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

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Palladium-catalyzed Enantioselective Allylic

Substitutions on Bifunctional Substrates


zur Erlangung der Würde eines Doktors der Philosophie

vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel


Stéphanie Angèle Richoz

aus Ursy (FR), Schweiz

Basel, 2012

Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel


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

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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




1.2.1 Catalytic cycle

1.2.2 Catalysts and Ligands

1.2.3 Substrates Symmetrically substituted allyl systems Meso-substrates

1.2.4 Leaving groups

π-σ-π isomerization

1.2.5 1.2.6 Nucleophile

β-hydride elimination





3.1.1 Substrate synthesis Coupling of ethyl propiolate to ethyl glyoxalate Reduction of dimethyl 2-oxoglutaconate Bromination Allylic substitution on vinyl/allyl monobromide Quantum Mechanic Study


3.2.1 Substrate synthesis (E)-Dibenzylether substrates (Z)-Dibenzylether substrates


3.3.1 Leaving group screening Ethyl carbonate substrates (E)-Ethyl carbonate substrate (compound 69) (Z)-Ethyl carbonate substrate (compound 75) Methyl carbonate substrates (E)-Methyl carbonate substrate (compound 70) (Z)-Methyl carbonate substrate (compound 76) Benzylcarbamate substrate 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) C-nucleophiles N-nucleophiles Benzimidazole, Indole and Me-indole as N-Nucleophiles O-Nucleophiles


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


3.5.1 Meso diester compound Substrate synthesis Allylic substitutions on meso diester (compound 144)

3.5.2 Racemo diester compound Substrate synthesis Allylic substitutions on racemo diester (compound 156)

3.5.3 Meso dibenzylether compound Substrate synthesis Allylic subsitutions on meso dibenzylether (compound 164)

3.5.4 Racemo dibenzyl ether compound Substrate synthesis Allylic substitution on racemo dibenzylether (compound 171)

3.5.5 Cyclic bi-lactone substrate Substrate synthesis 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









Chapter 1




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

–  –  –

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