Plenary Lectures (PL) Plenary Lectures PL-1 CRAFTING CHIRAL SPACE FOR MOLECULAR RECOGNITION IN A CATALYTIC SYNTHETIC REACTION Barry M. Trost Department of Chemistry, Stanford University Stanford, CA 94305-5080 Introducing asymmetry into organic structures represents a continuing contemporary challenge of particular importance for biologically important molecular targets. Rationally devising catalytic systems to achieve such a result is a most significant goal. Asymmetric reactions involving transition metal catalysis have focused exclusively on reactions 1) in which the enantiodiscriminating event of forming or breaking a bond occurs within the coordination sphere of the metal and, thereby, proximal to the asymmetric inducing groups and 2) in which only one type of bond is formed, i.e., C-H, C-O, or C-C. Catalytic allylic alkylations differ in both respects. Bond breakage or formation occurs outside the coordination sphere of the metal and, therefore, distal to any enantiodiscriminating groups. In addition, many different types of bonds can be formed—C-C, C-N, C-S, C-O, C-H etc. Efforts to define the requirements for asymmetric transition metal complexes that can effect such reactions generally, the types of catalytic processes in which asymmetry can be introduced, and the applicability of these catalytic processes will be outlined. The utility of this methodology for developing synthetic strategy to biologically significant heterocycles will be highlighted. Plenary Lectures PL-2 SYNTHESIS OF HETEROCYCLIC NATURAL PRODUCTS Thorsten Bach Lehrstuhl für Organische Chemie I, Technische Universität München Lichtenbergstr. 4, 85747 Garching, Germany [email protected] In recent years, a major research topic in our group has been the synthesis of heterocyclic natural products. We have developed photochemical methods for the synthesis of new saturated heterocyclic skeletons both in diastereoselective[1] and enantioselective[2] fashion. Based on transition metal catalysis and lithiation strategies we have explored methods for the regioselective substitution of polybrominated five-membered heterocycles (furans, thiazoles, benzofurans).[3] Examples for successfully completed syntheses of heterocyclic natural products include the total syntheses of (+)-preussin (1),[4] (+)-cystothiazole E (2),[5] and (+)-wailupemycin B (3).[6] HO O 2 5 11 Ph N HO O O Me 7 O 5 1 1 O 14 OOMe OMe 4' N 4 N S 2' 2 3 2 S In the talk, the basic ideas behind the above-mentioned concepts will be outlined and the results of more recent studies will be presented. Current synthetic target compounds include terpenes and alkaloids as well as biologically active thiazoles and furans. [1] (a) T. Bach, Synlett 2000, 1699-1707. (b) T. Bach, C. Krüger, K. Harms, Synthesis 2000, 305-320. (c) T. Bach, M. Kemmler, E. Herdtweck, J. Org. Chem. 2003, 68, 1994-1997. [2] T. Bach, H. Bergmann, B. Grosch, K. Harms, J. Am. Chem. Soc. 2002, 124, 7982- 7990 and refs. cited therein. [3] T. Bach, M. Bartels, Synthesis 2003, 925-939, and refs. cited therein. [4] T. Bach, H. Brummerhop, K. Harms, Chem. Eur. J. 2000, 6, 3838-3848. [5] T. Bach, S. Heuser, Chem. Eur. J. 2002, 8, 5585-5592. [6] S. Kirsch, T. Bach, Angew. Chem., accepted for publication. Plenary Lectures PL-3 FROM AMINO ACIDS TO FUNCTIONAL HETEROCYCLES Stephen Hanessian Department of Chemistry, Université de Montréal, P.O. Box 6128, Station Centre-ville, Montréal, QC, H3C 3J7 Nature’s ubiquitous biosynthetic pathways are reflected in the structures of the multitude of metabolites it produces. Many of these have intriguing chemical structures that belong to families of biogenetically-related classes of compounds. The various arrays of functional and stereochemical motifs present in such compounds have presented synthesis chemists with exciting challenges in the design and implementation of asymmetric processes. Indeed, some of the more innovative advances in organic chemistry have been instigated by the desire to achieve stereochemical control in conjunction with the synthesis of natural products. We shall highlight results from a number of on-going projects in which natural and unnatural amino acids were used as starting materials in the synthesis of heterocyclic molecules possessing diverse biological activities. Plenary Lectures PL-4 STITCHING WITH NITROGEN K. Barry Sharpless The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA, USA [email protected] Molecules produced by the living systems have always inspired synthetic organic chemists and, as a consequence, today’s favorite targets, both in academic and industrial pharmaceutical chemistry laboratories, are some of the most complex natural substances ever discovered. Due to their inherent complexity, the time required for structure-activity studies and then synthesis of sufficient quantities of the chosen leads is staggering. This is particularly true when extensive carbon-carbon bond frameworks need to be constructed. Lacking Nature’s enzymatic control, synthetic organic chemists have learned to rely on such highly reactive agents as organolithiums and enolates. Thus, modern organic synthesis depends heavily on inert atmospheres and dry solvents to support the use of these extremely basic and/or acidic species, requiring that most heteroatom functionality in turn be protected and protic solvents are avoided. A heavy price is therefore exacted when the goal is to synthesize the extensive carbon-carbon bond frameworks found in many natural products. Fortunately, the universe of possible small molecule drug candidates remains virtually unexplored: the ratio of synthesized to reasonably possible structures is roughly the same as the mass of a proton is to the mass of the sun. With this kind of structure space available, we propose a synthetic strategy which relies upon heteroatom-carbon bond connections and the use of at least one relatively high-energy, “spring-loaded” component, making the bond-forming processes pre-programmed and exergonic. New molecules of dazzling complexity can arise from very short reaction sequences between spring-loaded blocks which become permanently united together via heteroatoms. We begin with nitrogen, which is second only to carbon in its connectivity potential in organic chemistry. Plenary Lectures PL-5 SYNTHESIS OF POLYHETEROCYCLIC NITROGEN-CONTAINING MARINE NATURAL PRODUCTS Mercedes Álvarez,a1 Fernando Albericio,a2 and John A. Jouleb aBiomedical Research Institute, Barcelona Scientific Park-University of Barcelona, Josep Samitier 1-5, 08028 Barcelona (Spain) bChemistry Department, The University of Manchester, M13 9 PL Manchester (UK) The synthetic routes used for the preparation of marine alkaloids such as ascididemin, variolin B and lamellarins will be described. Marine natural products constitute an important source of bioactive substances with a wide range of potentially valuable activities and constitute a unique platform from which to obtain chemical diversity. An important set of alkaloids with structures without precedent in the terrestrial natural products have been isolated from sponges, tunicates and molluscs. Around 10 % of the extracts of these marine invertebrates exhibit cytotoxicity against different tumour cell lines. Because only small quantities can be produced by isolation procedures, there is a need for the development of efficient methods for the synthesis of these interesting natural products, to facilitate their biological evaluation. We will describe new synthetic procedures for the preparation of ascididemin and variolin B and the application of known synthetic routes to the preparation of compound libraries related to the lamellarins. 3 2 R R R1 HO OH N NH2 4 N OH N R N O R5 N MeO N CO2Me N N N O 6 N R O R8 H2N 7 R O Ascididemin Variolin B Lamellarins A-N Lamellarin O 1 Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Avda. Joan XXIII sn, 08028- Barcelona, Spain 2 Organic Chemistry Department, University of Barcelona, Martí Franques 1-11, 08028-Barcelona, Spain Plenary Lectures PL-6 TOTAL ENANTIOSELECTIVE SYNTHESIS AND IN VIVO BIOLOGICAL EVALUATION OF A FLUORESCENT BODIPY ALPHA-GALACTOSYLCERAMIDE Y. Vo-Hoang,[a] L. Micouin,*[a] C. Ronet, [b] G. Gachelin[b] and M. Bonin*[a] [a] Laboratoire de Chimie Thérapeutique associée au CNRS et à l’Université René Descartes (UMR 8638) Faculté des Sciences Pharmaceutiques et Biologiques, 4, avenue de l’Observatoire 75 270 Paris cedex 06 [b] Unité de Biologie Moléculaire du Gène, INSERM U277, Département Immunologie Institut Pasteur, 25 rue du Docteur Roux, 75 015 Paris Natural Killer T (NKT) cells are a distinct subset of mature lymphocytes that coexpress markers of both natural killer (NK) and T cells, and use a semi-invariant αβ-T-cell receptor (TCR). It has been established that KRN 7000 1, an α-Galactosylceramide (α- GalCer) derived from a marine sponge1, specifically activate NKT cells through a CD1d/α- GalCer/TCR interaction. It then induces rapid release of large amounts of cytokines characteristic of both type 1 (IFN-γ)and type 2 (IL-4) immune response2. In a variety of models of autoimmune pathologies (multiple sclerosis3 and autoimmune diabete4), as well as in tumor rejection5, activation of NKT cells by α-GalCer initiate immune responses by modulating Th1/Th2 balance. OH HO OH O (CH ) CH HO H O 2 24 3 N N O O HO 9 B N NH OH HO F HO NH O F O HO O C H (CH2)13CH3 13 27 OH OH KRN7000 1 BODIPY α-GalCer 2 In an attempt to bring some new insights into the cells and the factors involved in in vivo NKT cells activation, the original fluorescent α-GalCer derivative 2 has been prepared following a convergent synthetic scheme6. This biological probe 2 has shown to be as active as KRN7000 1 in typical apoptosis test. We also demonstrated that its behaviour depends on the way of administration. After intraperitoneal injection the BODIPY molecule 2 was dominantly trapped by peritoneal macrophages. After intravenous injection fluorescent material has been found both in spleen and liver antigen presenting cells (APCs). This novel chemical reagent is thus likely to become a highly promising tool for in and ex vivo studies on its trafficking in APCs.