Ruthenium-catalyzed asymmetric cycloadditions and 1,4-additions

Thesis

Reference

Ruthenium-catalyzed asymmetric cycloadditions and 1,4-additions

BADOIU, Andréi

Abstract

Le but des travaux décrits dans ce manuscrit est d'étendre le domaine d'application des complexes de ruthénium, acides de Lewis de type "tabouret de piano", synthétisés au laboratoire dans le cadre de réactions asymétriques. Les travaux antérieurs ont permis d'obtenir des procédures robustes et applicables sur grande échelle pour aussi bien pour la synthèse des précurseurs métalliques que des ligands et des réactions de Diels-Alder énantiosélectives. Les résultats décrits ci-après s'inscrivent donc dans la continuation des travaux de Florian Viton sur les réactions de cycloadditions dipolaires énantioselectives.

D'importantes améliorations de la synthèse des différents précurseurs de catalyseurs ont pu être obtenues en simplifiant les procédures expérimentales. De plus, ces optimisations ont permis d'obtenir des procédés plus sûrs et rendent possible une meilleure purification et récupération des espèces catalytiquement actives. De bons résultats ont été obtenus dans le cadre de cycloadditions 1,3-dipolaires énantioselectives pour de nombreuses combinaisons dipole/dipolarophile. La [...]

BADOIU, Andréi. Ruthenium-catalyzed asymmetric cycloadditions and 1,4-additions. Thèse de doctorat : Univ. Genève, 2010, no. Sc. 4199

URN : urn:nbn:ch:unige-116838

DOI : 10.13097/archive-ouverte/unige:11683

Available at:

http://archive-ouverte.unige.ch/unige:11683

Disclaimer: layout of this document may differ from the published version.

1 / 1

Département de chimie organique Professeur E. P. Kündig _______________________________________________________________________

Ruthenium-Catalyzed Asymmetric Cycloadditions and 1,4-Additions

THÈSE

présentée à la Faculté des sciences de l’Université de Genève pour obtenir le grade de Docteur ès sciences, mention chimie

par

Andrei BĂDOIU de

Bucarest (Roumanie)

Thèse N^o 4199

GENÈVE

Atelier d'impression ReproMail - Uni Mail 2010

Dedicated to the memory of

Dr. Christophe Saudan

The work described in this manuscript is the result of the doctoral studies carried out in the group of Professor Ernst Peter Kündig, in the Department of Organic Chemistry of the University of Geneva, in the period October 2005 – January 2010.

First of all I would like to express my gratitude and indebtedness to Professor Kündig for giving me the opportunity of carrying out my doctoral studies in his group. I greatly appreciate the trust and liberty I have been given throughout my research, along with the guidance and advices that had a positive contribution on both my professional and personal development.

It is both a great honor and a pleasure to have Professor Philippe Renaud (University of Berne) and Professor Jérôme Lacour (University of Geneva) judging this thesis. I would like to thank you both for taking the time to consider my research work.

None of the work described would have been possible without the generous help of the analysis teams: NMR (Dr. Damien Jeannerat, André Pinto, Dr. Bruno Vitorge), MS (Eliane Sandmeier, Philippe Perottet, Nathalie Oudry) and X-ray (Dr. Gerald Bernardinelli, Dr. Céline Besnard). I am greatly indebted to Patrick Romanens, Marlene Berthod and Stéphane Grass for technical support and synthesis of intermediates, as well as for their sincere friendship.

I would like to thank my colleagues, past and present, from most of the departments in Sciences II. Work or fun, good or bad, sad or happy, your presence made this thesis a reality and I am grateful to you for being there, most of you more friends than colleagues.

Special thanks to Bettina Bressel and David Linder for their miraculous help and active involvement in the correction and formatting of the manuscript.

MulŃumiri din inimă pentru sprijinul si încrederea accordate pentru părinŃii mei, Florea Dumitraşcu si prieteni. Angi, fără tine nimic nu ar fi fost posibil!

Ar: aryl

BArF: tetrakis-[3,5-bis-(trifluoromethyl)- phenyl] borate

bd: broad doublet

bdd: broad doublet of doublets Bn: benzyl

bs: broad singlet bt: broad triplet C: concentration calcd.: calculated

CAN: cerium ammonium nitrate cat.: catalyst, catalytic amount CD: circular dichroism

CEWG: conjugated electron withdrawing group

COD: 1,4-cyclooctadiene conv.: conversion

Cp: cyclopentadienyl d: doublet

DA: Diels Alder

DBFOX: dibenzofuran-oxazoline DBU: 1,8-diazabicycloundec-7-ene 1,3-DC: 1,3-dipolar cycloaddition dd: doublet of doublets

DFT: density functional theory DMF: N,N-dimethylformamide DMSO: dimethylsulfoxide

2,6-DMTP: 2,6-dimethyl thiophenol DPM: diphenylmethyl

dt: doublet of triplets dr: diastereomeric ratio

EDG: electron donating group ee: enantiomeric excess EI: electron impact

enal: α,β-unsaturated aldehyde enone: α,β-unsaturated ketone ent: opposite enantiomer of equiv.: equivalent

ESI: electrospray ionization EWG: electron withdrawing group FMO: frontier molecular orbital GC: gas chromatography

Grad.: gradient GS: ground state

Hdry: height of a dry column hν: light, electromagnetic radiation

HOMO: highest occupied molecular orbital HPLC: high performance liquid

chromatography

HRMS: high resolution mass spectroscopy i-Pr: iso-propyl, 2-propyl

IR: infrared spectroscopy Ind: indenyl

Iso: isocratic elution J: coupling constant k: rate constant l: length

LA: Lewis acid

LUMO: lowest unoccupied molecular orbital m: multiplet

MA: Michael addition, 1,4-addition maj.: major

mCPBA: meta-chloro perbenzoic acid Me: methyl

min.: minor

MO: molecular orbital

MS: molecular sieves, mass spectrometry (low resolution)

MTBE: methyl tert-butyl ether m/z: mass/charge ratio

N₂: dinitrogen, molecular nitrogen Nap: naphthyl

n.d.: not determined

NMR: nuclear magnetic resonance n. r.: no reaction

n-Pr: 1-propyl Ph: phenyl

PMB: para-methoxy benzyl PMP: para-methoxy phenyl

proton sponge: 1,8-bis-dimethylamino naphthalene

2-Py: 2-pyridyl

PyBOX: pyridine bis-oxazoline q: quartet

rac: racemic

r. t.: room temperature Rf: retention factor s: singlet

SMA: sulfa-Michael addition t: time, triplet

T: temperature t-Bu: tert-butyl

THF: tetrahydrofurane

THP: tetrahydropyranyl, tetrahydropyran TLC: thin layer chromatography

TOF: turnover frequency t_R: retention time

UV: ultraviolet Symbols

δ: chemical shift λ: wave length

∆: subtraction

σ: Hammett electronic parameter ρ: reaction constant

Øe: equivalent diameter ν: wavenumber of absorbance Units

o: degree Å: Ångström d: day

oC: degree Celsius g: gram (mg, g, kg) h: hour

Hz: hertz (Hz, kHz, MHz) K: degree Kelvin

L: liter (µL, mL, L) m: meter (mm, cm, m) M: molarity

min.: minute mmol: millimole ppm: parts per million s: second

Cycloadditions et additions 1,4 asymétriques catalysées par ruthénium

Le but des travaux décrits dans ce manuscrit est d’étendre le domaine d’application des complexes de ruthénium, acides de Lewis de type « tabouret de piano », synthétisés au laboratoire dans le cadre de réactions asymétriques. Les travaux antérieurs ont permis d’obtenir des procédures robustes et applicables sur grande échelle pour aussi bien pour la synthèse des précurseurs métalliques que des ligands et des réactions de Diels-Alder énantiosélectives. Les résultats décrits ci-après s’inscrivent donc dans la continuation des travaux de Florian Viton sur les réactions de cycloadditions dipolaires énantioselectives.

D’importantes améliorations de la synthèse des différents précurseurs de catalyseurs ont pu être obtenues en simplifiant les procédures expérimentales. De plus, ces optimisations ont permis d’obtenir des procédés plus sûrs et rendent possible une meilleure purification et récupération des espèces catalytiquement actives.

Schema 1. Conversion directe du complexe naphthalene en précatalyseur Ru-acetone.

De bons résultats ont été obtenus dans le cadre de cycloadditions 1,3-dipolaires énantioselectives pour de nombreuses combinaisons dipole/dipolarophile. La sélectivité obtenue a pu être

rationalisée et il a pu être montré que les facteurs électroniques influencent fortement la régio- sélectivité (diaryl nitrones) et l’énantio-selectivité (N- methyl nitrones). Des études computationnelles ont permis l’interprétation

des résultats en obtenant une meilleure compréhension du mécanisme des réactions. Enfin,

NO2

CF3

Cl H

Me OM e

R² = 0.9903

-1.0 -0.5 0.0 0.5 1.0 1.5

-1 -0.5 0 0.5 1

σP +

log[(3,5-R/3,4-R) / (3,5-H/3,4-H)]

N O + Ph

Ar CHO

N O Ph Ar

OHC

3,5-end o 3,4-endo

l’aplication du N-oxide de morphanthridine a permis la synthèse d’un principe actif avec de bons rendements, ouvrant la voie à de nouvelles applications.

Schema 2. Réactions de 1,3-CD catalysées par le Ru de N-“alkyle” nitrones et d’enals.

Le champ d’application des acides de Lewis décrits a pu être étendu à l’addition de Michael de nucléophiles mous sur des énones. Bien que les possibilités en termes de substrats ne soient quelque peu limitées, les additions énantiosélectives d’arylthiols sur des énones catalysées au Ru montrent le potentiel existant pour développer de nouvelles applications. D’excellents résultats en termes d’activité et de sélectivité ont été obtenus malgré le contrôle difficile de la stéréochimie et de la possible inhibition du catalyseur. Enfin, les additions 1,4 de athrone sur des énones donnent de bons résultats qui laissent augurer le potentiel inexploré de tels catalyseurs.

De par leurs synthèse aisée, leur robustesse et les possibilités de recyclage, les Acides de Lewis développés au sein du laboratoire se sont montrés être d’excellents catalyseurs pour une variété de réaction de cycloadditions dipolaires et d’additions 1,4.

Les efforts déployés pour mieux appréhender le champ d’applications de tels systèmes catalytiques se poursuivent au sein du groupe.

SbF₆

P Ru P O

*

SbF6

P Ru P O

*

SbF6

P Ru P SAr

*

SbF₆

P Ru

P O

*

SAr O

ArS

H

O

SbF₆

P Ru

P O

*

SAr H

Me Me

SH 95 % y

85 % ee

This research work led to the following publications and oral communications:

PUBLICATIONS

1. Kündig, E. P. and Bădoiu, A. in “Phosphorus Ligands in Asymmetric Catalysis”, Wiley-VCH, Weinheim, A. Börner Ed., 2008, vol. 1, 437.

2. Bădoiu, A.; Brinkmann, Y.; Viton, F.; Kündig, E. P. Pure Appl. Chem. 2008, 5, 1013.

3. Bădoiu, A.; Bernardinelli, G.; Mareda, J.; Kündig, E. P.; Viton, F. Chem. Asian J.

2008, 3, 1298.

4. Bădoiu, A.; Bernardinelli, G.; Besnard, C..; Kündig, E. P. Org. Biomol. Chem. 2010, 8, 193.

ORAL COMMUNICATIONS

1. Viton, F.; Bădoiu, A.; Kündig, E. P. “Asymmetric 1,3-Dipolar Cycloaddition Reactions Between Methacrolein and Diarylnitrones Catalyzed by Chiral Iron and Ruthenium Lewis Acid Complexes” – short oral presentation, 1^st European Chemistry Congress, August 27-31, 2006, Budapest, Hungary, C-PO-172.

2. Bădoiu, A.; Kündig, E. P. “Lewis Acid-Catalyzed Asymmetric Cycloaddition Reactions” – oral presentation, 2^nd Workshop of the International Research Training Group “Catalysts and Catalytic Reactions for Organic Synthesis” (GRK1038), March 15-16, 2007, Basel, Switzerland.

3. Bădoiu, A.; Brinkmann, Y.; Viton, F.; Kündig, E. P. “Asymmetric Lewis Acid- catalyzed 1,3-Dipolar Cycloadditions” – oral presentation and poster, 14th IUPAC Symposium on Organometallic Chemistry Directed Towards Organic Synthesis (OMCOS 14), August 2-6, 2007, Nara, Japan-OPA3/P101.

4. Bădoiu, A.; Brinkmann, Y.; Viton, F.; Kündig, E. P. “Asymmetric Lewis Acid- catalyzed 1,3-Dipolar Cycloadditions” – oral presentation, CUSO Summer School

“Target Synthesis: Challenges, Strategies and Methods, September 2-6, 2007, Villars, Switzerland.

5. Bădoiu, A.; Brinkmann, Y.; Viton, F.; Kündig, E. P. “Asymmetric Lewis Acid- catalyzed 1,3-Dipolar Cycloadditions” – oral presentation, Swiss Chemical Society Fall Meeting, September 12, 2007, Lausanne, Switzerland, Organic Chemistry-227.

6. Bădoiu, A.; Brinkmann, Y.; Viton, F.; Kündig, E. P. “Asymmetric Lewis Acid- catalyzed 1,3-Dipolar Cycloadditions” – oral presentation, Oppolzer Lectures – University of Geneva, September 14, 2007, Geneva, Switzerland.

7. Bădoiu, A.; Viton, F.; Kündig, E. P. “A versatile Ruthenium catalyst: from cycloadditions to Michael additions” – winning oral presentation – 7^th Swiss Snow Symposium, February 6-8, 2009, Lenk in Simmental, Switzerland.

1 Introduction...- 1 -

1.1 General introduction ...- 1 -

1.1.1 Chirality ...- 2 -

1.1.2 Asymmetric synthesis ...- 4 -

1.1.3 Catalyst and catalysis ...- 5 -

1.1.4 Modern applications of asymmetric catalysis...- 6 -

1.1.5 Lewis acids in catalysis...- 8 -

1.2 Half-sandwich Lewis acids ...- 9 -

1.2.1 Development of new C₂-symmetrical diphosphinite ligands...- 9 -

1.2.2 Synthesis of the complexes and the first applications to catalysis...- 9 -

1.2.3 Rationalization of observed selectivity...- 12 -

1.2.4 Extension of the applications to 1,3-dipolar cycloaddition reactions ...- 16 -

1.2.5 Alternative ligands and synthesis of the ruthenium complexes...- 17 -

1.2.6 DA reactions of ketones with enones and 1,3-DC reactions of nitrile oxides with enals...- 19 -

1.2.7 Aim of the project and current state of work ...- 20 -

1.3 References...- 22 -

2 Ligand and pre-catalyst synthesis ... 28

2.1 Introduction... 28

2.2 Ligand synthesis... 28

2.3 Synthesis of the ruthenium pre-catalysts and an improved complex recovery. 29 2.4 The alternative route for the synthesis of the ruthenium pre-catalysts ... 30

2.5 An alternative route for the synthesis of the Ru pre-catalysts ... 30

2.6 References... 33

3 1,3-Dipolar cycloaddition reactions... 35

3.1 Introduction... 35

3.1.1 General aspects ... 35

3.1.2 Mechanistic aspects ... 37

3.1.3 Selectivity in the 1,3-dipolar cycloaddition reaction ... 43 3.1.4 Asymmetric catalytic 1,3-dipolar cycloaddition reactions with nitrones . 46

3.1.5 Recent advances in the asymmetric catalyzed 1,3-DCs of nitrones with

enals………...48

3.2 Nitrones... 58

3.2.1 General aspects ... 58

3.2.2 Synthesis of the nitrones used... 59

3.3 1,3-Dipolar cycloadditions of diarylnitrones with enals... 62

3.3.1 Non-catalyzed 1,3-DC reactions of methacrolein with diphenylnitrone .. 62

3.3.2 Determination of the enantiomeric excess ... 63

3.3.3 Ru-catalyzed asymmetric 1,3-DC reactions of methacrolein with diphenylnitrone ... 63

3.3.4 Non-catalyzed 1,3-DC reactions of methacrolein with various diarylnitrones ... 64

3.3.5 Temperature studies for the non-catalyzed 1,3-DC reaction of methacrolein with various diarylnitrones... 65

3.3.6 NMR analysis of the Ru-catalyzed 1,3-DC reaction of methacrolein with diphenylnitrone ... 67

3.3.7 Study of the counterion effect on the Ru-catalyzed 1,3-DC reaction of methacrolein with diphenylnitrone ... 69

3.3.8 Rationalization of observed selectivity and determination of the absolute configuration of the products ... 70

3.3.9 Ru-catalyzed asymmetric 1,3-DC reactions of methacrolein with diarylnitrones ... 74

3.3.10 Hammett plots... 76

3.3.11 Computational Methods... 79

3.3.12 Modeling ... 80

3.3.13 Opening of the isoxazolidine core ... 83

3.3.14 N-PMP, α-aryl nitrones ... 85

3.3.15 Asymmetric Ru-catalyzed 1,3-DC of morphanthridine N-oxide with methacrolein... 88

3.4 1,3-Dipolar cycloadditions of N-“alkyl” nitrones with enals... 91

3.4.1 Introduction... 91

3.4.2 Non-catalyzed 1,3-DC reactions of N-“alkyl” nitrones with enals... 92

3.4.3 Ru-catalyzed 1,3-DC reactions of N-“alkyl” nitrones with enals ... 103

3.5 Conclusions... 115

3.6 References... 116

4 Michael addition of soft nuleophiles to enals and enones... 128

4.1 Asymmetric Ru-catalyzed Michael addition of thiols to enals and enones .... 128

4.1.1 Introduction... 128

4.1.2 Preliminary results: Ru-catalyzed SMA-asymmetric protonation of thiophenol with methacrolein ... 133

4.1.3 Non-catalyzed SMA of thiols with enones ... 134

4.1.4 Preliminary results of the Ru-catalyzed asymmetric SMA of thiophenol to enones………..134

4.1.5 Optimization of the Ru-catalyzed asymmetric SMA of thiophenol to 2- cyclohexen-1-one ... 135

4.1.6 Thiols screening for the Ru-catalyzed asymmetric SMA to 2-cyclohexen- 1-one………138

4.1.7 Re-optimization and scale-up of the Ru-catalyzed asymmetric SMA of 2,6-DMTP to 2-cyclohexen-1-one ... 140

4.1.8 Substrate scope in the Ru-catalyzed asymmetric SMA of 2,6-DMTP to enones………..142

4.1.9 Investigation of the mechanism for the Ru-catalyzed asymmetric SMA of thiols to enals ... 145

4.1.10 Rationalization of the observed selectivity in the Ru-catalyzed asymmetric SMA of thiols to enones ... 151

4.2 Anthrone: [4+2] cycloaddition versus 1,4-addition ... 155

4.2.1 Introduction... 155

4.2.2 Preliminary results in the Ru-catalyzed asymmetric 1,4-addition of anthrone to enals and enones ... 157

4.3 Conclusions... 160

4.4 References... 161

5 Experimental section ... 166

5.1 Generalities ... 166

5.2 1,3-DC of nitrones with enals ... 168

5.2.1 Diarylnitrones ... 168

5.2.2 Non-catalyzed 1,3-DCs of diarylnitrones with methacrolein ... 169

5.2.3 Reduction of the products from the non-catalyzed 1,3-DCs of diarylnitrones with methacrolein ... 175

5.2.4 Ru-catalyzed 1,3-DCs of diarylnitrones with methacrolein ... 182

5.2.5 Reduction of the products from the Ru-catalyzed 1,3-DCs of diarylnitrones with methacrolein ... 189

5.2.6 Oxidative deprotection of PMP with CAN... 197

5.2.7 Ester derivatization in view of assignment of the absolute configuration by X-ray analysis ... 198

5.2.8 Reductive amination-salt formation in view of assignment of the absolute configuration by X-ray analysis... 199

5.2.9 Ring opening of the isoxazolidine ring with TMSI ... 202

5.2.10 ¹H NMR study of the 1,3-DC of diphenyl nitrone with methacrolein at variable temperatures ... 203

5.2.11 ¹H NMR study of the 1,3-DC of N-phenyl, α-p-NO2-phenyl nitrone with methacrolein at variable temperatures ... 203

5.2.12 ¹H NMR study of the 1,3-DC of N-phenyl, α-p-OMe-phenyl nitrone with methacrolein at variable temperatures ... 204

5.2.13 ¹H NMR study of the 1,3-DC of diphenyl nitrone with methacrolein at ^_10 °C……….204

5.2.14 New method for the pre-catalyst recovery... 204

5.2.15 Ru-catalyzed asymmetric 1,3-DC of methacrolein with in situ-generated morphanthridine oxide¹²... 205

5.2.16 N-“alkyl”, α-aryl nitrones ... 207

5.2.17 Non-catalyzed 1,3-DCs of N-“alkyl” nitrones with methacrolein ... 209

5.2.18 Reduction of the products from the Ru-catalyzed 1,3-DCs of N-“alkyl” nitrones with methacrolein... 220

5.2.19 Ru-catalyzed 1,3-dipolar cycloaddition reaction between nitrones and

methacrolein... 228

5.2.20 Reduction of the products from the Ru-catalyzed 1,3-DCs of N-“alkyl” nitrones with methacrolein... 235

5.3 1,4-Additions of aryl thiols to enones... 244

5.3.1 Non-catalyzed 1,4-additions of aryl thiols to enones... 244

5.3.2 Ru-catalyzed 1,4-additions of aryl thiols to enones... 252

5.3.3 NMR studies of the mechanism of the Ru-catalyzed SMA of aryl thiols to enones………..261

5.4 Crystallographic data ... 262

5.5 References... 274

- 1 -

1 Introduction

1.1 General introduction

We live in an asymmetric world. Whether we consider the passage of time, spatial relationships, geometric or functional transformations, the aspects relating to abstract objects, theoretical models, language, arts, or even knowledge, in all cases we face asymmetry. One can argue that the Big Bang itself was not symmetric. Asymmetry is part of all that we are, all that we know and do (Figure 1.1-1). In fact, in absolute terms, for us symmetry does not exist.

Figure 1.1-1 Asymmetry.

In order to control asymmetry, we devised reference frames and systems, theories and rules, units and scales. Being inherent to all things, asymmetry defined, defines and will define life as we know it.

- 2 - 1.1.1 Chirality

More specifically, in chemistry, asymmetry can be understood and quantified by means of stereochemistry (from the Greek stereos, meaning “solid”), the study of the chemistry in three dimensions (3D). In stereochemistry terms, any object or molecule which has no improper axis of symmetry is defined as chiral.¹

Chirality as a concept was discovered in the second half of the 19^th century, but it took scientists more than one hundred years to take it in common use. The term itself (derived from the Greek kheir, meaning “hand”), was first introduced by Lord Kelvin in 1904: "I call any geometrical figure, or group of points, chiral, and say it has chirality, if its image in a plane mirror, ideally realized, cannot be brought to coincide with itself"

(Figure 1.1-2).²

Figure 1.1-2 Chirality illustrated with the hands.

In 1812, the French physicist Biot passed a beam of planar polarized light through a quartz plate cut at right angles to its crystal axis, discovering the phenomenon of optical rotation.³ Years later (in 1848), during his study of the crystallization of sodium ammonium tartrate in special conditions, the French chemist Louis Pasteur noticed that two types of crystals were formed and that they were non-superimposable mirror images (hemihedric crystals, like in quartz). Careful separation of these crystals and determination of the optical rotation of solutions of each of the two types of crystals revealed that the phenomenon of optical rotation also occurs in solution. He correlated these aspects into the concept that the crystals of (+)- and (-)-tartaric acid were enantiomorphous and that the molecules are enantiomers, mirror image of one another,

- 3 -

non-superposable objects, “forms that resemble one another as would left- and right- hand gloves”.⁴

Rapid advances were made in the field of structural chemistry through the work of Kekule,⁵ who introduced the concept of the tetrahedral carbon atom. Shortly after, van’t Hoff⁶ and Le Biel⁷ simultaneously proposed the Cabcd tetrahedral model as the structural basis for enantiomerism (Figure 1.1-3). Considering a tetrahedron with a, b, c, and d as atoms situated in the corners and a central C atom, two nonsuperposable arrangements (enantiomers) are possible.

Figure 1.1-3 The Cabcd model for the tetrahedral carbon.

Along with the progresses accomplished in structural determination and compound characterization, chemists came to the understanding that the basic building blocks of biologically active molecules (e.g. sugars, amino acids, some terpenes) are usually found in nature as a single enantiomer. Moreover, the stereogenic information of these simple compounds was found to profoundly influence the structure and function of higher order systems (e. g. carbohydrates, proteins, nucleic acids, lipids).

From a practical point of view, chirality gained paramount importance within the fast developing pharmaceutical industry. With the establishment of large pharmaceutical companies, first in Europe and then in the U.S., assiduous research and development led to an increase of the complexity of the products. It soon became clear that the different enantiomers of a given product may produce different pharmacodynamic and pharmacokinetic activities (negative in some cases, Figure 1.1-4).⁸

- 4 -

Figure 1.1-4 Physiological effects of the two enantiomers of selected drugs.

Increasing mass production and global distribution, and the constantly growing demand for non-racemic compounds, be it drugs, agrochemicals, or flavours and fragrances led to an increasing effort devoted to developing new routes for the synthesis of such compounds in non-racemic form.

1.1.2 Asymmetric synthesis

Defined by Marckwald in 1904, the asymmetric synthesis is the chemical transformation through which new stereogenic centers are generated in a controlled manner.⁹ A definition which is valid still today, it reflects the maturity reached by the field of synthetic organic chemistry at the beginning of the 20^th century.

For many years the only viable option for non-racemic synthesis was the chemical manipulation of the building blocks provided by the natural chiral pool. This route, while cheap and straightforward, most of the time involved long synthetic sequences with rather low overall yields. As an alternative to the above, racemic synthesis followed by separation (usually by crystallization) of enantiomers was also successfully used, but the maximum theoretical yield was limited to 50 % (unless a racemisation step can be adapted to the synthesis as in the dynamic resolution processes). Yet another strategy used in asymmetric synthesis is the use of chiral auxiliaries. Easily introduced (and

- 5 -

removed) in key positions of the substrate and accessible from the chiral pool, chiral auxiliaries are enantiopure fragments that due to their structure convey intrinsic chirality, in a controlled manner, during a given transformation. Despite some success in asymmetric synthesis, this strategy has some disadvantages, namely the additional steps involved and the use of stoechiometric auxiliary.

1.1.3 Catalyst and catalysis

This name of Greek origin (from catalysis – to annul, to untie, to dissolve) was given by Berzelius in 1835 to a compound that facilitates the advancement of a chemical reaction.¹⁰ It took a century before the French chemist Paul Sabatier crystallized the actual sense of the term catalyst: a compound that is able to accelerate a given chemical reaction without being a starting material or a product and which is regenerated at the end of the reaction.¹¹ The catalyst accelerates a transformation by introducing new reaction pathways and lowering the activation energy of the rate determining step. The modern understanding of the term was extended to include the activation of a given reaction (that will not work without catalyst) or to selectivity issues.

The industrial revolution evolved the theoretical concept to mass practical applications in industry. During the coal-based chemistry era (before the Second World War), catalyst development has known a slow but steady increase. It was however with the advent of the petrochemical industry (natural gas- and oil-based feedstock) boom in the 50’s that the importance of catalysis was recognized. Initially applied only to selective oxidation, hydroformylation and polymerization reactions, catalysts began to gain in complexity and versatility.

Catalysts can be divided into heterogeneous and homogeneous, based on their solubility in the reaction mixture. For industrial processes, the catalysts used are by and large heterogeneous (mainly due to ease of catalyst recycling and immobilization which open the potential for continuous processing with molecularly defined catalysts).

Nonetheless, the last decades have known a steady increase in the use of homogeneous catalysts.

- 6 -

1.1.4 Modern applications of asymmetric catalysis

Based on the existing knowledge and knowhow on catalysis, the most powerful method to generate enantioenriched building blocks for the chemical synthesis (except nature, e. g. biocatalysis) was born in the form of asymmetric catalysis. This field has known an impressive progress and today still continues to fascinate and inspire the scientific community, as innumerable variations of metal- or organocatalysts are known for every reaction one could imagine, a result of the unleashed curiosity of academia and the needs of chemical industry.¹² With a striking increase of chiral drugs being approved from 58 % in 1992 to 75 % in 2006, the commercial application of asymmetric catalysis has never been more important.¹³

Among the first catalysts used for asymmetric reactions were organic molecules, hence the name organocatalysts. In 1912 Bredig and coworkers noticed that cinchona alkaloids can efficiently catalyze the addition of HCN to benzaldehyde and that the product is optically active.¹⁴ Except for some scarce examples, the field did not know important developments until the proline-catalyzed reaction developed in the 70’s (also named the Hajos-Parrish-Eder-Sauer-Weichert reaction).¹⁵ Since (and especially in the last decade), the field of organocatalysis evolved exceptionally.¹⁶

In parallel, impressive advances were accomplished in the field of organometallic chemistry and it did not take long before appropriate enantiopure ligands derived from natural products were attached to metal fragments. Countless combinations of ligands and metals can be rationally designed such that the desired activity and selectivities for a given transformation are achieved.

Tremendous advances have been made in this field since the Cu-catalyzed asymmetric cyclopropanation reported by Nozaki and Noyori in the 60’s.¹⁷ Witness to these achievements stands the Nobel Prize in chemistry awarded in 2001 to Knowles and Noyori for the catalytic asymmetric hydrogenation reactions (Figure 1.1-5)¹⁸ and to Sharpless for the catalytic asymmetric oxidation reactions.¹⁹

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Figure 1.1-5 Illustration of the asymmetric catalytic hydrogenation reaction.

Amongst the various applications of asymmetric catalysis to organic synthesis, several examples have attracted the interest of the chemical industry.²⁰ Among the finest achievements in this field are the iridium catalyzed asymmetric hydrogenation developed by Novartis²¹ and the Takasago enantioselective rhodium catalyzed allylic amine isomerisation (Scheme 1.1-1).²²

Scheme 1.1-1 Selected examples of industrial processes using asymmetric catalytic reactions as the key steps.

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While the asymmetric catalytic hydrogenation and oxidation reactions are by far the best developed and applied for industrial applications, recent trends show a marked increase in the medium-scale applications of a variety of asymmetric catalytic processes in view of building block synthesis.

1.1.5 Lewis acids in catalysis

Defined in 1923 by Gilbert Newton Lewis as compounds that can accept a pair of electrons,²³ the Lewis acids can activate numerous chemical reactions, usually in a catalytic fashion.²⁴ Most of the metals known can act as Lewis acidic centers in reagents used for the organic synthesis.

Modification of the classic Lewis acids commonly used in synthesis (e. g. AlCl₃, BF₃·OEt₂, SnCl₄, TiCl₄) by introduction of enantiopure ligands at the metal center allowed for development of Lewis acidic-catalysts for asymmetric transformations. In depth studies of the various combinations of metals and ligands coupled with rational structural designed led to the identification of extremely active and selective catalysts.

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1.2 Half-sandwich Lewis acids

1.2.1 Development of new C2-symmetrical diphosphinite ligands

The project of synthesis and applications of half-sandwich transition metal-based Lewis acid complexes (as catalysts for asymmetric processes), now ten years old, has evolved to be a well-established and prolific subject in the chemistry of the Kündig group.

The origin of this project, even before the Fe and Ru complexes came into play, lies deep within the groups’ traditional field of research, namely the chemistry of the chromium arene half-sandwich complexes.²⁵

While working on the synthesis of cyclic non-racemic diols in the early 90’s, the group developed a new class of C2-symmetrical diphosphinite ligands bearing a variety of substituents on the phosphorus atoms.²⁶ Among these ligands, the ones bearing electron- poor substituents at the phosphorus proved to be the most interesting due to their electronic properties.

The initial hypothesis was that the replacement of two cis-CO ligands (in a transition metal complex) by a bidentate chiral ligand with similar bonding characteristics would lead to new asymmetric catalysts. Finding the right combination of chiral backbone and substitution in order to emulate the electronic properties of the CO ligand is a difficult task, as attested by the number of such ligands reported so far.²⁷ While the CF3-substituted ligands were the closest electronically to PF3 and CO, the ligand bearing perfluorophenyl moieties turned out to be both electron poor and bulky enough to convey stereogenic information to the metal environment.

1.2.2 Synthesis of the complexes and the first applications to catalysis

Hersh et al. previously showed that the monocationic complex [FeCp(CO)₂(THF)][BF₄] is an efficient catalyst for the Diels-Alder (DA) reaction between acrolein and cyclopentadiene.²⁸ Hossain et al. found that substitution of one of the CO ligands with PPh₃ completely suppressed the activity of the complex while

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introducing a less electron-rich P(OMe)3 ligand allowed for conservation of activity.²⁹ With the chiral electron-poor diphosphinite ligands already in hand, the Kündig group prepared the [FeCp(L)Me] complex (2) by photolysis of the [FeCp(CO)₂Me] complex (1) followed by treatment with HBF₄ at ^_78 ^oC and addition of acrolein to give the corresponding acrolein complex 3 in high yield (Scheme 1.2-1).

* [FeCp(CO)₂]₂ OC Fe

OC

Me (C₆F₅)₂P Fe P(C₆F₅)₂ O Me

79 % 65 % O

93 % 1. K, THF

sonication 2. MeI

(R,R)-BIPHOP-F hv, toluene

1. HBF₄·OEt₂ CH₂Cl₂, - 78^oC 2. acrolein

- 78 to - 20^oC

BF₄

(C₆F₅)₂P Fe

P(C₆F₅)₂ O O

O

H

* 1

3 2

Scheme 1.2-1 Synthetic route towards iron pre-catalysts 3.

Using complex (R,R)-3 as pre-catalyst for the DA reaction of α,β-unsaturated aldehydes with various dienes led to the expected adducts in good yields and excellent selectivities (Table 1.2-1).³⁰,^26c Despite the limitations due to the thermal (stable below

_20 ^oC in solution) and acid sensitivity of the complexes, the results represent one of the finest achievements in the field.³¹

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Table 1.2-1 Fe-catalyzed asymmetric Diels-Alder reactions.³⁰

These first results prompted a more systematic study. Modifications of the Cp roof and variation of the chiral diol backbone of the diphosphinite ligand were envisaged in order to modify the steric and electronic environment around the metal. Changing the backbone from a cyclic diol (CYCLOP-F) to an acyclic one established another milestone in the project (Figure 1.2-1).³²

Figure 1.2-1 The new generation of C2-chiral diphosphinite ligands.

BIPHOP-F turned out to be easier to synthesize than CYCLOP-F. Equally good results for the DA reactions could be obtained when using as catalysts the complexes

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incorporating this ligand.³³ Even today, BIPHOP-F remains the ligand of choice for a range of applications.³⁴

Starting from crystallographic data of some of the complexes synthesized, theoretical studies and computational modeling have brought important insights into catalyst-enal interactions and diene approach in DA cycloaddition reactions, taking another step forward in the rationalization of observed selectivity.³⁵

1.2.3 The Ru complexes, models and rationalization of observed selectivity

The synthesis, characterization and application of a series of Ru complexes, analogous in structure to the Fe complexes as catalysts for the DA reactions have had a major influence on the future development of the project.³⁶ These pre-catalysts proved to be less active than their Fe analogues, but compensated through thermal stability, minor water and air sensitivity, easy recovery, as well as accessible and fast ligand / counterion

“tuning”. The development of a one-pot method allowed for an efficient pre-catalyst synthesis that can be easily scaled up (up to 5g, Scheme 1.2-2).³⁷

Scheme 1.2-2 One-pot synthesis of ruthenium pre-catalyst5.^36,37

Simple counterion metathesis allowed for the synthesis of a variety of complexes that have been tested in the benchmark DA reaction of methacrolein with cyclopentadiene.³⁸ This study showed the important contributions of the structure and properties of the counterions on the reaction rate, leading to a comprehensive comparison of the Ru and Fe pre-catalysts.^39,40

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Based on the X-ray structures of several complexes, simple, non-optimized models (cartoons) could be created computationally in order to visualize the chiral pocket surrounding the Lewis acidic metal center (Figure 1.2-2).

Figure 1.2-2 X-ray-based front and back views of the [Ru(R,R-BIPHOP-F)Cp]⁺ fragment.

The space-filling model above, based on the X-ray structure of complex 5, shows the pocket formed by the cyclopentadienyl roof (covering the top part of the complex) and the ligand (wrapping around the metal to shield the back, lateral sides, and most of the bottom part, Figure 1.2-2).

Thus, starting from the X-ray structures of complexes and creating a Connolly molecular surface (ChemBio 3D, 1.1 Å, 100 % resolution, color coded for atoms) only for the [RuCp(L)]⁺ fragment, a 3D rendering of the steric environment around the metal center could help understand how the monodentate ligands (be it water, acetone, or, most importantly, an enal) coordinate the metal (Figure 1.2-3).

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Figure 1.2-3 X-ray-based side views of the [Ru(R,R-BIPHOP-F)Cp(methacrolein)]⁺ fragment.

The space around the metal, named “chiral pocket”, is not symmetrical when viewed from either of the lateral sides (Figure 1.2-3). This occurs due to the chiral backbone of the ligand. With an α,β-unsaturated carbonyl compound coordinated at the Lewis acidic metal center, one of the faces of the C-C double bond of the enal (in this case the Cα-Si face) is shielded by one of the perfluophenyl groups of the ligand, so that the approach of the diene or dipole occurs from the opposite (the Cα-Re) face. These simple models have been used extensively for the rationalization of selectivity and understanding of the approach of the reactive species for the various transformations the iron and ruthenium complexes were used as catalysts.

Based on the models above it was hypothesized that the TOF of the catalyst could be increased by enlarging the roof ligand. Consequently, a complex bearing the indenyl fragment (8) as roof was synthesized. The sequence of reactions makes use of the greater

labilization of CO-ligands by the indenyl moiety when compared to Cp complexes (Scheme 1.2-3

Scheme 1.2-3).

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Scheme 1.2-3 Synthetic route towards the ruthenium indenyl pre-catalyst 8.^36,41

Application of pre-catalyst 8 in the standard benchmark reactions showed that the initial assumption was correct as higher TOF numbers were observed compared to the Cp complexes. In the indenyl complexes the roof ligand occupies the space where the counterion was placed in the Cp analogues. In addition to an increased reactivity, the indenyl complexes showed perfect exo selectivity, another contribution from the bulkier roof which is able to control the approach of the diene onto the coordinated enal.⁴¹

Analysis of the [Ru(acetone)(BIPHOP-F)Ind][SbF₆] complex (8) revealed an unusual fluxional behavior of the 7-member metallacycle formed by the central metal and the diphosphinite ligand. Interestingly, this phenomenon was found to be present also in the Cp analogues bearing the newly introduced BINOP-F ligands (BINOL-derived diphosphinite ligand).⁴¹ Notwithstanding the fluxional nature of the complexes, the C₂- symmetrical backbone of the diphosphinite ligand renders the chiral pocket identical before and after the motion. As a consequence, when used as pre-catalysts for the DA reactions, these complexes allowed for excellent activity and selectivity.

Concomitant with our work in this area, a number of other half-sandwich Lewis acid complexes were used successfully in [4+2] cycloaddition reactions. They are dicationic complexes of ruthenium,⁴² osmium,⁴³ rhodium⁴⁴ and iridium⁴⁵ and incorporate non-C₂-symmetric bidentate phosphorus and/or nitrogen ligands.

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1.2.4 Extension of the applications to 1,3-dipolar cycloaddition reactions

Having studied the DA reactions well in depth, it was time to put the pre-catalysts to the test for new transformations. It was soon found that cyclic nitrones, very active dipoles, can successfully undergo 1,3-dipolar cycloadditions (1,3-DCs) to enals to give the expected isoxazolidines with high yields, diastereo-, and enantioselectivity (Table 1.2-2).^46,39 This was the first example of a one-point binding metal-catalyzed asymmetric 1,3-DC of nitrones with enals.

Table 1.2-2 Fe-catalyzed asymmetric 1,3-DC of cyclic nitrones with enals.⁴⁶

Selectivity can be rationalized by cartoons (models) based on X-ray structures of the methacrolein complex 3 (Figure 1.2-4). This confirms that selectivity can be controlled entirely by the catalyst despite the various inherent problems with using these reactive dipoles, such as competitive catalyst-nitrone coordination, dimerization of the nitrones, or the fast background reaction.

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Figure 1.2-4 Rationalization of diastereo- and enantio-selectivity by means of an X-ray- based model of complex 3.⁴⁷

In the case of diarylnitrones, it was observed that by changing the electronic properties of the substituents on the α-aryl group of the nitrone, the regioisomeric ratio of the two possible products changes significantly. This was further developed in the framework of this thesis (see chapter 3.3, page 62).

1.2.5 Alternative ligands and alternative synthesis of the ruthenium complexes A systematic study of the ligand backbone involving both steric and electronic modifications, as well as synthesis of non-C₂-symmetrical ligands, with different substituents at the two phosphorus atoms was conducted.⁴⁸

Breaking the symmetry of the diphosphinite ligand not only drastically changed the shape of the chiral pocket but also modified the electronic properties of the metal.

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Moreover, by making use of a chiral counterion (TRISPHAT)⁴⁹ the diastereomeric salts formed could be separated and their association constants studied to show an important match-mismatch effect.

When synthesizing the neutral Ru-I intermediates containing the ligands described above, it was found in some instances that yields were much lower than usual. This was attributed to either steric or electronic constraints preventing the ligand to bind effectively to the ruthenium center. In order to circumvent this problem, an alternative route was developed relying on protocols developed within the Kündig group (Scheme 1.2-4).⁵⁰,⁵¹

Scheme 1.2-4 Alternative synthetic sequence for the pre-catalyst intermediate 4.

Modular and milder, this route involves ligand exchange in complex 13 to give the desired complexes in good yields. An important feature of this synthesis is that counterion metathesis can be easily achieved during the workup for the synthesis of the [RuCp(CH3CN)3][PF6] complex (11), while ligand incorporation is carried out at a late stage in the synthesis.

As in the case of the study of the ligands, there were many separate observations concerning the effect of the counterions on the reactivity and selectivity, but no thorough investigation. Making use of extensive NMR diffusion techniques, the interactions between the counterions with the monocationic metal center, the diphosphinite ligand and the substrates were examined in detail. The nature of the ion pairs determines the average

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distance and position of the counterion with respect to the Lewis acidic metal, and thus to the chiral pocket. Ion pairing was shown to vary significantly with solvent and to have a marked effect on both kinetics of the DA reactions (as shown before^37,38,41) and on the selectivity since the counter ion can also interact with the substrates.⁵²

1.2.6 DA reactions of ketones with enones and 1,3-DC reactions of nitrile oxides with enals

The substrate scope of the asymmetric catalytic DA reactions was more recently extended to the first examples using α,β-unsaturated ketones as dienophiles.⁵³ The organocatalytic variant of this transformation was published earlier by MacMillan et al.⁵⁴ The results are even more remarkable as it is a well known fact that keto- dienophiles are less active reaction partners in the DA reaction than their aldehyde analogues. Moreover, Lewis acids bind enals selectively in an anti-s-trans conformation;

in the case of the enones, the two possible coordination orientations become very similar both sterically and electronically. Thus, in the case of enones, stereocontrol and Lewis acid activation is much harder to achieve.

Despite the limitations outlined above, a variety of enones can be used with both acyclic and cyclic dienes to provide the expected adducts in good yields and with selectivities from good to excellent.⁵³ Since the intermolecular reactions led to good results, this was also extended to the intramolecular version in view of the synthesis of advanced intermediates for the synthesis of natural products.⁵⁵ An extension of the examplesof enal- and enone-based trienes and the completion of the synthesis for several natural products are currently under investigation.⁵⁶

With the experience gained by using very reactive cyclic nitrones as dipoles for asymmetric 1,3-DC reactions,⁴⁶ an extension to other dipoles was envisaged. Nitrile oxides, easily accessible substrates, were already used in asymmetric catalytic reactions.⁵⁷

However, these very active dipoles tend to dimerize rapidly and are more susceptible to bind irreversibly the monocationic metal center of the catalyst. Despite the limitations mentioned and the formation of double addition products, in the presence of the Ru complex 5 and with slow addition of a solution containing the aromatic nitrile

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oxides, the expected isoxazolines could be obtained in moderate to good yields and enantioselectivities up to 93 % (Scheme 1.2-5). This was the first reported example of asymmetric catalytic 1,3-DC reactions of nitrile oxides with enals.³⁴

Scheme 1.2-5 Ruthenium-catalyzed asymmetric 1,3-DC reactions of aryl nitrile oxides with methacrolein.³⁴

Worth mentioning are the efforts directed towards the synthesis of dicationic arene ruthenium complexes as more powerful Lewis acid catalysts.⁵⁸ Unfortunately, these complexes proved not only difficult to synthesize and characterize, but also too active and sensitive for use in catalysis.

Work being developed at present on the asymmetric IMDA and its extension to synthesis of natural products,⁵⁶ application of the Ru-complexes as catalysts for the Mukaiyama-Michael reactions and Friedel-Crafts alkylations as well as study of the conformation of enals and enones in the chiral pocket⁵⁹ will further expand this research field.

1.2.7 Aim of the project and current state of work

Backed by the understanding of the catalytic system and with a robust, active, selective and recyclable complex as pre-catalyst, it is the moment to seek the boundaries in terms of stability and activity in search of new applications.

The aim of the project as initially proposed was to reproduce and optimize the initial results on the asymmetric catalyzed 1,3-DC of diaryl nitrones with methacrolein³⁹ as well as providing a valid theoretical interpretation of the observed selectivity. In addition, an extension to other substrates, namely nitrones bearing cleavable groups at the nitrogen atom, was also envisaged. The results were recently published⁴⁷ and are amply

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discussed in the following chapters. An overview of the results obtained with complex 5 as pre-catalyst for the asymmetric 1,3-DC of methacrolein with nitrile oxides and cyclic and acyclic nitrones was also recently published.⁶⁰

In addition to the project above, a more general aim was to apply the ruthenium pre-catalysts to new transformations, expanding the range of applications that these complexes can catalyze. As the following chapters will show, careful investigation of the results obtained in the past provided the key to novel findings, revealing unexpected levels of reactivity and stability for the versatile half-sandwich chiral Lewis acids developed in the Kündig group.

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1.3 References

1 (a) Basic organic stereochemistry; Eliel, L. E.; Wilen, S. H.; Doyle, M. P.; Wiley- Interscience, 2001; (b) Stereochemistry of organic compounds; Eliel, L. E.; Wilen, S. H.; Mander, L. N.; Wiley: New York, 1994; (c) Stereochemistry of carbon compounds; Eliel, L. E.; McGraw-Hill: New York, 1962.

2 For the first communication see: Kevin, Lord; The Second Robert Boyle Lecture in J. Oxford Univ. Junior Scientific Club 1894, 18, 25.

3 Biot, J. B. Mem. Cl. Sci. Math. Phys. Inst. Imp. Fr. 1812, 13, 1.

4 Pasteur, L.; lectures given at the Societe Chimique de Paris, on the 20^th of Jan. and 3^rd of Feb., 1860.

5 Kekule, A. Ann. 1858, 154.

6 van’t Hoff, J. H. Bull. Soc. Chem. Fr. 1875, 295.

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9 Marckwald, W. Ber. Dtsch. Chem. Ger. 1904, 37, 349 and 1368.

10 Roberts, M.W. Catalysis Lett. 2000, 67, 1.

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Eng. Chem. 1926, 18, 1005.

12 (a) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis, Springer-Verlag: Heidelberg, 1999; b) Ojima, I. Catalytic Asymmetric Synthesis, John Wiley & Sons: New York, 2000; c) Heitbaum, M.; Glorius, F.;

Escher, I. Angew. Chem. Int. Ed. 2006, 45, 4732.

13 a) Blaser, H. U.; Schmidt, E. Asymmetric Catalysis on Industrial Scale, Wiley- VCH: Weinheim, 2004; b) Johnson, N. B.; Lennon, I. C.; Moran, P. H.; Ramsden, J. A. Acc. Chem. Res. 2007, 40, 1291.

14 (a) Bredig Ber. 1908, 41, 752; (b) Bredig Biochem. Zeit. 1913, 46, 7.

15 (a) Eder Angew. Chem. Int. Ed. Engl. 1971, 10, 496; (b) Hajos J. Org. Chem. 1974, 39, 1615.

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16 For recent reviews on organocatalysis see: (a) Shi, Y. Acc. Chem. Res. 2004, 37, 488; (b) Chem. Rev. 2007, 107 (all papers in the issue 12); (c) Enantioselective Organocatalysis, Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2007.

17 (a) Nosaki, H.; Takaya, H.; Moriuti, S.; Noyori, R. Tetrahedron 1968, 24, 3655; (b) Nosaki, H.; Moriuti, S.; Takaya, H.; Noyori, R. Tetrahedron Lett. 1966, 22, 5239.

18 (a) Knowles, W. S. Angew. Chem. Int. Ed. 2002, 41, 1998; (b) Noyori, R. Angew.

Chem. Int. Ed. 2002, 41, 2008.

19 Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2024.

20 (a) Blaser, H. U.; Studer, M. Chirality 1999, 11, 459; (b) Blaser, H. U. Chem.

Commun. 2003, 293.

21 (a) Spindler, F.; Pugin, B.; Ciba-Geigy A.-G., Switzerland Pat. 87-810435256982, 1988; (b) Spindler, F.; Pugin, B.; Jalett, H.-P.; Buser, H.-P.; Pittelkow, U.; Blaser, H.-U. Chemical Industries (Dekker) 1996, 68, 153.

22 (a) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345 ; (b) Noyori, R. Science 1990, 248, 1194.

23 Lewis, G. N. in Valence and the Structure of Atoms and Molecules; Chemical Catalog Company, Inc.: New York, 1923.

24 (a) Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-VCH: Weinheim, 2000; (b) Lewis Acid Reagents; Ymamoto, H., Ed.; Oxford University Press, 1999;

(c) Santelli, M.; Pons, J.-M. in Lewis Acids and Selectivity in Organic Synthesis;

CRC Press: Boca Raton, 1996.

25 (a) Kündig, E. P.; Timms, P. L. J. Chem. Soc., Chem. Commun. 1977, 912; (b) Kündig, E. P. Pure Appl. Chem. 1985, 57, 1855; (c) Kündig, E. P.; Uemura, M.

Kagakudojin 1985, 105, 175; (d) Kündig, E. P.; Do Thi, N. P.; Paglia, P.;

Simmons, D. P.; Spichiger, S.; Wenger, E. In Organometallics in Organic Synthesis; de Meijere, A.; tom Dieck, H. E.; Eds.; Springer Verlag: Berlin, 1987, p. 265; (e) Pape, A. R.; Kaliappan, K. P.; Kündig, E. P. Chem. Rev. 2000, 100, 2917; (f) Kündig, E. P.; Pache, S. H. In Science of Synthesis, Imamoto, T.; Ed.;

Thieme: Stuttgart/New York, 2008, Vol. 2, p. 155; (g) Topics in Organometallic Chemistry, Kündig, E. P.; Ed.; Springer: Berlin, 2004, Vol. 7.

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26 (a) Cunningham, A. F.; Kündig, E. P. J. Org. Chem. 1988, 53, 1823; (b) Kündig, E.

P.; Dupre, C.; Bourdin, B.; Cunningham, A. F.; Pons, D. Helv. Chim. Acta. 1994, 77, 421; (c) Kündig, E. P.; Quattropani, A.; Inage, M.; Ripa, A.; Dupre, C.;

Cunningham, A. F.; Bourdin, B. Pure Appl. Chem. 1996, 68, 97.

27 Kündig, E. P.; Badoiu, A. In Phosphorus Ligands in Asymmetric Catalysis;

Börner, A.; Ed.; Wiley-VCH: Weinheim, 2008; Part II, Chap. 4.4.2; p. 437.

28 (a) Honeychuck, R. V.; Bonnensen, P. V.; Farahi, J.; W. H. J. Org. Chem. 1987, 52, 5293; (b) Bonnensen, P. V.; Puckett, C. L.; Honeychuck, R. V.; Hersh, W. H. J.

Am. Chem. Soc. 1989, 111, 6070.

29 Olson, A. S.; Seitz, W. J.; Hossain, M. M. Tetrahedron Lett. 1991, 32, 5299; b) Saha, A. K.; Hossain, M. M. Tetrahedron Lett. 1993, 34, 3833.

30 Kündig, E. P.; Bourdin, B.; Bernardinelli, G. Angew. Chem. Int. Ed. Engl. 1994, 33, 1856.

31 The results described are part of the excellent work from Bernadette Bourdin (PhD student in the Kündig group) who developed an accessible and viable route to these complexes and their application as pre-catalysts for the asymmetric DA reaction.

An initial rationalization of the observed selectivity was also proposed; Bourdin, B.

Thesis No 2716 University of Geneva, Geneva, 1994.

32 This work was carried out by Marion E. Bruin during her doctoral studies in the Kündig group; Bruin, M. E. Thesis No 3051 University of Geneva, Geneva, 1999.

33 Bruin, M. E.; Kündig, E. P. Chem. Commun. 1998, 2635.

34 Brinkmann, Y.; Reniguntala, J. M.; Jazzar, R.; Bernardinelli, G.; Kündig, E. P.

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35 This work was carried out by María José Mayor-Lopez, a doctoral student in the group of Prof. Jaques Webber at the University of Geneva; Mayor-Lopez, M. J.

Thesis No 3059 University of Geneva, Geneva, 1999, and references cited therein.

36 Saudan, C. M. Thesis No 3244 University of Geneva, Geneva, 2001.

37 Kündig, E. P.; Saudan., C. M.; Bernardinelli, G. Angew. Chem. Int. Ed. 1999, 38, 1220.

38 Kündig, E. P.; Saudan., C. M.; Viton, F. Adv. Synth. Catal. 2001, 343, 51.

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39 Viton, F. Thesis No 3410 University of Geneva, Geneva, 2002.

40 Also introduced by Christophe M. Saudan was a study of the Lewis acidity strength determination by IR analysis of the corresponding CO complexes as well as by means of NMR analysis of the trans-crotonaldehyde complex, all adding more detail to the understanding of the catalytic system (see ref. 36)

41 Kündig, E. P.; Saudan., C. M.; Alezra, V.; Viton, F.; Bernardinelli, G. Angew.

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42 (a) Davies, D. L.; Fawcett, J.; Garratt, S. A.; Russell, D. R. Chem. Commun. 1997, 1351; (b) Davenport, A. J.; Davies, D. L.; Fawcett, J.; Russell, D. R. J. Chem. Soc., Perkin Trans. 1 2001, 1500; (c) Davies, D. L.; Fawcett, J.; Garratt, S. A.; Russell, D. R. Organometallics 2001, 20, 3029; (d) Carmona, D.; Cativiela, C.; Elipe, S.;

Lahoz, F. J.; Lamata, M. P.; López-Ram de Víu, M. P.; Oro, L. A.; Vega, C.;

Viguri, F. Chem. Commun. 1997, 2351; (e) Carmona, D.; Vega, C.; Garcia, N.;

Lahoz, F. J.; Elipe, S.; Oro, L. A.; Lamata, M. P.; Viguri, F.; Borao, R.

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Rodriguez, R.; Lahoz, F. J.; Dobrinovitch, I. T.; Oro, L. A. Dalton Trans.

2008, 3328; (g) Faller, J. W.; Liu, X.; Parr, J. Chirality 2000, 12, 325; (h) Faller, J.

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43 Faller, J. W.; Parr, J. Organometallics 2001, 20, 697.

44 (a) Carmona, D.; Cativiela, C.; García-Correas, R.; Lahoz, F. J.; Lamata, M. P.;

López, J. A.; López-Ram de Víu, M. P.; Oro, L. A.; San José, E.; Viguri, F. Chem.

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