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Direction des bibliothèques AVIS Ce document a été numérisé par la Division de la gestion des documents et des archives de l Université de Montréal. L auteur a autorisé l Université de Montréal à reproduire
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Direction des bibliothèques AVIS Ce document a été numérisé par la Division de la gestion des documents et des archives de l Université de Montréal. L auteur a autorisé l Université de Montréal à reproduire et diffuser, en totalité ou en partie, par quelque moyen que ce soit et sur quelque support que ce soit, et exclusivement à des fins non lucratives d enseignement et de recherche, des copies de ce mémoire ou de cette thèse. L auteur et les coauteurs le cas échéant conservent la propriété du droit d auteur et des droits moraux qui protègent ce document. Ni la thèse ou le mémoire, ni des extraits substantiels de ce document, ne doivent être imprimés ou autrement reproduits sans l autorisation de l auteur. Afin de se conformer à la Loi canadienne sur la protection des renseignements personnels, quelques formulaires secondaires, coordonnées ou signatures intégrées au texte ont pu être enlevés de ce document. Bien que cela ait pu affecter la pagination, il n y a aucun contenu manquant. NOTICE This document was digitized by the Records Management & Archives Division of Université de Montréal. The author of this thesis or dissertation has granted a nonexclusive license allowing Université de Montréal to reproduce and publish the document, in part or in whole, and in any format, solely for noncommercial educational and research purposes. The author and co-authors if applicable retain copyright ownership and moral rights in this document. Neither the whole thesis or dissertation, nor substantial extracts from it, may be printed or otherwise reproduced without the author s permission. In compliance with the Canadian Privacy Act some supporting forms, contact information or signatures may have been removed from the document. While this may affect the document page count, it does not represent any loss of content from the document. Université de Montréal Progress Towards a Total Synthesis of (±)-Longithorone C Par Joseph E. Zakarian Département de chimie, Faculté des arts et de sciences Memoire présenté à la Faculté des études supérieures en vue de l'obtention du grade de Maître ès sciences (M.Sc.) en chimie Juillet 2007 Joseph E. Zakarian, 2007 Université de Montréal Faculté des études supérieures Ce mémoire intitulé: Progress Towards a Total Synthesis of (±)-Longithorone C Présenté par Joseph E. Zakarian a été évalué par un jury composé des personnes suivantes: Président-rapporteur: André B. Charette Directeur de recherche: Shawn K. Collins Membre du jury : William D. Lubell Mémoire accepté le: To my Wife Araks For the loving support IV Table of Contents Title Page... i fi... Jury IdentI IcatIon... Dedication Page... iii Summary... vii Résumé... viii Acknowledgements....ix List of Figures... x List ofschemes... xii List of Tables... xv Abbreviations... xvi Chapter : Introduction to the Longithorones: Paracyclophane Natural Products... Ring Closing Olefin Metathesis as a Route to Strained Systems.... Synthesis of Longithorone A.... Introduction and Synthetic Challenges.... Preparing [2]Paracycophanes by Enyne Metathesis.... Installation ofthe Atropisomeric Control Element..... Enyne Metathesis Macrocycization using an Atropisomeric Control Element... Conclusion.... Synthesis oflongithorone B.... [3,3]-Rearrangement in Forming Ortho-Allyl PhenoI3.... Intramolecular Coupling of the Famesylated Side Chain by Friedel-Crafts Alkylation.... Conclusion.... Longithorone C: A Representative Compound.... Synthetic Challenges and Goals.... Forming [2]Paracycophanes: A Model Study.... Determining the Optimal Site for Metathesis along the Ansa-Bridge and Formation of Tri-substituted Olefins by RCM.... Conclusion v Chapter II: Model Studies Directed Towards the Total Synthesis of Longithorone C via Macrocyclic Olefin Metathesis II. Retrosynthetic Analysis and Model Studies II.2 Synthesis ofpentafluoro-2,5-dihydroxybenzoate II.3 Synthesis of the AHylic AlcohoI II.4 Macrocyclic Olefin Metathesis ofmodel System using trans,trans-famesoi II.5 Synthesis of cis-famesol First Generation Synthesis of cis-famesoi Second Generation Synthesis of cis-famesol II.6 Metathesis ofmodel System Incorporating cis-famesoi II.7 Synthesis ofcis-olefin II.8 Metathesis ofmodel System 94 using cis-olefin II.9 Conclusion Chapter III: Attacking the Total Synthesis of (±)-Longithorone C: Attachment of Alkyl Chains via Coupling Reactions Negishi Coupling Reactions Copper Catalyzed Grignard Reaction III.2. Optimizing Mg-X Exchange III.2.2 Optimizing s N i/s N 2-type Product Ratio III.2.3 Mechanism behind the alyproduct Ratios IIL2.4 Attaching cis-olefin 93 via the Copper Catalyzed Grignard Reaction Determining Stereochemistry ofthe Side Chains Conclusion Chapter IV: Improved Gearing Elements for Macrocyclic Olefin Metathesis: A Mode) Stndy IV.l IV.2 IV.3 IV.4 IV.5 Improved Gearing Element used in Model Systems..... Molecular Modeling using the Bistrifluoromethyl Auxiliary on Model Systems Molecular Modeling using the Bistrifluoromethyl Auxiliary on an AH Carbon System.... Determining the Ideal Gearing Element in the Formation of an AH-Carbon [2]Paracyclophane..... Conclusion VI Chapter V: Approach Towards the Total Synthesis of (±)-Longithorone C V.l RRCM in Forming an AlI-Carbon [2]Paracycophane V.2 Future Work for Completing the Total Synthesis of Longithorone C V.3 Conclusion Chapter VI: Experimental... 8 VI. General Experimental Notes VI.2 Experimental Procedures and Data Vll Summary The growing number of cyc0phane containing natural products and total syntheses that employ cyc0phane intermediates has stimulated renewed interest in their asymmetric preparation and planar chirality. A synthetic approach is proposed towards the total synthe sis of longithorone C. This [2]paracyclophane quinone is a member of a group of macrocycic farnesylated quinones isolated from the tunicate Aplidium longithorax. The development of an efficient preparative method will be discussed for the macrocycic ansa-bridge by ring-cosing olefin metathesis (RCM) in racemic form. The investigation of various fluorinated auxiliaries as novel gearing elements and their effect on macrocycization is presented. The mechanism by which these gearing elements function has been studied by molecular modeling. Copper-catalyzed Grignard reactions have been optimized in order to selectively couple prenylated side chains to aromatic halides. Finally, a variety of olefin metathesis catalysts were studied for the preparation of a [2]paracyclophane containing three stereodefined tri-substituted olefins. Key Words: gearing elements, longithorone C, paracycophanes, ring-cosing olefin metathesis (RCM). V Résumé Le nombre grandissant de produits naturels contenant des cyclophanes ou de synthèses totales utilisant des cyclophanes comme intennédiaires a stimulé un nouvel intérêt pour la synthèse asymétrique de ces molécules possédant une chiralité plane. Une approche synthétique vers la synthèse totale de la longithorone C a été proposée. Cette quinone, possédant un [2]paracyclophane, est membre d'un groupe de quinones macrocycliques contenant une chaîne ressemblant à famesol dans leur squelette et a été isolée à partir de Aplidium longithorax. Le développement d'une méthode efficace pour la préparation de ce macrocycle contenant un pont-ansa par métathèse d'oléfines par fenneture de cycle dans sa fonne racémique sera discuté. L'investigation d'une variété d'auxiliaires fluorés comme nouveaux éléments directeurs et leur effet sur la macrocyclisation seront présentés. Le mécanisme par lequel ces éléments directeurs fonctionnent a été étudié par modélisation moléculaire. Une réaction de Grignard catalysée par le cuivre a été optimisée dans le but d'installer les châmes latérales allyliques à l'halogénure aromatique. Finalement, une variété de catalyseurs de métathèse d'oléfines a été étudié pour la préparation d'un [2]paracyclophane contenant trois oléfines trisubstitués stéréodéfinies. Mots clés: éléments directeurs, longithorone C, paracyclophanes, métathèse d'oléfine par fenneture de cycle (RCM). IX Acknowledgements would like to express my sincere gratitude to Professor Shawn K. Collins for giving me the opportunity to work in his group. He is an excellent teacher who has guided me throughout my degree. would also like to thank past and present members of the Collins group who have contributed to the research projects that have been involved with, namely, Pierre André Fournier and Alain Grandbois. Thanks to the assistance provided by Dr. Min Tan Phan Viet, Sylvie Bilodeau, and Cedric Malveau for the help they have provided in acquiring sorne of the NMR data that have been presented here, as weil as for their patience in answering my questions. Thanks to Alexandra Furtos, Karine Venne, and Dalbir Sekhon for the help in acquiring mass spectral data, for the patience in answering my questions, and for letting me know when my lab coat needed replacement. To ail my mends who have made this such a pleasurable experience: thanks for the good times! Last but not least, would like to thank my family. My parents and two sisters have al ways supported ail of my endeavors, and my lovely wife Araks Malkhassian for the patience through ail those long hours of work. am grateful for their unconditional love and support. would not have been able to do this without you. x List of Figures Figure Figure 2 The Longithorone Family ofnatural Products Retrosynthetic Analysis oflongithorone A Involving Molecular and Transannular Diels-Alder Reactions Figure 3 Retrosynthetic Analysis of Longithorone A Involving Enyne Metathesis Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Intramolecular and Intermolecular Enyne Metathesis Reactions Retrosynthetic Analysis of Longithorone B Structural Similarities Between Longithorone A, B, and C Initial Retrosynthetic Analysis of Longithorone C Retrosynthetic Analysis ofa Model System using cis-farneso Retrosynthetic Analysis of Revised Model System using trans-farneso Figure 0 Figure Il Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Revised Model System Stereocontrol During Triflation of p-ketoester 8 using DMF as Solvent. 34 Proposed Model Study using Disubstituted Olefin Retrosynthetic Analysis of Longithorone C Copper Catalyzed Grignard Reactions...,... Retrosynthetic Analysis using Copper Catalyzed Grignard Reactions Magnesium-Halogen Exchange Role of Copper Catalyst in Organomagnesium Cross-Coupling Reactions. 48 Proposed Synthetic Pathway for Copper Catalyzed Coupling of Grignard Reagents...,..., Xl Figure 9 Figure 20 Figure 2 Figure 22 Figure 23 Figure 24 Regiocontrol in Copper Catalyzed Grignard Reactions Formation of cr-allyl Copper Species 29 with Acetate Formation of l'-allyl Copper Species 30 with Acetate Stereochemistry of Relay Side Chain Quadrupolar Interactions using a CF 3 -Based Gearing Element Results of Higher Drder DFT Calculations on Model System (Red color denotes areas of increased electron density due to fluorine atoms) Figure 25 Results of Higher Drder DFT Calculations on AH Carbon System (Red color denotes areas of increased electron density due to fluorine atoms). 65 Figure 26 Figure 27 Model System used in Determining the Ideal Gearing Element Retrosynthetic Analysis for the Model System used for Determining the Ideal Gearing Element Figure 28 Figure 29 Retrosynthetic Analysis for Longithorone C Proposed Reaction Steps for the Completion of Longithorone C Figure 30 Figure 3 Proposed Mechanism for Dxidation of Benzaldehydes to Phenols Proposed Chiral Catalysts for the Asymmetric Synthesis of Longithorone C Figure 32 Proposed Chiral Auxiliaries for the Asymmetric Synthesis of Longithorone C Xll List of Schemes Scheme Studies of Enyne Metathesis in Macrocycization Reactions Scheme 2 Preparation of Enyne Precursor 3..., Scheme 3 Enyne Metathesis using an Atropisomeric Control Element... 0 Scheme 4 Removal of the Atropisomeric Control Element..... .., Scheme 5 Enyne Metathesis Lacking an Atropisomeric Control Element...,... Il Scheme 6 Additive Effect on the Transition States of the [3,3]-Sigmatropic Rearrangements Scheme 7 Preparation of [2]Paracycophanes by Friedel-Crafts Alkylation... 4 Scheme 8 Initial Attempts in Forming [2]Paracyclophanes Scheme 9 Benzylesters as Gearing Elements Scheme 0 Pentafluorobenzylesters as Gearing Elements Scheme Il Energy Minimization using AMI and MP2 Methods Scheme 2 Determining the Ideal Site for Metathesis...,... 2 Scheme 3 Attempted Formation of a Tri-substituted Olefin by RCM Scheme 4 Relay-Ring Closing Metathesis Scheme 5 Model Study Incorporating Relay-Ring Closing Metathesis Scheme 6 Synthesis ofpentafluoro-2,5-dihydroxybenzoate 60 via Mitsunobu Chemistry Scheme 7 Synthesis ofpentafluoro-2,5-dihydroxybenzoate 60 via an Alkylation Procedure..., Scheme 8 Synthesis of Allylic Side Chain Scheme 9 Alkylation using trans,trans-farnesoi65 and Allylic AlcohoI xm Scheme 20 RRCM ofmacrocycle Scheme 2 Gibbs' Synthesis of cis,trans-farnesoi Scheme 22 Synthesis of cis-famesol 62 using Geranylacetone Scheme 23 Synthesis of Geranylacetone Scheme 24 Preparation of cis,trans-fameso62 from Geranylacetone Scheme 25 Alkylation using cis,trans-fameso62 and Allylic Alcohol Scheme 26 RRCM ofmacrocycle Scheme 27 Preparation of Olefin 93 Following Modified Corey Procedure Scheme 28 Alkylation using Side Chain 93 and Allylic AlcohoI Scheme 29 RRCM ofmodel System Scheme 30 Negishi Coupling using Prenylbromide Scheme 3 Negishi Coupling using Iodide Scheme 32 Negishi Coupling using Alkyl Bromide Scheme 33 Synthesis ofi-propyl-2,5-diiodobenzoate Scheme 34 Synthesis ofbromide 25 and Acetate Scheme 35 Optimized Reaction Conditions in Forming Aryl.iodide Scheme 36 Formation of the Allylic Acetate 3 Derived from cis-olefin Scheme 37 Optimized Reaction Conditions in Forming Ole fin Scheme 38 Synthesis of Acetate 36 and Stereochemistry ofolefin Scheme 39 Preparation of Bistrifluoromethyl Benzyl Ester Scheme 40 Improved Bistrifluoromethyl Gearing Element on Model System Scheme 4 Synthesis of Bromide XIV Scheme 42 Synthesis ofpentafluorobenzyl ester 55 and Trifluoromethylbenzyl ester Scheme 43 NOESY ofmacrocycle Scheme 44 Synthesis ofmacrocyclization Precursors 74 and Scheme 45 Optimum Reaction Conditions for RRCM on Real System... 90 xv List of Tables Table Table 2 Table 3 Table 4 Effeet of Ester Group, Halide, and Grignard on Mg-X exehange Optimizing y / cr Produet Ratio RRCM ofmodel Compound [2]Paraeyelophane 57 and RRCM in forming Cyc0phanes 73 and XVI Abbreviations Ac ACN Ar COSY d dba DCM dd DIAD DIBAL-H DMF dppf dt ee eq FePc g GC h HM HMPA HRMS acetyl acetonitrile aryl correlation spectroscopy doublet dibenzylideneacetone dichloromethane doublet of doublets isopropyldiazodicarboxylate diisobutylaluminum hydride dimethylformamide (diphenylphosphino)ferrocene doublet of triplets enantiomeric excess equivalent iron tetrasulfophthalocyanine gram gas chromatography hour half-metathesis hexamethylphosphoramide high resolution mass spectrometry XVll Hz HWE imid. J kcal KHMDS m mm ml mol mmol NBS NMP NMR NOESY PG ppm py q RCM RRCM r.t. s hertz Homer-Wadsworth-Emmons imidazole coupling constant kilocalorie potassium hexamethyldisilazide multiplet minute milliliter mole millimole N-bromosuccinimide N-methylpyrrolidone nucear magnetic resonance nucear overhauser enhancement spectroscopy protecting group parts per million pyridine quartet ring-cosing olefin metathesis relay ring-cosing metathesis room temperature singlet XVlll t TBAF TBDMS TBDPS TFA TLC UV triplet tetrabutylammonium floride tert-butyldimethylsilyl tert-butyldiphenylsilyl trifluoroacetic acid thin layer chromatography ultraviolet Chapter : Introduction to the Longithorones: Paracyclophane Natural Products This chapter will focus on the longithorone family of natural products that contain a paracyclophane core and the synthesis of these macrocyclic natural products.. - Ring Closing Olefin Metathesis as a Route to Strained Systems. The olefin ring-closing metathesis (ReM) reaction has emerged as one of the most powerful transforms in organic synthesis. Indeed, the broad scope and reliability of this reaction has greatly simplified the total synthesis of a wide variety of architecturally complex natural and unnatural products. 2 For example, Smith and co-workers developed in 999, the first total synthesis of cylindrocyclophane F, a unique natural product possessing a 22-membered [7, 7]paracyclophane ring. 3 Recent advancements in metathesis catalyst design have allowed chemists to reexamine olefin metathesis as a route to systems bearing strained olefins embedded in (a) Trnka, T. M.; Grubbs, R. H. Ace. Chem. Res. 200,34, 8. (b) FÜfstner, A. Angew. Chem., Int. Ed. 2000,39,302. (c) Nicolaou, K. c.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,44, (d) Grubbs, R. H. Handbook ofmetathesis, Three Volume Set Fürstner, A; Langernann, K. J. Org. Chem, 996,6/, Smith, A B. III; Kozmin, S. A; Paone, D. V. J. Am. Chem. Soc. 999, /2/, 2 their skeletons. 4 The variety of different catalysts that have been developed allows for the possibility to select a catalyst having the necessary level of reactivity to access a strained system but also to avoid catalysts which may be so reactive as to favor ringopening ofthe desired ring system. 5 Ring closing metathesis (ReM) is now a standard method for the preparation of both carbocyclic and heterocyclic ring systems in sizes ranging from five- and sixmembered cycles to macrocyclic compounds. 6 Despite its popularity, the preparation of certain molecules via olefin 'metathesis remains a challenge. In particular, strained ring systems are problematic. In sorne cases, the ring opening process can be far more thermodynamically favorable than ring closing while in other cases the system may be too strained to permit cyclization. 6.:: A fascinating challenge for olefinmetathesis could be the preparation of strained macrocyclic structures such as the longithorone natural products. In 997, Schmitz and co-workers isolated a group of nine,famesylated quinones isolated from a tunicate Aplidium longithorax that featured new macrocyclic skeletons. Their carbon skeletons resemble a farnesyl unit bridginga quinone at either the meta- or para-positions (Figure 4 (a) Scholl, M.; Ding, S.; Lee, C. W.; Gmbbs, R. H. Org. Lett. 999, l, (b) Ackermann, L.; Filistner, A.; Weskamp, T.; Kohl, F. J.; Herrmann, W. A. Tetrahedron Lett. 999, 40, (c) Huang, J. K.; Schanz, H.-J.; Stevens, E. D.; Nolan, S. P. Organometallics. 999, 8, (d) Jafarpour, L.; Schanz, H.-J.; Stevens, E. D.; Nolan, S. P. Organometallics. 999, 8, (e) Fürstner, A.; Thie,-O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S. P.. Org. Chem. 2000,65, () Collins, S. K. J. Organomet. Chem. 2006, 69, Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett.. 200, 3, (a) Paquette, L. A.;. Basu, K.; Eppich, J. C.; Hofferberth, J. E. He/v. Chim. Acta 2002,0, (b) Deiters, A.; Martin, S. F. Chem. Rev. 2004,5, (c) Nakamura,.; Yamamoto, Y. Chem. Rev. 2004,5, ,. ... 3 ).7 To date, the only biological adivityreported for these marine compounds pertains to longithorone A. 8 longlthorone J longithorone K longlthorone o longlthorone B longlthorone C longithorone A Figure - The Longithorone Family' or natural Products. lu l',.:!.2 - Synthesis of Longithorone A Introduction and Synthetic Challenges. In 2002, Shair and co-workers reported an elegant synthesis of the cytotoxic marine natural product longithorone A, based on the original proposed biosynthesis by Schmitz and co-workers. 9,0 The Shair group proposed the following retrosynthetic J: analysis comprised of both intermo.c,ijj.ar. and transannular Diels-Alder reactions in the 7 Fu, X.; Hossain, B.; Schmitz, F. J.; van der,helm, D. J. Org. Chem. 997,62, For information on the biological activity oflongithorone A, see: (a) Fu, X.; Ferre ira, M. L. G.; Schmitz, FJ. J. Nat. Prad. 999,.62, (b) Davidson, B. S. Chem. Rev. 993,93, (c) Faulkner, D. J. Nat. Prad. Rep.998, /5,.3: Layton, M. E.; Morales, C.
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