WWW.ABSTRACT.XLIBX.INFO
FREE ELECTRONIC LIBRARY - Abstract, dissertation, book
 
<< HOME
CONTACTS



Pages:   || 2 | 3 | 4 | 5 |   ...   | 17 |

«Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der ...»

-- [ Page 1 ] --

Palladium-catalyzed Enantioselective Allylic

Substitutions on Bifunctional Substrates

Inauguraldissertation

zur Erlangung der Würde eines Doktors der Philosophie

vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel

von

Stéphanie Angèle Richoz

aus Ursy (FR), Schweiz

Basel, 2012

Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel

edoc.unibas.ch

Dieses Werk ist unter dem Vertrag „Creative Commons Namensnennung-Keine kommerzielle Nutzung-Keine Bearbeitung 2.5 Schweiz“ lizenziert. Die vollständige Lizenz kann unter creativecommons.org/licences/by-nc-nd/2.5/ch eingesehen werden.

Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Dr. Murat Acemoglu Prof. Dr. Andreas Pfaltz Prof. Dr. Wolf-Dietrich Woggon Basel, den 26. Juni 2012 Prof. Dr. Martin Spiess Dekan Namensnennung-Keine kommerzielle Nutzung-Keine Bearbeitung 2.5 Schweiz

Sie dürfen:

das Werk vervielfältigen, verbreiten und öffentlich zugänglich machen

Zu den folgenden Bedingungen:

Namensnennung. Sie müssen den Namen des Autors/Rechteinhabers in der von ihm festgelegten Weise nennen (wodurch aber nicht der Eindruck entstehen darf, Sie oder die Nutzung des Werkes durch Sie würden entlohnt).

Keine kommerzielle Nutzung. Dieses Werk darf nicht für kommerzielle Zwecke verwendet werden.

Keine Bearbeitung. Dieses Werk darf nicht bearbeitet oder in anderer Weise verändert werden.

Im Falle einer Verbreitung müssen Sie anderen die Lizenzbedingungen, unter welche dieses Werk fällt, • mitteilen. Am Einfachsten ist es, einen Link auf diese Seite einzubinden.

Jede der vorgenannten Bedingungen kann aufgehoben werden, sofern Sie die Einwilligung des • Rechteinhabers dazu erhalten.

Diese Lizenz lässt die Urheberpersönlichkeitsrechte unberührt.

• Die gesetzlichen Schranken des Urheberrechts bleiben hiervon unberührt.

Die Commons Deed ist eine Zusammenfassung des Lizenzvertrags in allgemeinverständlicher Sprache:

http://creativecommons.org/licenses/by-nc-nd/2.5/ch/legalcode.de

Haftungsausschluss:

Die Commons Deed ist kein Lizenzvertrag. Sie ist lediglich ein Referenztext, der den zugrundeliegenden Lizenzvertrag übersichtlich und in allgemeinverständlicher Sprache wiedergibt. Die Deed selbst entfaltet keine juristische Wirkung und erscheint im eigentlichen Lizenzvertrag nicht. Creative Commons ist keine Rechtsanwaltsgesellschaft und leistet keine Rechtsberatung. Die Weitergabe und Verlinkung des Commons Deeds führt zu keinem Mandatsverhältnis.

Quelle: http://creativecommons.org/licenses/by-nc-nd/2.5/ch/ Datum: 3.4.2009 This thesis was supervised by Prof. Dr. Murat Acemoglu (Novartis) and Prof. Dr. Andreas Pfaltz (University of Basel) from March 2009 to June 2012 in the Chemical and Analytic Development Unit at Novartis Pharma AG in Basel.

Aknowledgments First of all, I would like to thank my supervisor Prof. Dr. Murat Acemoglu for giving my the opportunity to work at Novartis, for providing me with an interesting research project and for his support during the thesis.

I would like to thank Prof. Dr. Andreas Pfaltz for giving me the opportunity to participate as a member of his research group and for being the advisor and examinator of this thesis.

I would like to thank Prof. Dr. Wolf-Dietrich Woggon for co-examination of this thesis and Prof. Dr. Marcel Mayor for chairing the defense.

I am very grateful to Hans Stettler for the many insightful and stimulating discussions, for his advices during the thesis deepening my understanding of organic chemistry.

For the good working atmosphere in the lab and his friendliness, I would like to thank Robert Schreiber.

I would like to thank Dr. Christian Guenat, Eva Bürgin, Francis Roll for the HR-MS measurements.

I would like to thank Thomas Lochmann, Regis Denay, Kayan Gabriel Akyel for the support of my NMR measurements.

I would like to thank Elodie Letot for the IR measurments.

I would like to thank Michele Gasser and Monique Kessler for their help with chiral seperations.

I would like to thank Shaodong Zhang, Duc Tran Ngoc, Matthew May, Yann Peter, Geoffroy Rose, Estelle Durantie, Clement Popineau, Jesper Christensen, Pascale Holzerny for the time shared at Novartis.

I would like to thank Micheline Wirtz for her organizational work and her kindness and everyone from builiding WSJ-145 for the time shared at Novartis.

Je suis très reconnaissante à mes parents pour leurs soutiens durant toutes ces années et pour leurs encouragements durant mes études.

I am very grateful to my fiancé Raphael for his advices and support and to my friends who supported me during this time.

I would like to thank Novartis, especially the chemical and analytical development department, which has made this work possible.

Table of Contents

1. INTRODUCTION

1.1 GENERAL INTRODUCTION

1.2 PALLADIUM CATALYZED ENANTIOSELECTIVE ALLYLIC SUBSTITUTION

1.2.1 Catalytic cycle

1.2.2 Catalysts and Ligands

1.2.3 Substrates

1.2.3.1 Symmetrically substituted allyl systems

1.2.3.2 Meso-substrates

1.2.4 Leaving groups





π-σ-π isomerization

1.2.5 1.2.6 Nucleophile

β-hydride elimination

1.2.7

2. PURPOSE OF THIS WORK

3. RESULTS AND DISCUSSIONS

3.1 DI-ESTER SUBSTRATES

3.1.1 Substrate synthesis

3.1.1.1 Coupling of ethyl propiolate to ethyl glyoxalate

3.1.1.2 Reduction of dimethyl 2-oxoglutaconate

3.1.1.3 Bromination

3.1.1.4 Allylic substitution on vinyl/allyl monobromide

3.1.1.5 Quantum Mechanic Study

3.2 DIBENZYLETHER SUBSTRATES

3.2.1 Substrate synthesis

3.2.1.1 (E)-Dibenzylether substrates

3.2.1.2 (Z)-Dibenzylether substrates

3.3 ALLYLIC SUBSTITUTIONS ON DIBENZYLETHER SUBSTRATES

3.3.1 Leaving group screening

3.3.1.1 Ethyl carbonate substrates

3.3.1.1.1 (E)-Ethyl carbonate substrate (compound 69)

3.3.1.1.2 (Z)-Ethyl carbonate substrate (compound 75)

3.3.1.2 Methyl carbonate substrates

3.3.1.2.1 (E)-Methyl carbonate substrate (compound 70)

3.3.1.2.2 (Z)-Methyl carbonate substrate (compound 76)

3.3.1.3 Benzylcarbamate substrate

3.3.1.4 Chloracetate substrate

3.3.2 E/Z isomerization

3.3.3 Ligand screening with (E)-Chloracetate substrate (compound 72)

3.3.4 Solvent screening with (E)-Chloracetate substrate (compound 72)

3.3.5 Base screening with (E)-Chloracetate substrate (compound 72)

3.3.6 Catalyst

3.3.7 Catalyst Loading screening with (E)-Chloracetate substrate (compound 72)................. 57 3.3.8 Nucleophile scope with (E)-Chloracetate substrate (compound 72)

3.3.8.1 C-nucleophiles

3.3.8.2 N-nucleophiles

3.3.8.2.1 Benzimidazole, Indole and Me-indole as N-Nucleophiles

3.3.8.3 O-Nucleophiles

3.4 DETERMINATION OF THE ABSOLUTE CONFIGURATION

3.4.2 Reaction of (E)-Chloracetate compound 72 with (S,S)-Trost ANDEN and BnNH2 as N-nucleophile

3.5 ALLYLIC SUBSTITUTIONS ON DIMERIC SUBSTRATES

3.5.1 Meso diester compound

3.5.1.1 Substrate synthesis

3.5.1.2 Allylic substitutions on meso diester (compound 144)

3.5.2 Racemo diester compound

3.5.2.1 Substrate synthesis

3.5.2.2 Allylic substitutions on racemo diester (compound 156)

3.5.3 Meso dibenzylether compound

3.5.3.1 Substrate synthesis

3.5.3.2 Allylic subsitutions on meso dibenzylether (compound 164)

3.5.4 Racemo dibenzyl ether compound

3.5.4.1 Substrate synthesis

3.5.4.2 Allylic substitution on racemo dibenzylether (compound 171)

3.5.5 Cyclic bi-lactone substrate

3.5.5.1 Substrate synthesis

3.5.5.2 Allylic substitution on bi-lactone compound

3.6 DERIVATIZATION AND APPLICATION OF CHIRAL ALLYLIC AMINES AND ETHERS................ 87 3.6.1 Synthesis of oxazolidinone derivatives

3.6.2 Selective benzyl deprotection and functionalization

3.6.3 Epoxidation of phenol product 114

4. SUMMARY AND CONCLUSION

5. EXPERIMENTAL PART

5.1 GENERAL INFORMATIONS

5.2 SYNTHESIS OF THE COMPOUNDS

5.3 GENERAL PROCEDURES FOR ALLYLIC SUBSTITUTIONS

6. APPENDIX

6.1 ABBREVIATIONS

7. REFERENCES

Chapter 1

Introduction

Introduction

___________________________________________________________________________

1. Introduction

1.1 General introduction Metal catalyzed allylic substitution has been demonstrated to be a versatile and important tool in organic synthesis1-8. Through this reaction, the formation of many types of bonds such as C-C, C-N, C-O, C-S and C-P is possible. Furthermore, depending on the conditions, different chemo-, regio- and stereoselectivities can be achieved. Palladium has been widely used and is a well-studied metal in allylic substitution. Moreover, palladium complexes have proven to be useful compounds with a broad range of applications.

The first π-allyl-palladium complex was reported by Smidt and Hafner9 in 1959 when they described the discovery of a [Pd(allyl)Cl]2 complex. Less than 10 years after this article, in 1965, Tsuji et al.10 presented the first C-C bond formation using the same π-allylpalladium complex in stoichiometric amount. In 1970, the discovery that zero-valent palladium complexes are active catalysts in catalytic amount was found by chemists from Toray Industries in Japan and from the Union Carbide Corporation Chemicals and Plastics11,12.

Three years later, Trost et al. started to investigate the field and were the first group to achieve stoichiometric enantioselective allylic substitutions13 and, in 1977, catalytic enantioselective allylic substitutions14. Nowadays, this field is still an interesting research area where the search for new chiral ligands and new applications for the reaction has raised an increased interest.

1.2 Palladium catalyzed enantioselective allylic substitution

Performing a palladium catalyzed enantioselective allylic substitution involves taking different factors into account, such as catalyst, ligand, nucleophile etc. Depending on the substrate, several changes are needed to optimize the reaction conditions and to get the desired product in high enantioselectivity.

–  –  –

1.2.1 Catalytic cycle The generally accepted mechanism for palladium-catalyzed allylic substitutions with “soft” nucleophiles imply as the first step, the coordination of the low valent palladium(0) catalyst to the double bond of substrate 1 into a η2-complex 2 (step A scheme 1). An oxidative addition follows which affords the η3-π-allylpalladium complex 3 (step B)15. This activated substrate is then attacked by a nucleophile to form a η2-complex 4 (step C). Decomplexation of the Pd complex releases the palladium and the desired product 5 (step D) Scheme 1: Catalytic cycle 1.2.2 Catalysts and Ligands Different sources of palladium catalysts are known, Pd2(dba)316 (dba = dibenzylidene acetone) and [Pd(allyl)Cl]2 being the most frequently employed. With these catalysts, complexes are generated in situ by combination with the desired ligand. [Pd(allyl)Cl] 2 is in oxidation sate +2 but is reduced to the activated Pd(0) by nucleophilic attack on the allyl group17.

-2Introduction ___________________________________________________________________________

In the 1970’s, a broad range of different ligands have been developed to improve the enantioselectivity of palladium catalyzed reactions. In 1972, the first C2-symmetric chiral ligand was introduced by Kagan18 with the DIOP ligand. Since then, several C2-symmetric ligands19 were developed and excellent results were obtained in hydrogenation with chelating diphosphines, i.e. Chiraphos20,21 and Binap22,23 (scheme 2). Unfortunately transferring these ligands into allylic substitution resulted into deceiving results probably due to the fact that in the allylic substitution the nucleophilic attack is taking place outside the coordination sphere of the complex which is not the case in hydrogenations3,24. Consequently, in 1986, Hayashi25,26 developed optically active ferrocenylphosphine ligands containing a side chain capable of interacting with the nucleophile and allowing the direction of the attack on a specific allylic terminus. Nevertheless, in the early 1990, two groups demonstrated that high enantioselectivites could also be achieved with a C2-symmetric ligand: The Pfaltz group with bisoxazolidines27-29 and the Trost group30 with new types of diphosphines.

Scheme 2: First ligands used in allylic substitution Since then, the Trost ligands based on 2-(diphenylphosphino)benzoic acid (DPPBA), scheme 3, have been applied in several allylic alkylation reactions and were involved in a number of

–  –  –

applications31-32. The configuration of these ligands generates Pd fragments with large bite angles which allow the palladium-ligand complex to embrace the allyl function of the substrate forming a chiral pocket (scheme 4). With this concept, Trost developed a model which allows predicting the product stereochemistry depending on the DPPBA chiral ligand used33. In this model, the asymmetric induction is established on steric interactions between the “wall” (phenyl substitutents of the chiral ligand) and the incoming nucleophile.

Depending on how the ligand “sits” on the allyl substrate, one terminus should be favored for nucleophilic attack. However, in recent research it has been demonstrated that these ligands are forming oligomers making the reaction mechanism difficult to elucidate34-36. In 2009, Lloyd-Jones et al.37 elucidated the monomeric forms of the cationic Pd-η3-allyl complexes bearing the trans-cyclohexylenediamine-based Trost ligand ((R,R)-standard, scheme 3) through NMR, isotopic labeling and computation. They identified that hydrogen-bond interaction of one N-H unit in Pd-ligand complex allowed to accelerate ionization and nucleophile attack. This new model may be helpful in the interpretation of the selectivity in allylic subsitution reactions catalyzed by Pd complexes of Trost ligands.

Scheme 3: Different DPPBA Trost ligands

–  –  –



Pages:   || 2 | 3 | 4 | 5 |   ...   | 17 |


Similar works:

«Engaging Foucault Volume 2 edited by Marjan Ivković Gazela Pudar Draško Srđan Prodanović Institute for Philosophy and Social Theory University of Belgrade Engaging Foucault Volume 2 Edited by Marjan Ivković, Gazela Pudar Draško, Srđan Prodanović University of Belgrade | Institute for Philosophy and Social Theory Engaging Foucault volume 2 Edition Conferentia Title Engaging Foucault (Vol. 2) Edited by Marjan Ivković, Gazela Pudar Draško, Srđan Prodanović Reviewers Ana Birešev,...»

«48 УДК 1 (47+57) (091) «19» К. С. Кондратенко Индуктивный метод Н. О. Лосского В статье проанализирована логика, лежащая в основе философии Лосского. Автор исследует логическую связь гносеологии и метафизики в системе Лосского, раскрывает метод прямой индукции, используемый...»

«FACTA UNIVERSITATIS Series: Linguistics and Literature Vol. 3, No 2, 2005, pp. 185 192 SHAMAN'S CIRCLE: CIRCULARITY IN NATIVE AMERICAN CULTURE UDC 821.111(73)-1.09 Marta Dimitrijević Faculty of Philosophy, Niš, Serbia Abstract. The aim of this paper is to provide an outline of Nancy Wood's book of poems entitled Shaman's Circle. The poems provide an illustration of some of the key points of Native American culture, with an emphasis on how the beliefs and rituals of Native Americans follow the...»

«carl spaeter gmbh carl spaeter gmbh Spaeter Gruppe: Ausbildung duales Studium Carl Spaeter GmbH Personalabteilung Philosophenweg 17 47051 Duisburg Branche: Handel und Distribution Mitarbeiter: bundesweit ca. 1.700 Mitarbeiter Spaeter Duisburg: Willkommen SPAETER Duisburg. Wir handeln für Ihren Erfolg. SPAETER Duisburg und Hebels Stahlservice präsentieren sich vom 15. bis zum 18. März gemeinsam auf der Spaeter Bietigheim: Unternehmen CARL SPAETER GmbH CARL SPAETER GmbH. Höpfigheimer Straße...»

«Rolf Keck Uncle Sam gegen Onkel Hồ: U.S. Flugblattpropaganda in Vietnam, 1954-1973 Inauguraldissertation zur Erlangung des akademischen Grades: Doctor philosophiae (Dr. phil.) Justus-Liebig-Universität, Giessen: Fachbereich 04, Geschichtsund Kulturwissenschaften Wissenschaftlicher Betreuer: Prof. Dr. Hans-Jürgen Schröder Gefördert durch: Hans-Böckler-Stiftung, Düsseldorf Publikation: Universitätsbibliothek Giessen Giessener Elektronische Bibliothek Druck: Elzer Kopierund Plottstudio,...»

«STROUD’S QUEST FOR REALITY BILL BREWER Barry Stroud begins his investigation into the metaphysics of colour with a discussion of the elusiveness of the genuinely philosophical quest for reality. He insists upon a distinction between two ways in which the idea of a correspondence between perceptions or beliefs and the facts may be understood: first, as equivalent to the plain truth of the perceptions/beliefs in question; second, as conveying the metaphysical reality of the corresponding...»

«Zur Homepage der Dissertation Gesungene Aufklärung Untersuchungen zu nordwestdeutschen Gesangbuchreformen im späten 18. Jahrhundert Von der Carl von Ossietzky Universität Oldenburg – Fachbereich IV Humanund Gesellschaftswissenschaften – zur Erlangung des Grades einer Doktorin der Philosophie (Dr. phil.) genehmigte Dissertation von Barbara Stroeve geboren am 4. Oktober 1971 in Walsrode Referent: Prof. Dr. Ernst Hinrichs Korreferent: Prof. Dr. Peter Schleuning Tag der Disputation:...»

«IS LESS MORE & MORE LESS.? THE EFFECT OF TWO TYPES OF INTERVIEWER EXPERIENCE ON “DON’T KNOW” RESPONSES IN CALENDAR AND STANDARDIZED INTERVIEWS by Ipek Bilgen A DISSERTATION Presented to the Faculty of The Graduate College at the University of Nebraska In Partial Fulfillment of Requirements For the Degree of Doctor of Philosophy Major: Survey Research and Methodology Under the Supervision of Professor Robert F. Belli Lincoln, Nebraska August, 2011 IS LESS MORE & MORE LESS.? THE EFFECT OF...»

«IDENTIFYING STUDENTS AT RISK AND BEYOND: A MACHINE LEARNING APPROACH A Dissertation Submitted to the Graduate School of the University of Notre Dame in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy by Everaldo Aguiar Nitesh V. Chawla, Co-Director Jay B. Brockman, Co-Director Graduate Program in Computer Science and Engineering Notre Dame, Indiana July 2015 c Copyright by Everaldo Aguiar All Rights Reserved IDENTIFYING STUDENTS AT RISK AND BEYOND: A MACHINE...»

«Declaration Nanoparticle Synthesis For Magnetic Hyperthermia This thesis is submitted in partial fulfilment of the requirements for the Degree of Doctor of Philosophy (Chemistry) Luanne Alice Thomas Supervised by Professor I. P. Parkin University College London Christopher Ingold Laboratories, 20 Gordon Street, WC1H 0AJ i Declaration I, Luanne A. Thomas, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been...»

«Pebble Games and Complexity by Siu Man Chan A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Computer Science in the Graduate Division of the University of California, Berkeley Committee in charge: Professor Elchanan Mossel, Co-chair Professor Luca Trevisan, Co-chair Professor Umesh Vazirani Professor David Aldous Spring 2013 Pebble Games and Complexity This work is licensed under a Creative Commons Attribution-ShareAlike 3.0...»

«The Male Coming-of-Age Theme in the Hebrew Bible by Stephen Michael Wilson Department of Religion Duke University Date:_Approved: _ Carol L. Meyers, Supervisor _ Stephen Chapman _ Ellen F. Davis _ Eric M. Meyers _ Susan Niditch Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Religion in the Graduate School of Duke University i v ABSTRACT The Male Coming-of-Age Theme in the Hebrew Bible by Stephen Michael Wilson...»





 
<<  HOME   |    CONTACTS
2016 www.abstract.xlibx.info - Free e-library - Abstract, dissertation, book

Materials of this site are available for review, all rights belong to their respective owners.
If you do not agree with the fact that your material is placed on this site, please, email us, we will within 1-2 business days delete him.