecular C-C-bond formation. Scheme 3. Synthesis of a-tocopherol This domino reaction has been used for the enantioselective synthesis of a-tocopherol (Vitamin E) [6] and several other compounds containing a chroman moiety [7]. Ref er en ces [1] (a) L.F. Tietze, G. Brasche, K. Gericke, Domino Reactions in Organic Synthesis, Wiley VCH, Weinheim 2006; (b) L.F. Tietze, A. Modi, Medicinal Research Reviews 2000, 20, 4, 304­322; (c) L.F. Tietze, Chem. Rev. 1996, 96, 115­136; (d) L.F. Tietze, U. Beifuss Angew. Chem. 1993, 105, 137­170; Angew. Chem. Int. Ed. Engl. 1993, 32, 131­163. [2] (a) J. Zhu, Eur. J. Org. Chem. 2003, 1133­1144, cited lit.; (b) A. Dцmling, I. Ugi, Angew. Chem. 2000, 112, 3300­3344, Angew. Chem. Int. Ed. 2000, 39, 3168­3210; (c) L.F. Tietze, A. Steinmetz, F. Balkenhohl, Bioorganic and Medicinal Chemistry Letters , 1997, 7, 1303­1306. [3] (a) L.F. Tietze, U. Beifuss, In Comprehensive Organic Synthesis; B.M. Trost, Ed.; Pergamon Press: Oxford, 1991; Vol. 2, p 341. [4] (a) L.F. Tietze, G. Kettschau, J.A. Gewert, A. Schuffenhauer, Curr. Org. Chem. 1998, 2, 19­62; (b) L.F. Tietze, G. Kettschau, Topics in Current Chemistry 1997, 189, 1­120. [5] L.F. Tietze, I. Krimmelbein, Chem. Eur. J. 2008, 14, 1541­1551. [6] L.F. Tietze F. Stecker, J. Zinngrebe, K.M. Sommer, Chem. Eur. J. 2006, 12, 8770­8776. [7] (a) L.F. Tietze, K.F. Wilckens, S. Yilmaz, F. Stecker, J. Zinngrebe, Heterocycles 2006, 70, 309­319; (b) L.F. Tietze, J. Zinngrebe, D.A. Spiegl, F. Stecker, Heterocycles 2007, 74, 473­489. 18 13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM
DNA Charge Transport Chemistry and Biology
Jacqueline K. Barton Division of Chemistry and Chemical Engineering. California Institute of Technology. Pasadena, CA, USA
Our laboratory has been interested in exploring both the fundamentals of how electrons and holes migrate through the base pair stack as well as the biological implications of this chemistry with respect to how DNA may be damaged and repaired. From our laboratory and others it has by now been demonstrated in a range of different experiments that double helical DNA does indeed mediate the efficient transport of charge, both electrons and holes, on timescales as short as picoseconds. [1] Moreover, recently our laboratory has focused studies on determining how the cell may harnass this chemistry to facilitate redox signaling among proteins bound to DNA, to funnel damage to specific sites and activate repair of damage to DNA. [2] The ability of DNA to serve as a medium for the transport of charge is intrinsic to its p-stacked structure. The B-DNA double helix is an array of heterocyclic aromatic base pairs, stacked at a distance of 3.4 Е, wrapped within a negatively charged sugar phosphate backbone. (Figure 1)
This analogy between DNA and solid state p-systems is useful in considering DNA charge transport: the interactions between the p-electrons of the DNA base pairs provide the electronic coupling necessary for DNA charge transport to occur. But it is important to consider also the differences between DNA, a pstacked macromolecular assembly in solution, and solid state p-stacks. In contrast to solid state p-stacks, DNA is conformationally dynamic, a property that is key to all of its biological functions. Conformational rearrangements of the DNA bases on the ps to ms time scale modulate base stacking interactions, redox potentials, and electronic coupling between the DNA bases. Thus the sequence-dependent dynamical motions of DNA both facilitate and inhibit long range charge transport through the base pair stack. [4] Charge transport through the base pair stack is gated by the motions of the DNA bases. Using electrochemical, biochemical, and biophysical measurements, we have now characterized some of the important features of DNA charge transport chemistry. [5] Importantly, we have found that charge transport through DNA can occur over very large molecular distances, > 200 Е. [6,7] In DNA assemblies containing a pendant photooxidant, we have shown that hole transport through the DNA duplex can promote oxidative damage to guanine doublets far from the site of the pendant oxidant. (Figure 2) Moreover this chemistry is independent of the oxidant utilized. It is a property of the DNA base pair stack.
Figure 1. An illustration of the stacked base pairs in DNA looking across the helix (above) and down the helix axis (below). It is no surprise that shortly after the double helical structure was proposed by Watson and Crick, scientists asked whether inherent in the structure of stacked base pairs there might be another functional property of DNA. Given the similarity to one dimensional aromatic crystals, it was proposed that the DNA p-stack might be a conduit for rapid and efficient charge migration. [3]
Figure 2. As schematically illustrated, in a DNA assembly with tethered photooxidant (red), oxidative damage to guanine doublets (yellow) can be promoted over long distances through DNA charge transport. This property is interesting to consider in the context of reactions within the cell. Indeed, we have also shown that DNA hole transport can proceed in the nucleosome core particle to effect damage to DNA from a distance. [8] Hence while DNA may be
19 CHEMISTRY: SCIENCE AT THE FRONTIER
packaged into chromatin, protecting the DNA library from the onslaught of harmful agents, this chromatin structure cannot protect the DNA from long range oxidative damage through DNA charge transport. Perhaps instead Nature funnels damage to particular sites, protecting others. [2] It is interesting also to note that we have demonstrated not only damage to DNA promoted from a distance but also the oxidation of DNA-bound proteins from a distance. [9] In particular, p53, a critically important cell cycle regulatory protein, bound to some promoters but not others can be oxidized from a distance leading to its dissociation from the DNA. We have proposed that this long range chemistry may provide a global signaling of oxidative stress within the cell, yielding the dissociation of p53 from some promoters but not others so as to activate the cell to respond to the conditions of oxidative stress. While DNA charge transport can proceed over long molecular distances, another critical characteristic of this chemistry is the exquisite sensitivity to perturbations in the intervening base stack. Single base pair mismatches, base lesions, and the structural changes associated with protein binding all lead to an inhibition of DNA charge transport. [5] (Figure 3)
Figure 4. 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 base excision repair enzymes are 4Fe-4S clusters, a common redox cofactor in biology. Although these clusters are not redox-active in the absence of DNA, we have demonstrated using DNA-modified electrodes that, in the presence of DNA, their potentials are shifted to a physiologically relevant range. [12,15] DNA binding thus facilitates oxidation of the clusters in a DNAmediated reaction. We have furthermore demonstrated that this potential shift is general to a range of DNA repair proteins that contain the 4Fe-4S clusters, and we have proposed DNA-mediated signaling among different repair
Figure 3. Illustrations of perturbations that inhibit long range charge transport through DNA: (left) DNA bulges; (center) DNA mismatches; (right) protein binding that kinks the DNA. We have demonstrated this sensitivity in not only through experiments monitoring an attenuation in long range oxidative damage but also in DNA electrochemistry experiments that monitor the attenuation in redox signal as a function of intervening perturbations in the base pair stack. [10,11] (Figure 4) This sensitivity in DNA charge transport to p-stacking perturbations has led to the development of novel biosensors capable of the detection of single base mismatches, lesions and DNA-protein interactions. Given this remarkable sensitivity of DNA charge transport in detecting DNA lesions, we have also asked whether Nature may harnass this chemistry also in the first steps of DNA repair, where base lesions are first detected. [12,14] Within cells there is an extraordinary repair machinery, the base excision repair enzymes, which constantly monitor the genome for base damage, and once
proteins bound to DNA in detecting base lesions. Essentially analogous to telephone repairmen looking for a break in the telephone line, proteins can carry out DNAmediated Electron Transfer Reactions with one another as long as the intervening DNA is intact; these electron transfers facilitate protein dissociation and a search of the genome. However, if there is an intervening lesion, DNA-mediated charge transport is inhibited, the proteins do not dissociate, and instead remain in the vicinity to repair the lesion. Hence this chemistry provides a means to redistribute the repair proteins where they are needed in the vicinity of the DNA lesion. We are now focused on delineating how DNA charge chemistry plays a role in the activity of base excision repair proteins as well as asking whether other DNAbinding proteins that contain redox cofactors may similarly employ DNA-mediated charge transport for long range signaling. Certainly this chemistry is unique in that the chemistry can occur with control over long molecular distances but with a remarkable sensitivity to intervening perturbations. There is
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Figure 5. An illustration of DNA-mediated electron transfer between two repair proteins (blue and gray). much to be unraveled still with respect to this rich DNA chemistry. A c k no w l ed gm ent s I am grateful to the NIH for their support of this research as well as to my coworkers and collaborators for their ideas and hard work. References [1] Topics in Current Chemistry, 236: 67-115, ed. Schuster GB, Springer Verlag (2004). [2] "Biological Contexts for DNA Charge Transport Chemistry," E. J. Merino, A. K. Boal, and J. K. Barton, Current Opinion in Chemical Biology, 12, 229 (2008). [3] "Semiconductivity of organic substances. IX. Nucleic acid in the dry state," D. D. Eley and D. I. Spivey, Trans. Faraday Soc. 58, 411 (1962). [4] "2-Aminopurine: A Probe of Structural Dynamics and Charge Transfer in DNA and DNA:RNA Hybrids,"M. A. O'Neill and J. K. Barton, Journal of the American Chemical Society, 124, 13053 (2002). [5] "Sequence-dependent DNA Dynamics: The Regulator of DNA-mediated Charge Transport," M. A. O'Neill and J. K. Barton, in Charge Transfer in DNA: From Mechanism to Application, ed. H.-A. Wagenknecht, Wiley-VCH, 27-75 (2005). [6] "Oxidative DNA Damage through Long Range Electron Transfer," D. B. Hall, R. E. Holmlin, and J. K. Barton, Nature, 382, 731 (1996). [7] "Long-Range Oxidative Damage to DNA: Effects of Distance 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 in Regulating p53: Oxidation of the DNA-bound Protein from a Distance," 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 on DNA-Modified Surfaces,"E. M. Boon, J. W. Salas, and J. K. Barton, Nature Biotechnology, 20, 282 (2002). [12] "DNA-bound Redox Activity of DNA Repair Glycosylases 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: A Redox Cofactor for DNA-mediated Charge Transport?,"A. K. Boal, E. Yavin and J. K. Barton, Journal of Inorganic Biochemistry, 101, 1913 (2007). [14] "Protein-DNA Charge Transport: Redox Activation of a DNA 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 the National Academy of Sciences, USA, 102, 3546 (2005). [15] "Direct Electrochemistry of Endonuclease III in the Presence and Absence of DNA," A. A. Gorodetsky, A. K. Boal and J. K. 21 CHEMISTRY: SCIENCE AT THE FRONTIER
M. Christina White Department of Chemistry, Roger Adams Laboratory, University of Illinois, Urbana, IL, USA
Streamlining Synthesis via C--H Oxidation
Among the frontier challenges in chemistry in the 21st century are (1) increasing control of chemical reactivity and (2) synthesizing complex molecules with higher levels of efficiency. Although it has been well demonstrated that given ample time and resources, highly complex molecules can be synthesized in the laboratory, too often current methods do not allow chemists to match the efficiency achieved in Nature. This is particularly relevant for molecules with non-polypropionate-like oxidation patterns (e.g. Taxol). Traditional organic methods for installing oxidized functionality rely heavily on acid-base reactions that require extensive functional group manipulations (FGMs) including wasteful protection-deprotection sequences. Due to their ubiquity in complex molecules and inertness to most organic transformation, C--H bonds have typically been ignored in the context of methods development for total synthesis. Highly selective oxidation methods, similar to those found in Nature, for the direct installation of oxygen, nitrogen and carbon functionalities into allylic and aliphatic C--H bonds of complex molecules and their intermediates will be discussed. Unlike Nature which uses
elaborate enzyme active sites, we rely on the subtle electronic and steric interactions between C--H bonds and small molecule transition metal complexes to achieve high selectivities. Our current understanding of these interactions gained through mechanistic studies will be discussed. Novel strategies for streamlining the process of complex molecule synthesis enabled by these methods will be presented. Collectively, we aim to change the way that complex molecules are constructed by redefining the reactivity principles of C--H bonds in complex molecule settings. Ref er enc es Aliphatic C--H Oxidation [1] Chen, M.S.; White, M.C. "A Predictably Selective Aliphatic C--H Oxidation Reaction for Complex Molecule Synthesis." Science, 2007, 318, 783-787. Allylic C--H Oxidation [2] Delcamp, J.H.; White, M.C. "Sequential Hydrocarbon Functionalization: Allylic C--H Oxidation/Vinylic C--H Arylation." J. Am. Chem. Soc. 2006, 128, 15076-15077. [3] Fraunhoffer, K.J.; Prabagaran, N.; Sirios, L.E.; White, M.C. "Macrolactonization via Hydrocarbon Oxidation." J. Am. Chem. Soc. 2006, 128, 9032-9033. [4] Chen, M.S.; Prabagaran, N.; Labenz, N.; White, M.C. "Serial Ligand Catalysis: A Highly Selective Allylic C-H Oxidation." J. Am. Chem. Soc. 2005, 127, 6970-6971. [5] Chen, M.S.; White, M.C. "A Sulfoxide-Promoted, Catalytic Method for the Regioselective Synthesis of Allylic Acetates from Monosubstituted Olefins via C-H Oxidation." J. Am. Chem. Soc. 2004, 126, 1346-1347. Allylic C--H Amination [6] Reed, S.A.; White, M.C. "Catalytic Intermolecular Linear Allylic C--H Amination via Heterobimetallic Catalysis." J. Am. Chem. Soc., 2008, 130, 3316-3318. [7] Fraunhoffer, K.J.; White, M.C. "syn-1,2-Amino Alcohols via Diastereoselective Allylic C--H Amination." J. Am. Chem. Soc. 2007, 129, 7274-7276. Streamlining Synthesis Strategies [8] Covell, D.J.; Vermeulen, N.A.; Labenz, N.A.; White, M.C. "Polyol Synthesis via Hydrocarbon Oxidation: De Novo Synthesis of L-Galactose." Angew. Chem., Int. Ed. Engl. 2006, 45, 8217-8220. [9] Fraunhoffer, K. J.; Bachovchin, D.A.; White, M.C. "Hydrocarbon Oxidation vs. C-C Bond Forming Approaches for Efficient Syntheses of Oxygenated Molecules." Org. Lett. 2005, 7, 223-226.
22 13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM
Recent Studies in Alkaloid Total Synthesis
Larry E. Overman Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, CA, USA
An important objective in chemical synthesis is the development of new transformations that rapidly evolve molecular complexity in a stereocontrolled fashion. One approach toward this goal is to combine two or more distinct reactions into a single transformation, producing a process often referred to as a sequential, tandem, cascade, or domino reaction. In this lecture, I discuss the implementation of several cascade processes as the key strategic element in the total synthesis of heterocyclic natural products. One illustrative example is described in this brief summary. A 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9Hcarbazole is a central structural feature of the Strychnos alkaloid minfiensine , and akuammiline alkaloids such as vincorine and echitamine (Figure 1). Extracts containing akuammiline alkaloids are used throughout the world in the practice of traditional medicine [1].
(iminoethano)-9H-carbazoles in high enantiomeric purity (Figure 2). Figure 2. Cascade asymmetric Heck /iminium ion cyclizations for forming 1,2,3,4-tetrahydro-9a,4a(iminoethano)-9H-carbazoles. The use of this cascade sequence to complete an efficient catalytic asymmetric total synthesis of (+)minfiensine is dsummarized in Figure 3[2].
Figure 1. Representative alkaloids containing a 1,2,3,4tetrahydro-9a,4a-(iminoethano)-9H-carbazole. Dihydro-9a,4a-(iminoethano)-9H-carbazoles having a 1,2- or 2,3-double bond could serve as versatile platforms for constructing alkaloids of the types illustrated in Figure 1. Stitching an ethylideneethano unit between the pyrrolidine nitrogen and C3 of such a precursor would generate the ring system of minfiensine, whereas inserting such a unit between the pyrrolidine nitrogen and C2 would generate the ring system of vincorine and congeners. A cascade catalytic-asymmetric Heck­iminium cyclization was developed that rapidly provides 3,4-dihydro-9a,4a-
Figure 3. Catalytic asymmetric total synthesis of (+)minfiensine. References [1] Ramirez, A.; Garcia-Rubio, S. Current. Med. Chem. 2003, 10, 1891­1915. [2] Dounay, A. B.; Humphreys, P. G.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2008, 130, 5368­5377
23 CHEMISTRY: SCIENCE AT THE FRONTIER
Phil S. Baran Chemistry Department, The Scripps Research Institute, La Jolla, California, USA
El Ciclo Catalнtico del Descubrimiento en Sнntesis Total The Catalytic Cycle of Discovery in Total Synthesis
Abstract Many would argue that the field of organic synthesis has made such phenomenal advances over the past five decades that given unlimited resources, the synthesis of almost any molecule is now possible. As such, total synthesis is becoming increasingly focused on preparing natural products in the most innovative and efficient manner possible. Selected studies from our lab will be presented on the total synthesis of complex natural products (see Figure below for selected targets). Desde la penicilina hasta el Taxol, los productos naturales no tienen competencia en la mejora de la salud mundial. De hecho, nueve de los veinte fбrmacos mбs vendidos por la industria farmaceъtica estбn inspirados o derivan de productos naturales. Incluso el fбrmaco mбs vendido de todos los tiempos, Lipitor, estб basado en un producto natural. El arte y ciencia de recrear estas entidades en el laboratorio, o sнntesis total, invariablemente da lugar a descubrimientos fundamentales tanto en el бmbito de la quнmica, como en el de la biologнa o la medicina. Nuestro grupo de investigaciуn tiene como objetivo resolver interesantes retos en la sнntesis de productos naturales y en acortar las distancias entre el punto de partida y el objetivo mediante el descubrimiento de nuevas reacciones quнmicas. De esta forma, estamos mбs interesados en hacer contribuciones esenciales para la quнmica. La creaciуn, descubrimiento y diseсo de nuevos mйtodos que van surgiendo en el camino hasta un producto natural, es lo que promueve nuestro entusiasmo. A partir de una cuidadosa selecciуn de las dianas y un anбlisis retrosintйtico creativo, el esfuerzo de la sнntesis total se convierte en una mбquina de descubrir que conduce al campo de la quнmica orgбnica hacia un nuevo nivel de sofisticaciуn y pragmatismo. En la Figura 1 se muestran recientes sнntesis totales, de las cuales todas ellas requieren de nuevas estrategias quнmicas. En un ejemplo representativo, la sнntesis total de `welwitindolinone' y otros alcaloides relacionados llevу a explorar la formaciуn oxidativa del enlace C-C mediante heteroacoplamiento de enolatos. De esta forma se obtienen importantes ventajas en cuestiуn de
eficiencia (ausencia de grupos protectores, halуgenos, grupos funcionales desechables), pragmatismo (secuencias extremadamente concisas), estereocontrol (completa distereoselectividad a menudo observada) y conservaciуn del estado de oxidaciуn (el estado de oxidaciуn aumenta de manera lineal en una sнntesis mediante el uso de funcionalidad innata) cuando la formaciуn oxidativa del enlace C-C se emplea estratйgicamente. Tal y como se muestra en la Figura 2, la sнntesis total de `welwitindolinone A' hace uso de la formaciуn oxidativa del enace C-C en su etapa clave. Esta sнntesis ilustra de manera clara y concisa las ventajas mencionadas anteriormente, ya que en ъnicamente ocho pasos de sнntesis, reactivos sencillos, ausencia de grupos protectores y diez dнas de trabajo con un solo estudiante de doctorado, son suficientes para construir este complejo producto natural marino de una forma enantioselectiva. A pesar de que la eliminaciуn de grupos protectores en la sнntesis de molйculas complejas ha sido siempre un objetivo a largo plazo, esta sнntesis parece ser el primer ejemplo hasta la fecha en alcanzar esta meta. En esta presentaciуn, se discutirбn los ejemplos mбs recientes de sнntesis totales alcanzadas con йxito, incluyendo molйculas tales como `cortistatin A', psycotrimine', `axinellamines A y B' y `vinigrol'. Figura 1. Selecciуn de sнntesis totales completadas con йxito (2004-2008).
24 13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM
Figura 2. Sencillo ejemplo de sнntesis total enantioselectiva de productos naturales complejos mediante formaciуn oxidativa del enlace C-C. Referencias [1] Chen, K.; Richter, J. M.; Baran, P. S. 1,3-Diol Synthesis via Controlled, Radical Mediated C­H Functionalization, J. Am. Chem. Soc., 2008, in press. [2] 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-preaxinellamine, Angew. Chem. Int. Ed. 2008, 47, 3578 ­ 3580. [5] Maimone, T. J.; Voica, A.-F.; Baran, P. S. A Concise Approach to Vinigrol, Angew. Chem. Int. Ed. 2008, 47, 3054 ­ 3056. [6] Burns, N. Z; Baran, P. S. On the Origin of the Haouamine Alkaloids, 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 the Direct 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.; Kцck, M. Massadine Chloride: a Biosynthetic Precursor of Massadine and Stylissadine, Angew. Chem. Int. Ed. 2007, 46, 6721-6724. [9] Kцck, M.; Grube, A.; Seiple, I.; Baran, P. S. The Pursuit of Palau'amine, Angew. Chem. Int. Ed. 2007, 46, 6586-6594 [10] Maimone, T. J.; Baran, P. S. Modern Synthetic Approaches 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, Nakamuric Acid, and the Axinellamine Carbon Skeleton, J. Am. Chem. Soc. 2007, 129, 4762 ­ 4775. [12] Baran, P. S.; Maimone, T. J.; Richter, J. M. Total Synthesis of Marine Natural Products Without Using Protecting 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 Enolate Heterocoupling, Angew. Chem. Int. Ed. 2006, 45, 7083­7086. [15] Baran, P. S.; Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero, C. A.; Gallagher, J. Enantioselective Total Synthesis of Avrainvillamide and the Stephacidins, J. Am. Chem. Soc. 2006, 128, 8678-8693. 25 CHEMISTRY: SCIENCE AT THE FRONTIER
Gregory C. Fu Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
Palladium -and Nickel- Catalyzed Coupling Reactions
Despite the tremendous accomplishments that have been described in the development of palladium-and nickel-catalyzed carbon­carbon bond-forming processes, it is nevertheless true that many significant opportunities remain. For example, to date the overwhelming majority of studies have focused on couplings between two sp2-hybridized reaction sites (e.g., an aryl metal with an aryl halide; Figure 1). Although biaryl and related linkages are certainly a common feature in many organic compounds, so, too, are Csp2­Csp3 and Csp3­Csp3 linkages.
Figure 2. Asymmetric Negishi reactions of allylic halides.
Figure 3. Asymmetric Hiyama reactions of _-halocarbonyl compounds.
Figure 1. Some carbon­carbon bond-forming processes of interest. As of 2001, there were few examples of palladium-or nickel-catalyzed coupling reactions of alkyl electrophiles. Slow oxidative addition of alkyl halides/sulfonates and facile ,-hydride elimination are two likely causes for this paucity of success. Indeed, nearly all of the successful couplings that had been described by 2001 involved specialized electrophiles that circumvent these impediments by being activated toward oxidative addition and by lacking , hydrogens (e.g., benzyl halides). During the past several years, we have pursued the discovery of palladium-and nickel-based catalysts for coupling activated and unactivated primary and secondary alkyl electrophiles that bear , hydrogens. Our recent efforts to develop broadly applicable methods, including enantioselective processes, will be discussed.
Figure 4. Asymmetric Suzuki reactions of homobenzylic halides.
26 13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM
New Developments Jean Pierre Genet Laboratoire de Synthиse Sйlective Organique
of Organometallic et Produits Naturels - UMR 7573, CNRS Ecole Nationale Supйrieure de Chimie de Paris,
Catalysts in
Paris, France
Organic Synthesis
Despite the tremendous accomplishments that have been described in the development of palladium-and nickel-catalyzed carbon­carbon bond-forming processes, it is nevertheless true that many significant opportunitieHomogeneous asymmetric catalysis is undoubtedly a powerful synthetic tool of the organic chemist, both on laboratory and production scale. Effective homogeneous asymmetric catalysts are organometallic complexes that consist of one or more chiral ligand coordinated to a metal center. The choice of the chiral ligand is decisive both for catalytic activity and for achieving high level of chiral induction. Atropisomeric biaryl diphosphines Noyori discovered the BINAP ligand in 1980, which resulted in an extraordinary expansion of the scope of asymmetric hydrogenation. [1] The elaboration of new ligand families such as the MeO-BIPHEP (Roche) or the SEGPHOS (Takasago) is significant of the new current challenges of chemists in the field of asymmetric catalysis (Figure 1). Licensing policies compel companies to synthesize their own original ligand families, displaying high activity and selectivity and the broadest possible scope in terms of substrates. Following our continuous interest in ligand design [2] , we have reported the synthesis of two original atropisomeric diphosphines SYNPHOS® [3], and DIFLUORPHOS® [4], with stereo electronically complementary backbones, based respectively on bi(benzodioxane) and bi(difluorobenzodioxole) moieties (Figure 1). We also propose detailed structural profiling [5] of these ligands and catalytic evaluation in asymmetric Ru-mediated hydrogenation compared to other leading atropisomeric diphosphines such as BINAP and MeO-BIPHEP. Figure 1. Rhodium-catalyzed reactions for carbon-carbon bounds formation. Asymmetric Pauson-Khand reaction In recent years, a great deal of research has been
devoted to asymmetric catalytic Pauson-Khand reaction (denoted as PKR reaction hereafter), which is characterized as transition metal mediated [2+2+1] cycloaddition of an alkyne, an alkene and CO. Many years ago , Jeong introduced the first rhodium catalyzed enantioselective PKR under CO atmosphere in the presence of an atropisomeric ligand.These early results were promising in terms of enantioselectivity, but they also exhibited some limitations with certain class of substrates. We have demonstrated that enantioselectivity and reaction yield were influenced by the electronic density on phosphorus, the dihedral angle of ligands and the electronic density of the alkyne substrate. Ligands bearing a narrower dihedral angle than BINAP, such as SYNPHOS and DIFLUORPHOS, were found to increase substantially the enantioselectivity of the reaction, compared to BINAP-type ligands. DIFLUORPHOS deshielded phosphine provided better enantioselectivity than BINAP, especially with electron-poor alkyne substrates (Scheme 1).[6] Scheme 1. Potassium organotrifluoroborates in organic synthesis Since the discovery of the Suzuki-Miyaura reaction, organoboranes have emerged as the reagents of choice in transition metal-catalyzed reactions. The main interesting feature of organoboron reagents is their low toxicity as well as for the by-product generated, making these compound environmentally friendly compared to other organometallic reagents and particularly organostannanes. However many trivalent organoboranes are not highly stable, particularly alkyl- and alkynylboranes. The lack of stability of organoboranes is due to the vacant orbital on boron, which can be attacked by
27 CHEMISTRY: SCIENCE AT THE FRONTIER
oxygen or water, resulting in the decomposition of the reagent. Efficient preparations of the highly stable potassium aryl, alkenyl and alkynyl trifluoroborates, which does not require the use of purified organoboronic acids, are now available [7]. Five years ago only a limited papers were published on these emerging compounds, to day an increased number of publications and patents on that topic have been reported in the literature.[7] Potassium trifluoro(organo) borates rhodium catalyzed reactions The 1,2- and 1,4- additions of organometallic reagents to unsaturated compounds are some of the most versatile reactions in organic synthesis. We have developed an efficient system using rhodium catalyst [RhCl(C2H4)]2 3 mol %, P(tBu)3, 3 mol%. In the presence of an electron-rich phosphine such as PBu3 and water (toluene/H2O) the reaction proved to be general, allowing the production of highly hindered diaryl carbinols and aliphatic aldehydes were also reactive under these conditions.[8] Interestingly, the same catalyst system in the absence of water allows a direct access to ketones from aldehydes via rhodium-catalyzed cross-coupling reaction with potassium trifluoro (organo) borates [9a]. We also have described for the first time a straightforward preparation to congested benzophenones frameworks from aryl aldehydes and potassium aryltriffluoroborates. This reaction occurring under neutral conditions, allows formation of di-,tri- and even tetra-ortho substituted benzophenones thanks to the use of stable phosphonium salt of P(t-Bu)3.(Scheme 2) .[9b]
and selectively to enones (Scheme 3). [7] The reaction has been applied to a,b unsaturated amides, ester and lactones. Scheme 3 N-protected amidoacrylates The tandem -1,4 addition enantioselective protonation of N-protected amidoacrylates would provide a new and efficient route to enantiomerically enriched a-amino acids derivatives. We have shown that choosing a suitable proton source could control the · chiral center. Indeed the conjugate addition of potassium aryl and alkenyl-trifluoroborates to Nacylamidoacrylates mediated by a chiral rhodium complex in the presence of achiral phenol derivatives furnishes a variety of _-amino acid derivatives with good enantioselectivities up to 89.5% ee using RhBINAP catalyst.[10] The best proton source was found to be inexpensive and non-toxic 2methoxyphenol or guaiacol. The influence of steric hindrance from methyl to isopropyl and t-butyl ester improved the enantioselectivity ee up to 95%.[11]
Scheme 2. Asymmetric conjugate addition of potassium trifluoro (organo) borates to Michael acceptors Enones The asymmetric 1,4-addition of potassium organotrifluoroborates turned out to be trickier than the racemic version. Most rhodium catalysts described earlier by Batey, Miyaura, Hayashi underwent poor conversions and/or low enantiomeric excesses. We have reported, after careful optimization of the reaction system including ligand, solvent, temperature, that [Rh (cod)2]PF6 associated to chiral phosphine BINAP, JOSIPHOS and MeOBIPHEP that the presence of water is also crucial for this reaction: in its absence, the reaction was very slow and the asymmetric induction too. On the other hand, an excess of water slows the reaction down and in pure water no asymmetric induction was observed. Indeed, for practical purposes, one should therefore use an excess of water compared to boron reagent (typically 10:1 mixture of toluene/water). Potassium trifluoro (organo) borates react efficiently
Figure 2 However lower yields were generally achieved using t-butyl ester a good compromise is the use of isopropyl ester. Reaction pathway of the tandem 1,4 enantioselective Rh-catalyzed reaction Initially we believed that this reaction proceeded through an oxa p-allyl rhodium intermediate as established by Hayashi. Actually, it appears that the presence of a free N-H bond in a position to the Michael acceptor was essential in order to achieve high level of enantioselectivity. Deuterium labeling studies show new interesting aspects of this rhodium-catalyzed -1,4 addition. The catalyst cycle involves (a) transmetallation of the aryl group from boron to rhodium (b) insertion of the olefin into the aryl-rhodium bond forming a rhodium alkyl species (c) ?-elimination giving a Rh-imino complex (d) 1,3 hydrogen shift from rhodium to carbon forming the Rh-NP intermediate and (e) its cleavage with guaiacol giving the addition product. The potential energy profiles have been studied by DFT calculations. The computed sequence of the elementary steps, relative intermediates and
28 13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM
transitions states agrees with the previous proposal step (c) is endothermic with an energy barrier of 27.8 kcal/mol (Figure 2).[11] This step being the rate-determining step. Thus, we anticipated that a more p acceptor than BINAP should facilitate th _-elimination and improve the selectivity. Having developed DIFLUORPHOS an original atropisomeric ligand with original steric and electronic properties [4,5]. We were pleased to find that under optimized conditions both yields and enantioselectivies were significantly increased using Rh- DIFLUORPHOS catalyst (Scheme 4) [11]. Scheme 4. Ruthenium-mediated asymmetric hydrogenation reactions. Chiral Ruthenium catalysts The first mononuclear hexacoordinate ruthenium complex bearing BINAP a ligand has been reported by Noyori [1]. In the last two decades we focused some efforts on the design of new, general and mild syntheses of chiral ruthenium complexes. Our methods are based on the easy availability of Ru(COD)(h3-methylallyl)2 from [RuCl2(COD)] n by treatment with methallyl Grignard [2]. Interestingly, in situ generated catalysts Ru(P*P)X2 have been synthesized from Ru(COD)(h3-methylallyl)2 and the appropriate chiral diphosphine by treatment with HX (X= Cl, Br, I) at room temperature, giving rise to a wide range of chiral catalysts (Scheme 5).In the course of collaboration with Firmenich, an industrial product-oriented project, a new type of catalyst with high reactivity was discovered by treatment of Ru (COD)(h3-methylallyl)2 and various ligands P*P (BINAP, DuPHOS, JOSIPHOS) in weakly coordinating solvent (CH2Cl2) with HBF2 (Scheme 5) [13]. Scheme 5
enantiomers of 3-hydroxy-2-methylpropanoic acid t-Butyl with high enantioselectivity (up to 96% ee) (Scheme 6).. [13] Scheme 6 The Dolabelides contain a 22- or 24- membered ring, including eleven stereogenic centers (Figure 3). Eight of them are hydroxyl or acetyl functions. Those challenging molecules and especially their syn and anti 1,3-diol sequences constitute an excellent target for our ongoing program on the use of rutheniummediated asymmetric hydrogenation for the preparation of biologically relevant natural products.[2] The synthesis of the C1-C13 fragment of Dolabelides was performed for the first time using catalytic asymmetric hydrogenation of b-keto esters and b-hydroxy ketones to install the hydroxyl groups at C3, C7, C9 and C11 stereocenters [14a]. This flexible strategy is also currently used for the preparation of Discodermolide (potent antimitotic agent). Thus, the synthesis of C1-C7,C9-C14 and C15-C24 key fragments of Discodermolide were achieved from a common intermediate. [14b] Figure 3
Applications in organic synthesis 3-hydroxy-2-methylpropionic acid methyl ester known as Roche ester represents a significant building block in organic synthesis and is present in a substantial number of both naturally occurring and synthetic biologically relevant molecules. We found that a generation of cationic chiral Ru-catalyst developed earlier in our group for the paradisone synthesis was highly efficient catalyst. The in situ generated Ru-SYNPHOS catalyst was prepared by treating a mixture of Ru (COD)(h3-methylallyl)2 and SYNPHOS [3] in dichloromethane by addition of 1 or 2eq of HBF4. This cationic Ru-SYNPHOS complex was the best catalyst for the hydrogenation reaction providing both 29 CHEMISTRY: SCIENCE AT THE FRONTIER
Ref er en ces [1] Ohkuma, T.; Kitamura, M.; Noyori, R. Asymmetric Hydrogenation in Catalytic Asymmetric Synthesis, 2nd edition, Ojima, I. Ed. Wiley, New York, 2000, 1-110. [2] Genet, J.P. Acc. Chem. Res., 2003, 36, 908-918. [3] (a) Duprat de Paule, S.; Jeulin, S.; RatovelomananaVidal, V.; Genet, J.-P.; Champion, N.; Dellis, P. Tetrahedron Lett. 2003, 44, 823-826. (b) Duprat de Paule, S.; Jeulin, S.; Ratovelomanana-Vidal, V.; Genкt, J.P.; Champion, N.; Dellis, P. Eur. J. Org. Chem. 2003, 1931-1941. Both antipodes of SYNPHOS® and DIFLURPHOS® are commercially available from Strem Chemicals. [4] Jeulin, S.; Duprat de Paule S.;Vidal V.; Genet J.P.; Champion, N.; Dellis P. Angew. Chem. Int. Ed. 2004, 43, 320-325. [5] Jeulin, S.; Duprat de Paule, S.; Ratovelomanana-Vidal, V.; Genet, J.P.; Champion, N.; Dellis P. Proc.Natl.Acd.Sci. USA 2004, 101, 5799­5804. [6] Kim,O.E.;Choi,C.;Kim,I.S.;Jeong,N.; Jeulin S.; Vidal V.; Genet, J.P. Adv. Synth. Cat 2007, 349, 1999-2006. [7] Darses S.; Genet J.P. Chem.Rev. 2008, 108, 288-325 and 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.; Genet J.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. 2008, 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. 2000, 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. 30 13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM
New Applications of Quinones and Quinols in Asymmetric Synthesis
M. Carmen Carreсo Organic Chemistry Department (C-I), Autonoma University of Madrid, Cantoblanco, Madrid, Spain
Quinone Diels-Alder reactions have been extensively used in organic synthesis for the stereoselective construction of polycyclic skeletons from which complex natural products were later synthesized [1]. Until recently, resolution of racemic adducts was the only way of access to enantiopure derivatives. Nowadays, some efficient chiral catalysts allow a direct synthesis of the enantiopure adducts [2]. Applications of quinones in asymmetric synthesis have been rarely based on the use of simple quinonic systems bearing a chiral auxilliary directly linked to the dienophilic bond. Enantiopure 2-p-tolylsulfinylquinones turned out to be powerful dienophiles opening an enantioselective access to different groups of complex structures using an asymmetric Diels-Alder reaction as key step. The sulfoxide was shown to play several important roles in the reactions of these dienophiles. This group was able to control the regiochemistry of sulfinylquinone cycloadditions with a range of substituted dienes [3]. High endo and p-facial diatereoselective reactions were always achieved due to an efficient differentiation of the diastereotopic faces of the quinone by the sulfoxide. Moreover, once the adduct was formed, elimination of p-toluenesulfenic acid occurred spontaneously allowing to recover the quinone skeleton in a single step. As a consequence of this domino process, enantiopure sulfinylquinones could act as homochiral synthetic equivalents of the unknown triple bonded quinones. The results shown in Scheme 1 illustrate the one-step synthesis of enantiopure 5-methyl5,8¬dihydro-1,4-naphthoquinone (SS)-4 by reaction between (SS)-2-p-tolylsulfinyl-p_benzoquinone 3 and piperylene. The sulfinyl quinone was readily accessible in two steps from 1,4-dimethoxybenzene 1 by sequential reaction with n-BuLi and (­)-menthylp_toluene sulfinate (SS)-2, followed by oxidative demethylation of the intermediate diaromatic sulfoxide with CAN4.
In order to apply this domino sequence to the synthesis of polycyclic targets, we focused on helicenes. These are well known representative of polycyclic aromatic compounds bearing a series of ortho-condensed aromatic rings that exist in a chiral non_planar helical disposition due to the steric hindrance of the external rings and their substituents [5]. The helical structures can be resolved into their enantiomers if the interconversion barrier between them is high enough. These artificial molecules present excellent properties of huge interest in the field of new materials, which are inherently associated to their enantiopurity. The smaller systems, [4]helicenes, have racemisation barriers which are highly dependent on the particular structure. Using our asymmetric DielsAlder reaction we could synthesize 12-alkyl-and 12methoxy-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 to further evaluate their configurational stability. 6 The dienes 7 were accessible from 7-methoxy-1-tetralone 4 by addition of a Grignard reagent (R1MgBr) followed by sequential aromatization of the dihydroaromatic ring, reductive dearomatization of the 2-methoxy substituted ring and transformation of the C-2 carbonyl into the enol triflate 6. This key intermediate was transformed into the vinyl substituted derivatives 7 by Stille coupling. Upon reaction with an excess of the sulfinylquinone (SS)-3, these dienes gave the dihydro [4]helicenequinones (P)-9 in a one-pot process where the domino Diels­Alder reaction/pyrolytic sulfoxide elimination sequence was followed by the oxidation of the B ring of the intermediate (12bR,P)-8 . This aromatization occurred in situ by the action of the excess of the quinone which was acting as an oxidant. The configurational stability of these [4]helicenequinones was highly dependent on the size of the R1 substituent at C-12 being the tert-butylsubstituted derivatives the only [4]helicenequinones that were indefinitely stable at room temperature. The values of the racemisation barriers, calculated from computations, confirmed the main role of the steric effects in the configurational integrity of these helical quinones.
Scheme 1
31 CHEMISTRY: SCIENCE AT THE FRONTIER
Scheme 2 The higher analogues, [5] and [7]helicenequinones, could also be synthesized in enantiomerically pure form from (SS)-3, by applying a similar strategy. The choice of the diene allowed the access to the bisquinones. Thus, reaction of vinyl dihydrophenantrene 10 with (SS)-3, afforded enantiopure [5]helicenequinone [7] (P)-11 which could be oxidized to the bisquinone (P)-12.
cycloaddition occurred with resolution of the diene in a double asymmetric induction process where the matched pair corresponded to the endo-cycloaddition of (SS)-15 approaching in an anti fashion to the (3R,5R) enantiomer of trans-3-hydroxy-5-methyl-1vinylciclohexene 16. Aromatization of the new generated ring of 17, deprotection of the OTBDMS group and photochemical oxidation led to rubiginone B2. Ochromycinone [8b] and deoxytetrangomycin [8b] were also synthesized by applying this strategy.
Scheme 3 Using a bisdiene such as 13, a domino process including the asymmetric Diels-Alder reaction/pyrolytic elimination of the sulfoxide and aromatization, in the presence of an excess of the quinone, took place twice, leading directly to the enantiopure [7]helicenequinone (M)-14 (Scheme 4). The vinyl and divinyl phenantrene derivatives 10 and 13 were available from the corresponding phenantrenone or phenantrenedione, using a Stille coupling to introduce the vinyl groups on the enoltriflate intermediate. Scheme 4 Starting from (SS)-2-p-tolylsulfinyl-1,4naphthoquinones, we could synthesize some angucyclinones,[8] a group of natural tetracyclic quinones showing antibiotic and antitumoral properties. The tetracyclic skeleton of rubiginone B2 (Scheme 5) was assembled by reaction between 5methoxy-2-p-tolylsulfinylnaphthoquinone (SS)-15 and the diene 16, which was used racemic. The
Scheme 5 Within the angucyclinone family, some members, such as Rubiginones A2 and C2 (Scheme 6) have an additional oxygenated function at C-4 of the hydroaroamatic A ring. The Diels-Alder strategy based on the resolution of the diene could not be applied in this case. We then considered the construction of the tetracyclic skeleton starting from an 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 of the cyclohexadienone moiety had been previously synthesized by us [10]. A methodologic study had evidenced that AlMe3 reacted with such p-quinols in a highly chemo-and diastereoselective manner leading to only one out of the four possible diastereomers resulting from conjugate addition. The process led to the efficient desimmetrization of the prochiral cyclohexadienone moiety of 20. As shown in Scheme 6, the synthesis of (SS)-20 was achieved in two steps from p-benzoquinone dimethylketal 19, by addition of the lithium anion derived from enantiopure (SS)-methyl p-tolyl sulfoxide to the carbonyl group followed by hydrolysis of the ketal group. p-Quinol 20 reacted with AlMe3 leading to derivative 21, which has the R configuration at the new C5 stereogenic center. The sulfoxide of 21 was oxidized into the sulfone to afford, after stereoselective reduction of th C=O and protection of the secondary carbinol, the _-hydroxy sulfone 22.
32 13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM
Previously, we had shown that after oxidation of the sulfoxide to a sulfone, compounds such as 21 suffered the elimination of methyl p_tolylsulfone by a Cs2CO3-promoted retrocondensation, allowing to recover a carbonyl group at C-4 [11]. Thus, ketone 23 was obtained in 86% yield, showing that the initial, _hydroxy sulfoxide can be considered as a chiral protecting group of a cyclohexanone. Treatment of 23 with Br2 and Et3N promoted an addition elimination process leading to an intermediate _-bromo enone, which was stereoselectively reduced and esterified to 24. This was the immediate precursor of the enantiopure vinyl cyclohexene 25, available after a Stille coupling in 78 % yield. Scheme 6 We then proceeded to the construction of the tetracyclic skeleton through the Diels­Alder reaction between the enantiopure vinyl cyclohexene 25 and 2-(p_tolylsulfinyl)-juglone methyl ether 26, which was used in racemic form since the role of the sulfoxide in this case was limited to the regiochemical control of the cycloaddition and to facilitate the recovery of the quinone structure from the initial adduct, by spontaneous elimination of p-tolylsulfenic acid (Scheme 6). Rubiginone C2 was finally obtained upon exposure of 27 to sunlight in the presence of air under solvent-free conditions. This unprecedented photoinduced one-pot transformation implied a domino sequence of three reactions: aromatization of the B ring, deprotection of the silyl ether and oxidation of the C-1 position into a carbonyl group. The other natural product, rubiginone A2, resulted from rubiginone C2, by methanolysis of the C-4 ester. The 11_methoxy regioisomers of both natural products were synthesized in a similar manner using racemic 3-p-tolylsulfinyl juglone methyl ether as dienophile [9a]. Other synthetic applications of sulfoxide bearing p-quinols, focused on natural polyoxygenated cyclohexanes and cyclohexenes from compounds 22 and 23, easily transfromed into the natural targets by sterereoselective processes occurring on the rigid cyclic systems. [12] A c k no w l ed gm ent s I am grateful to all my co-workers, especially Drs. Ribagorda and Urbano, for their contribution to the group's research results. Financial support from the Ministerio de Educaciуn y Ciencia (Spain) and Comunidad de Madrid is greatly acknowledged.
References [1] Review: Nicolaou, K. C.; Snyder, S. A. ; Montagnon, T.; Vassilikogiannakis, G.; Angew. Chem. Int. Ed. 2002, 41, 1668-1698. [2] For recent examples see: a) Pingfan Li.; Payette, J. N.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 9536-9537. b) Liu, D., Canales, E., Corey, E. J. J. Am. Chem. Soc. 2007, 129, 1498-1499. c) Jarvo, E. R.; Lawrence, B. M.; Jacobsen E. N. Angew. Chem. Int. Ed. 2005, 44, 6043-6046. [3] Carreсo, M. C.; Garcнa Ruano, J. L.; Toledo, M. A.; Urbano, A.; Remor, C. Z.; Stefani, V.; Fischer, J. J. Org.Chem. 1996, 61, 503-509. [4] Carreсo, M. C.; Garcнa Ruano, J. L.; Urbano, A. Synthesis, 1992, 651-653. [5] Vцgtle, F. Fascinating Molecules in Organic Chemistry, Wiley and Sons, New York, 1992, 156-180. [6] a) Carreсo, M. C.; Enrнquez. A. L.; Garcнa-Cerrada, S.; Sanz-Cuesta, M. J.; Urbano, A.; Maseras, F.; Novell-Canals, A. Chem. Eur. J. 2008, 14, 603-620. b) Carreсo, M. C.; Garcнa-Cerrada, S.; Sanz-Cuesta, M. J.; Urbano, A. Chem. Commun. 2001, 1452 ­ 1453. [7] a) Carreсo, M. C.; Garcнa-Cerrada, S.; Urbano, A. Chem. Eur. J. 2003, 9, 4118 ­4131. b) Carreсo, M. C.; Garcнa-Cerrada, S.; Urbano, A. Chem. Commun. 2002, 1412 ­ 1413; c) Carreсo, M. C.; Garcнa-Cerrada, S.; Urbano, A. J. Am. Chem. Soc. 2001, 123, 7929 ­7930. [8] a)Carreсo, M. C.; Urbano, A. ; Di Vitta, C. Chem. Eur. J. 2000, 6, 906 ­913. b) Carreсo, M. C.; Urbano, A. ; Di Vitta, C. Chem. Commun. 1999, 817 ­818. c) Carreсo, M. C.; Fischer, J.; Urbano, A. Angew. Chem. 1997, 109, 1695 ­ 1697. Angew. Chem. Int. Ed. Engl. 1997, 36, 1621 ­1623. [9] a) Carreсo, M. C.; Ribagorda, M.; Somoza, A.; Urbano, A. Chem. Eur. J. 2007, 13, 879 ­ 890. b) Carreсo, M. C.; Ribagorda, M.; Somoza, A.; Urbano, A. Angew. Chem. 2002, 114, 2879 ­2881. Angew. Chem. Int. Ed. 2002, 41, 2755 ­2757. [10] Carreсo, M. C.; Pйrez Gonzбlez, M.; Ribagorda, M.; Houk, K. N. J. Org. Chem. 1998, 63, 3687-3693. [11] a) Carreсo, M. C.; Merino, E.; Ribagorda, M.; Somoza, A.; Urbano, A. Org, Lett. 2005, 7, 1419-1422. b) Carreсo, M. C.; Pйrez Gonzбlez, M.; Ribagorda, M.; Somoza, A.; Urbano, A. Chem. Comm. 2002, 63, 3052-3053. [12] Carreсo, M. C.; Merino, E.; Ribagorda, M.; Somoza, A.; Urbano, A. Chem. Eur. J. 2007, 13, 1064-1077.
33 CHEMISTRY: SCIENCE AT THE FRONTIER
Stephen G. Davies Department of Chemistry, University of Oxford, Oxford, UK
Stereoselective Synthesis of Amino Diols
The amino diol motif is a recurring structural component in a diverse range of biologically active natural products and synthetic molecules. The asymmetric synthesis of a range of natural products [1,2] and other highly functionalised molecular architectures containing the amino diol unit utilising a variety of synthetic methodology including asymmetric conjugate addition of nitrogen nucleophiles,[3] novel cyclisation strategies[4] and ammonium-directed dihydroxylation is delineated.[4]
in the presence of NaHCO3 gave a 19:81 mixture of C(5)-epimeric N-benzyl pyrrolidines with in situ loss of the _-methylbenzyl cation, from which the major diastereoisomer was isolated in 63% yield in >98% de. In this process, ring-closure to the pyrrolidine and chemoselective N-deprotection had been affected in a single step. Subsequent manipulation of the primary iodide by displacement with AgOAc, and deprotection, gave the polyhydroxylated pyrrolidine as a single stereoisomer in good yield.[4]
The conjugate addition of lithium (S)-N-benzyl-N-(_methylbenzyl)amide to a _-silyloxy-_-, _-unsaturated ester with in situ enolate oxidation with (+)-CSO gives ready access to the corresponding _-hydroxy_-amino esters as a single diastereoisomer in good yield. This methodology had been utilised in the synthesis of a range of natural products including sphingosine and jaspine B.[2]
Oxidation of an allylic primary, secondary or tertiary amine with a peracid is known to occur preferentially at the nitrogen atom, giving the corresponding N-oxide. Recent investigations have shown that the in situ protection of the nitrogen atom of an allylic amine by protonation allows chemoselective oxidation of the double bond syn to the amino fragment, under hydrogen-bond controlled delivery
We have recently developed a novel iodinemediated ring-closure/debenzylation protocol of a tertiary, unsaturated amine. The utility of this exquisite transformation has been demonstrated via the 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_-amino ester. Treatment of this_-amino ester with I2 in MeCN
by the adjacent ammonium ion. Thus, treatment of 3-N,N-dibenzylamino-cyclohexene with trichloroacetic acid, followed by subsequent, sequential treatment with mCPBA gives 1,2-anti-2,3syn-3-amino-1,2-in quantitative yield and >90% de. This metal-free methodology has been successfully applied to the synthesis of all four possible diastereoisomers of 3-amino-cyclohexane-1,2-diol in >98% de.[5]
34 13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM
This work has recently been extended to encompass the chemo- and stereoselective cyclopropanation of a range of allylic amines, and a stereodivergent protocol for the preparation of 2-aminobicyclo[4.1.0]heptane derivatives has been developed.[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. Sбnchez-Fernбndez, 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. SбnchezFernбndez, 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. [3] 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. Price Mortimer, A. J. Russell and A. D. Smith, Tetrahedron: Asymmetry, 2006, 17, 1793. [4] S. G. Davies, R. L. Nicholson, P. D. Price, P. M. Roberts and 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 35 CHEMISTRY: SCIENCE AT THE FRONTIER
Joe Shih Discovery Chemistry Research and Technologies, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, USA
The Evolution of Lilly Oncology: From Targeted Cytotoxic Agents (Alimta®) to Kinase Inhibitors
The anticancer drug discovery effort at Lilly can be traced back to the early 1960s and 1970s. Using cytotoxicity-based cell screen as the primary strategy for lead identification, the Lilly team then led by Dr. Irving Johnson uncovered potent cytotoxic Vinca alkaloids in the extracts prepared from the leaves of Madagascar periwinkle (Vinca Rosea Linn G. Don). Through careful chemical structure elucidation and investigation of the pharmacological actions of these cytotoxic alkaloids, Vincristine and Vinblastine were successfully developed as the first class of anti-tubulin chemotherapeutic agents for the treatment of various leukemia (ALL, ML), Hodgkin/non-Hodgkin lymphoma and germ cell malignancies. Vincas (Vindesine was discovered and added later to the arsenal of Vincabased chemotherapeutic agents) have since become widely used to treat various type of cancers either as single agent or in combination with other chemotherapeutic agents. The success of Vincas stimulated considerable amount of interest at Lilly to continue investigate novel approaches in discovering effective agents in particular for the treatment of solid tumors (breast, lung, colon, pancreas and prostate cancers for example). In early 1980s, the anticancer program under the direction of Dr. Gerald Grindey decided to shift to the use of solid-tumor human tumor xenograft screening as way to identify broad-spectrum antitumor agents 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 in late 1980s and 1990s and eventually each received US FDA approval for marketing (Gemzar first in1996 for pancreatic cancer and Alimta in 2004 received the first approval for malignant pleural mesothelioma). Gemcitabine is a prodrug that requires enzymatic conversion to its bioactive diphosphate and triphosphate forms. The diphosphate form of gemcitabine inhibits the ribonucleotide reductase and the triphosphate form of gemcitabine can act as a DNA chain terminator once it was incorporated into the DNA. Gemzar is an effective anticancer agent for treating various forms of human cancers. In addition as the gold standard for the treatment of pancreatic cancer, Gemzar is also now approved for the treatment 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-pyrimidine based "classical" antifolate. It is derived from the successful 10-year antifolate drug discovery collaboration program between Lilly and the Princeton University (key collaborator: Professor Edward Taylor of the Chemistry Department, now retired). Three clinical candidates (Lometrexol, Alimta and GARFTII) were identified during the decade long collaboration and Alimta was identified through an active SAR program attempting originally in removing the chirality at the C-6 asymmetric center (thus simplify the separation issue of the two diastereomers) of the tetrahydropyridine-pyrimidine region of the GARFT (glycinamide ribonucleotide formyltransferase) inhibitor, Lometrexol. Replacement of the tetrahydropyridine ring with pyrrole led to the discovery Alimta. Alimta can be effectively prepared by using the palladium-based Sognagesia coupling between the 2-pivaloyl-5-iodo-pyrrolopyrimidine and the 4-ethynyl-diethylbenzoyl-Lglutamate, followed by hydrogenation and removal of the ester and amide protection groups. While the Chemical Modification of Lometrexol to Alimta seems straight forward, however, the mode of action of Alimta turned out to be very different and unique from its predecessor, Lometrexol. Through various careful cell-based cytotoxicity reversal studies and evaluation of polyglutamated form of Alimta against isolated human folate enzymes, it was concluded that Alimta can potently inhibit several key folate enzymes in the folate biochemical pathway involved in both the purine and the pyrimidine biosynthesis. These enzymes include GARFT, TS (thymidylate synthase) and DHFR (dihydrofolate reductase). For example, it was found that the pentaglutamate derivative of Alimta (AlimtaGlu5) can potently inhibit hTS (IC50= 1.3 nM), dDHFR (IC50= 7.2 nM) and GARFT (IC50= 65 nM). In addition to these three enzymes, Alimta polyglutamates also inhibit AICARFT (aminoimidazolecarboxamide ribonucleotide formyltransferase, IC50= 260 nM) and C-1 tetrahydofolate synthase.[1] Alimta was found to be an excellent substrate for the enzyme folylpolyglutamate synthetase (FPGS), through both
36 13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM
enzyme kinetic and cellular uptake studies it was found Alimta can be rapidly (<2h) converted into the polyglutamated forms (usually up to penta- and hexaglutamates) when incubated in the CCRF-CEM leukemia cells. The excellent polyglutamation profile coupled with the fact that Alimta can be efficiently transported into the cells by the active transport system, Reduced Folate Carrier (RFC), makes Alimta a very novel classical antifolate that can be effectively taken up into the tumor cells and affecting the cellular de novo DNA and RNA synthesis (which are essential for the rapidly dividing malignant cancerous cells) by simultaneously inhibiting several key folate-requiring enzymes of the folate pathway (Figure 1). Figure 1. Mechanism of action of ALIMTA® Alimta went into phase I clinical development in the early 1990s for safety assessment. The 21-day schedule of Pemetrexed administered at 600 mg/m2 on day 1 as a 10-minute intravenous infusion was carried into phase II trials. As a single agent, interesting activity was observed in mesothelioma, breast, gastrointestinal and NSCLC (non-small cell lung cancer), with myelosuppression as the major dose-limiting toxicity. Alimta's first registration trial was focused on malignant pleural mesothelioma (MPM) in combination with cisplatin since exciting responses were observed from the earlier phase II studies for Alimta/cisplatin against MPM. With the critical introduction of daily supplement of oral folic acid (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 can significantly increase the median survival time (MST) (13.3 month vs. 10.0 month) than patients on cisplatin only.[2] The lung functions of the MPM patients who received Alimta and cisplatin also improved significantly. Alimta was approved by US FDA in February 2004 as the first line therapy (in combination with cisplatin) for malignant pleural mesothelioma. Alimta was also found to be an effective antitumor agent for non-small cell lung cancer. It received US FDA approval as a 2nd line treatment (single agent) on October 2004 for NSCLC. Recently (April 2008), it has also received EU EMEA's approval as a 1st line treatment (in
combination with cisplatin) for NSCLC. Four years since the first approval for MPM in 2004, Alimta has now emerged as a major targeted-cytotoxic agent for the management of thoracic cancer with quite acceptable safety profile and manageable toxicity. Gemzar and Alimta have now become the cornerstones of the Lilly oncology franchise with total annual sales of more than 2.3 billion dollars (2007). With this success, the Lilly oncology program continues to evolve focusing on bringing more novel and effective agents for the management and treatment of various forms of cancer. Beginning in the late 1990s, with the success deciphering of human genome and advancement of molecular and cellular biology in understanding of the control of cell-signaling pathway, Lilly Oncology has shifted the focus and strategy once again into the area of kinase drug discovery. To tackle the challenging task of targeting kinase genome for drug discovery, we have built extensive infrastructures and capabilities at Lilly Research Laboratories for rapidly identifying hits and leads for various kinase targets. For example, we have used various approaches including targeted kinase compound cassette MTS (medium throughput screen), PLS (platform library science), high throughput SBDD (structure-based drug design), bioinformatics, kinase panel profiling (at Upstate) and phenotypic drug screening as novel tools for assisting rapid identification and iteration/optimization of novel actives into hits and leads. To illustrate this integrated approach for kinase drug discovery, a rapid SBDD effort in identifying potent p38a MAP kinase inhibitor for oncology indication is shown. p38a MAP kinase plays an important role in the signal transduction pathway and the activation of this kinase in macrophages and tumors can lead to the production of cytokines (TNFa, IL-1b) as well as the stimulation of various angiogenic factors (VEGF, bFGF, EGF, IGF1 and HGF) that could lead to angiogenesis and the development of tumors. For example, by using structure-based design approach in carefully analyzing the active site (ATP) of p38a MAP kinase, we have successfully converted a relatively no so potent benzimidazole aryl ketone hit (uM potency identified from c-Raf kinase screen) into a potent series of triarylimidazole class of p38a MAP kinase inhibitors (LSN 479754, IC50 ~ 5 nM). The N3 and 2-NH2 groups on the benzimidazole ring can serve each as the hydrogen bond acceptor and donor interacting pairs with the hinge region amide bonds. The larger benzimidazole warhead was nicely accommodated in the p38a MAP kinase active site since it was observed that the hinge of p38a MAP kinase is quite flexible and can move outward
37 CHEMISTRY: SCIENCE AT THE FRONTIER
(compared to other p38a MAK kinase structures with smaller warhead inhibitor, SB203580 for example) to tolerate bigger structure element such as benzimidazole. The binding mode of the solved inhibitor/enzyme complex of LSN470754 is exactly identical to what was predicted based on the original SBDD design.
Ref er enc es [1] 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, A Pyrrolo[2,3-d]pyrimidine Based Antifolate That Inhibits Multiple Folate Requiring Enzymes. cancer research, 57, 1116-1123 (1997) [2] H Pass, N. Vogelzang, S. Hahn, M. Carbone. Malignant pleural mesothelioma. Curr Probl Cancer. MayJun;28(3):93-174 (2004)
-- Figure 2. p38aMAP kinase/inhibitor co-crystal structures Green: LSN 479754, Yellow: SB203580 (Noticed the movement of the hinge region, Met109 Gyl110 to accommodate the larger benzimidazole warhead) Further modification of the LSN 479754 series quickly led to the identification of LSN2322600 which demonstrated potent effects both in vitro as well as p38a MAP kinase target inhibition in vivo (in either peripheral blood monocytes or in B-16F10 melanoma, TMED50=3.6 mg/kg). Compound LSN 2322600 also demonstrated good antitumor effects (tumor growth delay) in U87MG glioma (in combination with Temodar) or as a single agent in A549 lung xenograft. Excellent anti-inflammatory effect in collagen-induced arthritis (CIA) model (rat) was also observed for LSN2322600 (with both paw swelling and histology scores TMED50 = 1.5 mg/kg). The Phase I first human dose of LSN2322600 is scheduled to begin in Q2, 2008. In conclusion, Lilly Oncology has evolved successfully in the past 50 years, starting from the natural products based approach that led to the identification of novel chemotherapeutic agents such as Vinca alkaloid (Vincristine, Vinblastine and Vindesine). This was then followed by using the solid-tumor screening in xenografts to identify broadly active antimetabolite agents (Gemzar and Alimta) for human solid tumors. Gemzar and Alimta are excellent examples of the power of this approach; both drugs have now become one of the most important chemotherapeutic agents/arsenals in modern day clinical oncology for the front line treatment and management of various forms of cancer, including lung, pancreatic, bladder, ovarian, breast and mesothelioma cancer. Lilly Oncology is now actively involved in the discovery and development of an array of novel targeted agents including various kinase inhibitors as a way to show our continued commitment in bringing patients and physician the most effective drugs in the war against cancer. 38 13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM
Lilly Distinguished Career Award. Chemistry 2008 As part of the actions of promotion of R&D in Biomedicine in Spain, the Scientific Advisory Council of the Lilly Foundation proposed the creation of the Lilly Distinguished Career Award, deliverable in each Lilly Foundation Scientific Symposium, that seeks to recognize the scientific trajectory of the Spanish scientists, working either in Spain or abroad, that, once fulfilled its career, they have fertilized its area of knowledge, contributing to increase its scientific level, and to generate vocations among its collaborators. The concession of these prizes will be made with the collaboration of the Spanish Scientific Society corresponding to the area of knowledge of the Symposium, through a protocol agreed by the two parts. In the 13th Lilly Foundation Scientific Symposium "Chemistry: Science at the Frontier", the Lilly Foundation with the collaboration of the Royal Spanish Society of Chemistry, granted the Lilly Distinguished Career Award to Prof. Josй Elguero Bertolini, of the Institute of Medicinal Chemistry (CSIC) of Madrid, for his influence in connection with the improvement of the level of the Spanish organic chemistry, specially for his contributions in heterociclic, medicinal chemistry and physical organic chemistry, as well as for his influence on the younger generations of scientists. 39
Como parte de las acciones de promociуn de la I+D en Biomedicina en Espaсa, el Consejo Cientнfico Asesor de la Fundaciуn Lilly propuso la creaciуn del Lilly Distinguished Career Award, que se entregarб en cada ediciуn del Simposio Cientнfico de la Fundaciуn Lilly. El premio pretende reconocer la trayectoria investigadora de los cientнficos espaсoles que trabajan en Espaсa o en el extranjero que, una vez cumplida su carrera cientнfica, han fertilizado su бrea de conocimiento, contribuyendo a aumentar su nivel cientнfico, y a generar vocaciones entre sus colaboradores. La concesiуn de estos premios, que constarбn de un diploma y un trofeo diseсado al afecto, se harб con la colaboraciуn de la sociedad ­o en su caso sociedades- cientнfica espaсola correspondiente al бrea de conocimiento del Simposio, mediante un protocolo acordado por las dos partes. En el 13є Simposio Cientнfico de la Fundaciуn Lilly "Quнmica, Ciencia en la Frontera", el premio Lilly Distinguished Career Award se ha concedido al Prof. Josй Elguero Bertolini, del Instituto de Quнmica Mйdica (CSIC) de Madrid, por su influencia en el avance del nivel de la quнmica orgбnica espaсola, especialmente por sus contribuciones en la quнmica de heterociclos, quнmica mйdica y quнmica orgбnica fнsica, asн como por su magisterio sobre los investigadores de las generaciones mas jуvenes.
Chairpersons & Speakers
Chairmen Julio Бlvarez-Builla Jesъs Ezquerra Miguel Yus
Jean-Marie P. Lehn -Nobel LaureateProfessor at the Collиge de France Laboratoire de Chimie Supramolйculaire, Universitй Louis Pasteur. Paris, France [email protected] Jean-Pierre Sauvage CNRS Director of Research Institut de Chimie, Laboratoire de Chimie Organo-Minйrale, Universitй Louis Pasteur CNRS/UMR 7177 Strasbourg, France [email protected] Phil S. Baran Associate Professor Department of Chemistry, The Scripps Research Institute La Jolla, California, USA [email protected] Dennis Curran Distinguished Service Professor and Bayer Professor of Chemistry Department of Chemistry, Chevron Science Center Pittsburgh, USA [email protected] Gregory C. Fu Professor Massachusetts Institute of Technology Cambridge, MA, USA [email protected] Alois Fьrstner Director Max-Planck-Institut fьr Kohlenforschung Mьlheim an der Ruhr, Germany [email protected] Jean-Pierre Genet Professor Laboratoire de Synthиse Sйlective Organique et Produits Naturels, Ecole Nationale Supйrieure de Chimie de Paris Paris, France [email protected] Fernando Albericio Full Profesor Institute for Research in Biomedicine, Barcelona Science Park, University of Barcelona. Barcelona, Spain [email protected] Marнa del Carmen Carreсo Garcнa Full Professor Departamento de Quнmica Orgбnica, Facultad de Ciencias, Universidad Autуnoma de Madrid. Madrid, Spain [email protected] Stephen G. Davies Professor Chemistry Research Laboratory, Department of Chemistry, Oxford University. Oxford, UK [email protected] Lutz F. Tietze Professor Institut fьr Organische und Biomolekulare Chemie, Universitдt Gцttingen. Gцttingen, Germany [email protected]
Jacqueline K. Barton Arthur & Marian Hanisch Memorial Professor of Chemistry Division of Chemistry and Chemical Engineering California Institute of Technology. California, USA [email protected] Joe Shih Distinguished Lilly Scholar Lilly Research Laboratories, Eli Lilly. Indianapolis, USA [email protected] M. Christina White Assistant Professor Department of Chemistry, University of Illinois Urbana, IL, USA [email protected] Larry E. Overman Distinguished Professor of Chemistry University of California. Irvine, CA, USA [email protected] Julio Бlvarez-Builla Full Professor Organic Chemistry Department, Pharmacy School, University of Alcalб de Henares. Madrid, Spain [email protected] Miguel A.Yus Full Professor Organic Chemistry Department, Sciences School, University of Alicante. Alicante, Spain [email protected] Jesъs Ezquerra European Discovery Chemist Director Lilly Research Laboratories. Alcobendas, Madrid, Spain [email protected] Marнa Бngeles Martнnez-Grau Lilly Research Laboratories. Alcobendas, Madrid, Spain [email protected] Rafael Suau Full Profesor Organic Chemistry Department, Sciences School, University of Mбlaga. Mбlaga, Spain [email protected] Josй A. Gutiйrrez-Fuentes Director Fundaciуn Lilly Madrid, Spain [email protected] SCIENTIFIC COMMITTEE Julio Бlvarez-Builla Miguel Yus Jesъs Ezquerra Josй A Gutiйrrez-Fuentes
41 13th LILLY FOUNDATION SCIENTIFIC SYMPOSIUM CHEMISTRY: SCIENCE AT THE FRONTIER

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