Impact of Secondary Interactions in Asymmetric Catalysis

Impact of Secondary Interactions in

Anders Frölander

Doctoral Thesis

Stockholm 2007

Akademisk avhandling som med tillstånd av Kungliga Tekniska Högskolan i Stockholm framlägges till offentlig granskning för avläggande av teknologie doktorsexamen i kemi med inriktning mot organisk kemi fredagen den 1:a juni kl 10.00 i sal D3, KTH, Lindstedtsvägen 5, Stockholm. Avhandlingen försvaras på engelska. Opponent är Professor Gerard van Koten, Utrecht University, Nederländerna.

ISBN 978-91-7178-676-0 ISSN 1654-1081 TRITA-CHE-Report 2007: 29

Abstract

This thesis deals with secondary interactions in asymmetric catalysis and their impact on the outcome of catalytic reactions. The first part revolves around the metal-catalyzed asymmetric allylic alkylation reaction and how interactions within the catalyst affect the stereochemistry. An OH–Pd hydrogen bond in Pd(0)–π-olefin complexes of hydroxy-containing oxazoline ligands was identified by density functional theory computations and helped to rationalize the contrasting results obtained employing hydroxy- and methoxy-containing ligands in the catalytic reaction. This type of hydrogen bond was further studied in phenanthroline metal complexes. As expected for a hydrogen bond, the strength of the bond was found to increase with increased electron density at the metal and with increased acidity of the hydroxy protons. The second part deals with the use of hydroxy- and methoxy-containing phosphinooxazoline ligands in the rhodium- and iridium-catalyzed asymmetric hydrosilylation reaction. The enantioselectivities obtained were profoundly enhanced upon the addition of silver salts. This phenomenon was explained by an oxygen–metal coordination in the catalytic complexes, which was confirmed by NMR studies of an iridium complex. Interestingly, the rhodium and iridium catalysts nearly serve as pseudo-enantiomers giving products with different absolute configurations. The final part deals with ditopic pyridinobisoxazoline ligands and the application of their metal complexes in asymmetric cyanation reactions. Upon complexation, these ligands provide catalysts with both Lewis acidic and Lewis basic sites, capable of activating both the substrate and the cyanation reagent. Lanthanide and aluminum complexes of these ligands were found to catalyze the addition of the fairly unreactive cyanation reagents ethyl cyanoformate and acetyl cyanide to benzaldehyde, whereas complexes of ligands lacking the Lewis basic coordination sites failed to do so.

Keywords: asymmetric catalysis, secondary interaction, hydrogen bond, chiral ligand, allylic alkylation, hydrosilylation, cyanation, pymox, box, PHOX, pybox, palladium, iridium, rhodium, Lewis acid, Lewis base

List of Publications

This thesis is based on the following papers, referred to in the text by their Roman numerals I–V.

I. OH–Pd(0) Interaction as a Stabilizing Factor in Palladium-Catalyzed Allylic Alkylations Kristina Hallman, Anders Frölander, Tebikie Wondimagegn, Mats Svensson, and Christina Moberg Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5400-5404.

II. OH–Pd Hydrogen Bonding in Pd(0)–Olefin Complexes Containing Hydroxy-Substituted Ligands Anders Frölander, Ingeborg Csöregh, and Christina Moberg Preliminary manuscript.

III. Conformational Preferences and Enantiodiscrimination of Phosphino-4- (1-hydroxyalkyl)oxazoline–Metal–Olefin Complexes Resulting from an OH–Metal Hydrogen Bond Anders Frölander, Serghey Lutsenko, Timofei Privalov, and Christina Moberg J. Org. Chem. 2005, 70, 9882-9891.

IV. Ag+-Assisted Hydrosilylation: Complementary Behavior of Rh and Ir Catalysts (Reversal of Enantioselectivity) Anders Frölander and Christina Moberg Org. Lett. 2007, 9, 1371-1374.

V. Bifunctional Pybox Ligands – Application in Cyanations of Benzaldehyde Anders Frölander, Mélanie Tilliet, Stina Lundgren, Vincent Levacher, and Christina Moberg Preliminary manuscript.

Abbreviations and Acronyms

Å angstrom abs conf absolute configuration acac acetylacetone box bisoxazoline BSA N,O-bis(trimethylsilyl)acetamide B3LYP 3-parameter hybrid Becke exchange/Lee–Yang–Parr correlation b/l branched/linear cat catalyst cod 1,5-cyclooctadiene conv conversion dba dibenzylideneacetone DFT density functional theory DMAP 4-(N,N-dimetylamino)pyridine DMF dimethylformamide DMM dimethyl malonate DMSO dimethyl sulfoxide EDC-HCl 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide monohydrochloride ee enantiomeric excess ent enantiomer EXSY exchange spectroscopy GC gas chromatography HOBt 1-hydroxybenzotriazole HPLC high-performance liquid chromatography MS mass spectrometry NMM N-methylmorpholine NMR nuclear magnetic resonance NOESY nuclear Overhauser effect spectroscopy Nu nucleophile PHOX phosphinooxazoline pybox pyridinobisoxazoline pymox pyridinooxazoline rt room temperature THF tetrahydrofuran Ts para-toluenesulfonyl

Table of Contents

1. Introduction...... 1 1.1 Secondary Interactions in Asymmetric Catalysis...... 1 1.2 Aim of This Thesis...... 3 2. OH–Metal Hydrogen Bond and its Consequences for Enantioselection ....5 2.1 Introduction...... 5 2.1.1 Transition Metal-Catalyzed Asymmetric Allylic Substitutions ...... 5 2.2 Contrasting Behavior of Hydroxy-Containing Oxazoline Ligands in Asymmetric Allylic AlkylationsI ...... 11 2.2.1 Hydroxy- and Methoxy-Functionalized Bisoxazolines...... 13 2.3 The Hydroxy–Metal Hydrogen BondII ...... 19 2.3.1 Experimental Studies ...... 19 2.3.2 Computational Studies ...... 21 2.4 Application of Hydroxy- and Methoxy-Substituted Phosphinooxazoline Ligands in Asymmetric Allylic AlkylationsIII...... 23 2.4.1 Ligand Synthesis...... 23 2.4.2 Initial Computations...... 25 2.4.3 Palladium-Catalyzed Allylations of Linear Substrates...... 27 2.4.4 Additional Computations ...... 29 2.4.5 Palladium-Catalyzed Allylations of Cyclic Substrates...... 31 2.4.6 Iridium Catalysis ...... 32 2.5 Conclusions...... 34 3. Oxygen-Metal Coordination and its Consequences for Enantioselection 35 3.1 Introduction...... 35 3.1.1 Hydrosilylations...... 35 3.2 Hydroxy-Containing PHOX Ligands – Application in Rhodium- and Iridium-Catalyzed HydrosilylationsIV ...... 37 3.2.1 Hydrosilylations of Prochiral Ketones ...... 37 3.2.2 Study of the Oxygen–Metal Coordination ...... 40 3.3 Conclusions...... 41 4. Bifunctional Lewis Acid – Lewis Base Catalysis ...... 43 4.1 Introduction...... 43 4.1.1 Asymmetric Addition of Cyanide to Carbonyl Compounds ...... 43 4.2 Ditopic Pybox Ligands – Application in Cyanations of AldehydesV...44 4.2.1 Synthesis of Amino-Functionalized Pybox Ligands ...... 44 4.2.2 Cyanations of Benzaldehyde...... 46 4.3 Conclusions...... 49 5. Concluding Remarks and Outlook ...... 51 6. Acknowledgements...... 53 7. References...... 55

1 Introduction

Asymmetric catalysis is one of the most important methodologies for producing chiral enantiomerically enriched substances. Its main advantage lies in the possibility of transferring the chirality of a small amount of reagent, the catalyst, to a large amount of product. Asymmetric catalysis may be divided into biocatalysis, organocatalysis, and metal catalysis. The 2001 Nobel Prize in Chemistry was entirely devoted to the latter. A metal catalyst normally consists of a chiral ligand bound to a metal. Several catalytic reactions, allowing highly enantioselective formation of C–H, C–O, C– C, C–N as well as many other bonds, have been developed. More and more insight is gained regarding the mechanisms of catalytic reactions, but none or few of these reactions are fully understood. A totally rational design of a catalyst is therefore at this point not possible. In addition to the steric and electronic properties of the ligand and the nature of the metal, the solvent, counterions and additives can play a crucial role in the enantioselection process.

Ligands are classified as monodentate, bidentate, tridentate and so on, depending on how many coordination sites they occupy on the metal. Most ligands are so called σ-donors, i.e. they are sharing an electron lone pair with a Lewis acidic metal. To make the bond stronger, π-backdonation from metals in low oxidation states, like Pd(0) and Ir(I), is common. To make this possible, the ligand has to be a π-acceptor, a π-acid. Phosphorus ligands, especially electron-poor ones, are good π-acids. Ligands with unsaturated nitrogen atoms binding in to the metal also possess considerable π-acidity and their metal complexes are often more stable than those derived from tertiary amines.

1.1 Secondary Interactions in Asymmetric Catalysis In attempts to mimic enzymes, ligands possessing secondary coordination sites have been synthesized and applied to various catalytic processes. The term secondary interaction has been assigned to catalyst–substrate or catalyst–reagent interactions additional to the primary coordination.1 In this thesis the term is expanded somewhat to also include interactions within the catalyst to alter its

1 shape and properties. Secondary interactions are often of steric nature, but they can also take the form of coulomb attraction,2 hydrogen bonding,3 π- interactions,4 ligand–metal coordination5 etc., and either improve or deteriorate the catalyst. Successful ligands for asymmetric catalysis are often rigid. Despite this, there are some examples of the use of ligands with flexible hydroxy or methoxy side arms. Introduction of a hydroxy-containing side chain in a ferrocenylphosphine ligand was shown to have a beneficial effect on both the stereoselectivity and the activity in the asymmetric allylic alkylation reaction, probably due to an attractive interaction between the hydroxy group and the nucleophile.6 The substitution of a methoxy group for hydroxy in a diphosphine ligand led to increased enantioselectivity in rhodium(I)-catalyzed hydrogenations.7 Several examples have subsequently been described, whereby the oxygen atom in a hydroxy group takes part in coordination to the metal center in a catalytically active complex.8 Enhanced enantioselectivities are often obtained, probably as a result of increased rigidity of the system. Weak hydrogen bonds with late transition metals in low oxidation states serving as hydrogen bond acceptors do not seem to have been observed to have an effect in catalysis previously. This kind of interaction will, however, constitute an important type of secondary interaction in this thesis. This kind of interaction was initially discovered in metallocenyl alcohols of the Fe group metals using infrared spectroscopy,9 and has since then been observed in a number of cases.10 The interaction displays features similar to those of the classical hydrogen bond,11 with short M–H distances and elongated O–H bonds. Though this type of bond is commonly found in the solid state, it has also been observed in solution.12

These weak hydrogen bonds must be differentiated from the more common agostic interaction.13 Whereas the agostic interaction is a three-center two- electron bond, involving an electron-poor metal center, this type of weak hydrogen bond is a three-center four-electron bond and involves a basic metal center. A hydrogen bond to palladium has been reported,14 although there are far more examples involving platinum. A Pt–HN hydrogen bond has been observed in zwitterionic Pt(II) complexes with a properly situated ammonium group.15 Due to charge separation, this interaction is profoundly favored. An almost linear three-center Pt–HN arrangement was observed by X-ray crystallography.16 Another example is provided by the adsorption of water on platinum, where

2 evidence for platinum–hydroxy hydrogen bonds on a Pt(111) surface has been presented.17 Nickel(0) has also been shown, theoretically, to act as a hydrogen bond acceptor.18 The combination of a Lewis acid and a Lewis base to activate both an electrophile and a nucleophile is essential for many enantioselective catalytic processes.19 Incorporation of these functions in the same molecule may be necessary in order to avoid undesired reaction of the Lewis acid with the Lewis base.20 This constitutes another important class of secondary interactions.

1.2 Aim of This Thesis The aim of the work behind this thesis was to expand the knowledge of the impact of secondary interactions in asymmetric metal catalysis. This involved the study of how different secondary interactions influence the reaction outcome in metal-catalyzed asymmetric allylic alkylations, hydrosilylations of ketones, and the addition of cyanide to aldehydes.

4 2 OH–Metal Hydrogen Bond and its Consequences for Enantioselection Papers I–III

2.1 Introduction This chapter deals with hydroxy- and methoxy-containing oxazoline ligands and their application in the asymmetric allylic alkylation reaction. The enantioselectivity is influenced dramatically in the former type of ligands due to a conformational change caused by a hydrogen bond to the metal.

2.1.1 Transition Metal-Catalyzed Asymmetric Allylic Substitutions The transition metal-catalyzed asymmetric allylic substitution is a powerful reaction as it, under mild conditions, provides at least one new chiral center as well as a carbon–carbon or carbon–heteroatom bond. This reaction has been extensively examined with a variety of catalysts and substrates, since its first report by Trost and Strege in 1977.21 The metal of choice is often palladium, but the reaction is also catalyzed by a range of metals including iridium,22 molybdenum,23 and copper.24 The mechanism of the palladium-catalyzed allylic alkylation is fairly well established and the catalytic cycle is shown in Figure 1.25 The first step is association of the allylic substrate to the Pd(0) catalyst, forming the π-olefin complex 1. The second step, the oxidative addition, affords the Pd(II)–π-allyl complex 2. The third step is the nucleophilic attack, where a stabilized nucleophile (pKa<25), for instance dimethyl malonate, attacks the allyl ligand and a new Pd(0)–π-olefin complex 3 is formed. In the last step, the product dissociates and the Pd(0) catalyst is reformed. If an unstabilized nucleophile

(pKa>25) is used, the attack occurs at the Pd atom and the product is formed by reductive elimination. The reaction using stabilized nucleophiles has been much more widely studied and is the focus of this chapter.

5 Nu X 1 2 R1 R2 R R Pd(0)L2

Dissociation Association

Nu X

1 2 1 2 3 R R R R 1

Pd(0)L2 Pd(0)L2

Nucleophilic attack Oxidativ addition

Nu Pd(II)L2 X R1 R2

Figure 1. Catalytic cycle of the palladium-catalyzed allylic alkylation.

The first two steps of the catalytic cycle are both reversible if the leaving group (X) is acetate since the acetate ion is also a good nucleophile.26 Since both the oxidative addition and the nucleophilic attack occur with inversion of configuration, the allylation reaction proceeds with net retention of the stereochemistry. However, the picture is more complicated since the π-allyl complex 2 is involved in dynamic equilibria. There are two processes of particular interest here, syn/anti interconversion and apparent allyl rotation.25 Since these processes normally occur at a faster or comparable rate to that of the nucleophilic addition, the nucleophilic attack occurs under Curtin–Hammet conditions. This is generally of high importance for the enantioselection and in many cases crucial to achieve high selectivity. The syn/anti interconversion, also known as the π-σ-π (η3-η1-η3) isomerization (Scheme 1), occurs via a change in hapticity from 3 to 1 followed by a rotation around the carbon–carbon bond and subsequent formation of a syn–anti π-allyl complex. This process is also an endo/exo isomerization since it changes the direction of the bond between the central allylic carbon and its proton. In a similar manner the process can continue to form the anti–anti isomer. Substrates with large substituents, e.g. phenyl groups, normally exist as syn–syn isomers in solution, while cyclic substrates are locked in anti–anti conformations.

6 L2Pd PdL2 PdL2 PdL2 2 R R1 1 2 1 2 R R R R 2 R1 R

Scheme 1. The syn/anti interconversion.

The apparent allyl rotation (Scheme 2) is also an endo/exo isomerization, but without change of syn/anti geometry. If the two ligands L1 and L2 are different, as in a C1-symmetric bidentate ligand, this process generates a diastereomeric complex. On the other hand, if the ligands are identical, as in a C2-symmetric bidentate ligand, this process gives back the starting complex.

L1 L2 L1 L2 Pd Pd 1 R2 R R1 R2

Scheme 2. The apparent allyl rotation.

There are at least three possible mechanisms for the apparent allyl rotation. One is similar to the one for the syn/anti interconversion and involves a rotation around the palladium–carbon bond in a σ-complex.27 Dissociation of one ligand forming a tricoordinated palladium complex followed by rotation and reassociation is another.28 Finally, an external ligand such as a halide ion can coordinate and form a pentacoordinated complex, which then undergoes pseudorotation.29 In some cases π-allyl species have been shown to isomerize through a metal 30 exchange reaction as shown in Scheme 3. This SN2 type reaction of a Pd(0) complex with a π-allyl–palladium(II) complex is an enantioface exchange, rendering all three allyl carbons inverted. The same result can be obtained via the other isomerizations provided that R1 = R2 or the substrate carries two identical substituents on one of its allylic carbon atoms.

7 2 R R2 L (II) (0)L L (0) (II) L Pd Pd Pd Pd L L L L 1 R R1

Scheme 3. A metal exchange reaction.

The enantiodetermining step can be either the oxidative addition or the nucleophilic attack, depending on the choice of substrate.25 Employing a symmetrically substituted substrate (R1 = R2), the same π-allyl complex with a meso-allyl ligand is formed from both the starting enantiomers of a racemic substrate. If a chiral catalyst is used, the allylic termini become diastereotopic and the enantioselectivity is determined by the regiochemistry of the nucleophilic attack. The addition of dimethyl malonate to rac-(E)-1,3-diphenyl-2-propenyl acetate has emerged as a benchmark reaction and is often the reaction for which most new ligands are attempted initially (Scheme 4). The anion of the nucleophile can be preformed using sodium hydride, but generation of it in situ with a system consisting of BSA and KOAc has in a number of cases been shown to give higher enantioselectivities.31,32

3 OO [η -(C3H5)PdCl]2, OAc ligand, base O O Ph Ph * O O Ph Ph OO

Scheme 4. A typical asymmetric allylic alkylation.

The most stable π-allyl complex is usually that which leads to product. If the transition state of the nucleophilic attack is early,30a it will, according to the Hammond postulate33, resemble the π-allyl complex. The nucleophile will as a result add to the most electrophilic terminus of the most reactive π-allyl complex. If the transition state is late,34 the steric interactions in the produced π-olefin complexes are more important. During the nucleophilic attack, the allyl moiety will rotate in order to enable the palladium–olefin interaction and the least congested π-olefin complex is favored.

8 Employing a C2-symmetric bidentate ligand, only one π-allyl complex is possible, excluding the syn–anti and anti–anti complexes. The enantioselectivity is then directly determined by which of the two allylic termini that is attacked by the nucleophile (Figure 2).

R R O O O O N N N N Pd R Pd R Ph Ph Ph Ph

Figure 2. Possible attacks employing a C2-symmetric ligand.

With a C1-symmetric ligand there are two possible syn–syn π-allyl complexes (endo and exo) that can both be attacked at the two termini, resulting in four different pathways. Two pathways lead to the (R)-enantiomer of the product and two to the (S)-enantiomer (Figure 3).

R R O N O N N N Pd Pd Ph Ph Ph Ph

Figure 3. Possible nucleophilic attacks employing a C1-symmetric ligand.

If a ligand with two different donor atoms is used, the nucleophilic attack will normally occur only at one of the allylic termini. With a P,N-ligand the nucleophile will preferably attack at the terminus trans to the phosphorus atom, due to the larger trans-influence of phosphorus.35 In this case the

9 enantioselectivity is therefore determined by which π-allyl complex that reacts (Figure 4).

R R O O N P Ph N P Ph Pd Ph Pd Ph Ph Ph Ph Ph

Figure 4. Preferential attacks employing a C1-symmetric P,N-ligand.

Even with unsymmetrical substrates it is possible to convert a racemate to an enantiomerically pure product, but fast enantioface exchange is an absolute prerequisite (Scheme 5). If the substrate carries two identical substituents on one of its allylic carbon atoms, enantioface exchange can occur through π-σ-π isomerization at that terminus. If the enantioface exchange is much faster than – the nucleophilic attack (k1 >> k2[Nu ]), the latter will occur under Curtin– Hammet conditions. If the rates instead are comparable, the system will display a memory effect.

PdL2 X R2 2 2 R k2a Nu R 1 2 R R R1 R2 R1 R2

PdL2 2 2 2 R Nu R X R k2b 2 1 1 2 R1 R2 R R R R

Scheme 5. The asymmetric allylic alkylation reaction using unsymmetrical substrates.

10 A common reaction is seen in Scheme 6. Whether starting from the racemic branched substrate 4 or achiral cinnamyl acetate 5 both the branched product 6 and the linear achiral 7 are often obtained. Regioselectivity in favor of the branched product has traditionally been low using palladium catalysts, although recently catalysts containing electron-withdrawing ligands have been found to induce high branched/linear ratios.36 Other metals, including molybdenum and iridium, often give more of the branched product.

OAc

Ph 3 [η -(C3H5)PdCl]2, OO 4 ligand, base OO or O O O O ∗ O O

OAc OO Ph Ph 7 Ph 6 5

Scheme 6. A common asymmetric allylic alkylation reaction.

2.2 Contrasting Behavior of Hydroxy-Containing Oxazoline Ligands in Asymmetric Allylic Alkylations Ligands carrying flexible side chains with terminal hydroxy or methoxy groups have in a number of cases been shown to give interesting results in catalysis.6,7,8 Pyridinooxazoline (pymox) ligands 8–15 were synthesized in our group and subjected to the palladium-catalyzed asymmetric allylic alkylation with rac-(E)- 1,3-diphenyl-2-propenyl acetate and dimethyl malonate (Figure 5).37 The results show that the nature of the substituent in the 6 position of the pyridine ring has a great influence on the enantioselectivity. Ligands 8 and 9, with a hydroxymethyl or a methoxymethyl substituent, gave similar results in the catalytic reaction (88% and 82% ee, respectively). Larger differences in enantioselectivity were observed for ligands 10–15, which all carry bulky hydroxy- or methoxy-containing substituents. The two diastereomeric methoxy ligands 10 (R,R) and 11 (R,S) gave profoundly different ee’s (15 and >99%, respectively). This in itself is not unexpected, since two diastereomers obviously should provide different chiral environments. What is more surprising is that for the analogous hydroxy ligands 12 and 13, the opposite diastereomer (12, R,R)

11 gave the better ee (95 vs. 90%). Increasing the steric bulk on the hydroxy- containing arm gave an even greater effect (ligands 14 and 15, 99 vs. 39% ee). These results clearly suggest that the two types of ligands ought to have different conformations in the enantiodetermining step.

OO OAc 3 [η -(C3H5)PdCl]2, ligand O O Ph Ph * (MeOCO)2CH2, BSA, KOAc Ph Ph

O O N N N OH N OMe Ph (R) Ph (R) 8, 88% ee (R) 9, 82% ee (R)

O (R) O (S) O (R) N N N N OMe N OMe N OH Ph (R) Ph (R) Ph (R)

10, 15% ee (R) 11, >99% ee (R) 12, 95% ee (R)

O (S) O (R) O (S) N N N N OH N OH N OH Ph (R) Ph (R) Ph (R)

13, 90% ee (R) 14, >99% ee (R) 15, 39% ee (R)

Figure 5. Pyridinooxazoline ligands and results obtained in the palladium-catalyzed allylic alkylation.

Pyridines with a 1-methoxyalkyl substituent in the 2 position, adopt a conformation with the methoxy group in the plane of the ring, but with the oxygen anti to the nitrogen atom (16, Figure 6). This conformation mainly arises due to repulsion of the oxygen and nitrogen electron pairs, but also due to a stabilizing interaction between the nitrogen lone pair and the C–O antibonding σ- orbital, as shown previously in our group.38 On the other hand, pyridine derivatives with a 1-hydroxyalkyl substituent in the 2 position adopt a conformation with the oxygen syn to the nitrogen due to a hydroxy–nitrogen hydrogen bond (17, Figure 6). However, in a metal complex, the nitrogen lone pair is occupied and ligands 16 and 17 should adopt similar conformations.

12 OMe R N N R H O 16 17

Figure 6. Conformations of 2-(1-methoxyalkyl) (16) and 2-(1-hydroxyalkyl) pyridines (17).

In order to try to explain the catalytic results, palladium–π-allyl and palladium– π-olefin complexes of the hydroxy- and methoxy-containing ligands were studied with the aid of DFT calculations.39 The model complexes 18 and 19 (Figure 7) were shown to adopt similar lowest energy conformations in the π- allyl complexes, with the oxygen anti to the nitrogen and N–C–C–O dihedral angles close to 180°. Computations of the corresponding π-olefin complexes revealed a different conformation in complex 20. The hydroxy group was now syn to nitrogen and pointed towards the metal.

OMe O N O N N N O Pd Pd H

F 18 R = OH 20 19 R=OMe

Figure 7. Computed lowest energy conformations of Pd–π-allyl and Pd–π-olefin model complexes.

2.2.1 Hydroxy- and Methoxy-Functionalized Bisoxazolines Balavoine and co-workers reported interesting results employing the hydroxy- and methoxy-substituted bisoxazoline (box) ligands 21 and 22 (Figure 8) in the palladium-catalyzed allylic alkylation.40 The two ligands almost acted as pseudo- enantiomers, yielding different enantiomers of the product, 92% ee (S) and 85% ee (R), respectively. As explanation they suggested that a hydrogen bond between the hydroxy-containing ligand and the nucleophile affected the conformation of the hydroxy-containing ligand and thereby the stereochemistry of the reaction.41

13 In order to study whether the same type of conformational differences due to an OH–Pd hydrogen bond that were found for the pyridinooxazolines could explain these interesting results, we decided to synthesize ligands 23 and 24 with 4- hydroxymethyl and 4-methoxymethyl substituents and subject them to the catalytic reaction. The two ligands gave similar enantioselectivities in the catalytic reaction, 96 and 89% ee of the (S)-enantiomer. These results are in agreement with those obtained with the pyridinooxazolines, since in both cases bulky substituents on the arms are necessary to obtain a large difference in selectivity upon exchanging hydroxy groups for methoxy groups.

O O O O Ph Ph N N N N RO OR RO OR Ph Ph

21 R = H 92% ee (S) 23 R = H 96% ee (S) 22 R = Me 85% ee (R) 24 R = Me 89% ee (S)

Figure 8. Catalytic results using bisoxazoline ligands.

To elucidate the origin of these results, the complexes involved in the enantiodetermining step (the nucleophilic attack) were computed for ligands 23 and 24 using the B3LYP functional42 in Jaguar v4.0.43 The complexes were optimized using the lacvp**/6-31G(d,p) basis set.44,45 Ignoring syn–anti and anti–anti complexes, only one Pd(II)–π-allyl complex had to be considered for each ligand (25 and 26, Figure 9). No major differences were found for the two complexes, the N–C–C–O dihedral angles being 180° and 65° in 25 and –175° and 65° in 26.

O O Ph Ph N N RO Pd OR Ph Ph

25 R = H 26 R=Me

Figure 9. Palladium(II)–π-allyl complexes of ligands 23 and 24.

14 – The Pd(0)–π-olefin complexes were calculated using NH2 to model the nucleophile. Two complexes, arising from nucleophilic attack at the two diastereotopic allylic termini, exist for each ligand (Figure 10).

O O O O Ph Ph Ph Ph N N N N RO Pd OR RO Pd OR Ph Ph Nu Nu Ph Ph H H

27a = H 27b = H 28a = Me 28b = Me

Figure 10. Palladium(0)–π-olefin complexes of ligands 23 and 24.

The energies of the olefin complexes with the hydroxy-containing ligand (27a and 27b) were calculated. The most stable conformation of 27a (27a´) was found to be 8.6 kcal mol–1 lower in energy than the lowest energy conformation of 27b (27b´, Figure 11). As 27a is the precursor of the (S)-product and 27b the (R)- product when dimethyl malonate is the nucleophile, this is in agreement with the catalytic result [96% ee of the (S)-enantiomer].

27a´ 27b´

Figure 11. Computed conformational minima for the π-olefin complexes from ligand 23.

Interestingly, the olefin complexes displayed different conformations in comparison to the π-allyl complex. Both structures were stabilized by hydroxy–

15 palladium interactions. For 27a´ the N–C–C–O dihedral angles were found to be –67° and 55° and the hydrogen–palladium distances 2.3 and 2.7 Å, respectively. The Pd–O distances were found to be 3.2 and 3.5 Å and the O–H–Pd bond angles 157° and 141°, respectively. The O–H bonds were slightly elongated compared to those in the free ligand, the one closest to palladium by approximately 0.01 Å. Taken together, the data obtained show that the geometries of the interaction fulfill the requirements of an OH–Pd hydrogen bond.10c The energy difference between the calculated minima for the two olefin complexes of the methoxy ligand (28a and 28b) was calculated to be 1.1 kcal mol–1. The complex 28a, leading to the (R)-product, which corresponds to the (S) absolute configuration with dimethyl malonate, was found to be lower in energy. This is in agreement with the catalytic result (89% ee of the (S)-enantiomer). The complexes were both found to have two anti-periplanar methoxy groups with O– C–C–N dihedral angles close to 180o. To support our theory further, the π-allyl and π-olefin complexes of ligands 21 and 22 were also calculated. Similar to what was discovered for ligands 23 and 24, ligands 21 and 22 were found to adopt different conformations in their π- olefin complexes. The olefin complexes of ligand 21 were stabilized by two OH– Pd hydrogen bonds whereas ligand 22 had both its O–C–C–N dihedral angels close to 180°. The computational results had clearly shown that the hydroxy and methoxy ligands had different conformations in their Pd(0)–π-olefin complexes. The ligands showed, however, similar behavior in the Pd(II)–π-allyl complexes. If the differences found in the olefin complexes should be reflected in the stereochemical outcome, it is necessary that they are present in the transition state of the nucleophilic attack. To study if this was the case, the simplified transition state structures 29 and 30 were computed (Figure 12). NH3 was chosen to model the nucleophile in order to simplify the calculations.

16 O O N N RO Pd OR

Nu 29 = H 30 =Me

Figure 12. Simplified transition state structures derived from ligands 23 and 24.

The transition state for the hydroxy-containing complex 29 was found to have a conformation 29´ similar to that of the olefin complex and it was stabilized by two OH–Pd hydrogen bonds (Pd–H = 2.6 and 2.7 Å, Figure 13). The O–C–C–N dihedral angles in the transition state structure of the hydroxy-containing complex were both 62o, compared to 180o and –175o in the methoxy-containing complex 30.

29´

Figure 13. Computed conformational minima for the simplified transition state structure derived from ligand 23.

Based on the calculations, the catalytic results could be rationalized. There are four possible pathways, passing via transition states 31a, 31b, 32a, and 32b (Figure 14). The expected outcome using ligands 23 and 24 is the (S)-product through 31a. These results are obtained because the bulky groups are positioned in the same way as depicted for 31a, even though the conformations of the two ligands are different. The expected result for a ligand with opposite stereochemistry at the 4 position, for instance 21 and 22, is the (R)-enantiomer through transition state 32b. However, due to the OH–Pd hydrogen bond with ligand 21, the phenyl groups are positioned on the opposite side of the plane and the (S)-product is obtained through 31a.

Ph Ph Nu Nu Ph Ph H H

31a (S)-product 31b (R)-product

Ph Ph Nu Nu Ph Ph H H

32a (S)-product 32b (R)-product

Figure 14. The four possible transition states for a C2-symmetric ligand and its pseudo- enantiomer.

The presence of a hydrogen bond, which stabilizes the transition state (electron release from the palladium atom), could possibly also explain the increased activity with the hydroxy-containing ligands. Employing ligand 21, the reaction was completed within 2 hours while 96 hours were needed to achieve 65% conversion with ligand 22. With ligand 23 full conversion was obtained within 6.5 hours as compared to 24 hours with ligand 24, see Figure 8. To shed some additional light on this situation, the reaction rates were measured employing pyridinooxazolines 8 and 9 (Figure 5) in the catalytic reaction. Surprisingly, the rates were found to be similar, full conversion being reached after 14 hours. A rate-enhancement should, however, only be expected if the nucleophilic attack was the rate-determining step. This was clarified carrying out the reactions with a less reactive nucleophile. Using methyl acetoacetate, the rate of the reaction using ligand 8 did not change, clearly indicating that the rate- determining step was not the nucleophilic attack, but instead most likely the oxidative addition. Employing the even less reactive acetylacetone, the reaction was substantially decelerated resulting in only 36% conversion after 6 days. It could be concluded that the rate-determining step now had changed to be the nucleophilic attack. Unfortunately, at this stage, the reactions were too slow to allow a reliable comparison between ligands 8 and 9.

18 2.3 The Hydroxy–Metal Hydrogen Bond In order to gain extended knowledge about the hydrogen bonding to metals, which we had observed in our complexes used for catalysis, we decided to perform a more detailed study. We were mainly interested in how increased electron density at the metal center or increased acidity of the proton donor, would affect the strength of the bond. As a suitable ligand for this purpose we chose 2,9-bis(hydroxymethyl)phenanthroline (33).46 Among the nitrogen ligands, the phenanthrolines offer comparatively strong complexes due to extensive π- backdonation. Other advantages with this ligand are its rigidity, that it possesses two hydroxy groups and finally its symmetry, rendering no diastereomeric complexes even with unsymmetrically substituted olefins.

OH HO 33

2.3.1 Experimental Studies Palladium(0)–π-olefin complexes with bidentate nitrogen ligands (including phenanthrolines) are only stable when using electron deficient olefins.47 However, an electron-poor olefin drains the metal of electrons and weakens its potential as a proton acceptor. Furthermore, the accompanying heteroatoms might be better proton acceptors than the metal. Since ligand 33 carries two hydroxy groups, an olefin with only one hetero group or possibly one with 1,1- disubstitution pattern seemed to be the best choice. Such olefins, including trans- β-nitrostyrene derivatives, had successfully been used by the group of Stahl.48 For our studies, we considered (E)-1-nitro-2-phenylethene (34) and 1,1-dicyano- 2-phenylethene (35) to be suitable.

NO2 CN

Ph Ph CN 34 35

19 The desired complexes were formed smoothly by stirring the ligand, olefin, and

Pd2(dba)3 in acetone at room temperature. Complexes 36 and 37 were obtained as red and green solids, respectively. Complex 37 turned yellow upon contact with THF.

NN NN OH Pd HO OH Pd HO NO2 CN Ph Ph CN 36 37

Due to the low solubility of the complexes in most organic solvents, 1H NMR spectra had to be run in DMSO–d6 or THF–d8, solvents that are themselves reasonably good proton acceptors. The solubility was limited also in THF, especially for 36. In DMSO, olefin rotation was fast on the NMR time scale for both complexes leading to identical shifts in pairs for protons related by the symmetry of the ligand. Signals for the hydroxy and methylene protons were not detected in 37 at room temperature. A small downfield shift of about 0.3 ppm was observed for the hydroxy protons in 36 compared to the free ligand (33). The hydroxy groups are probably hydrogen bonded to DMSO molecules in 36 as well as in 33. In contrast, all protons gave rise to separate signals in THF. At 273 K the hydroxy protons in 36 appeared at 4.98 and 5.33 ppm, and those in 37 at 5.01 and 5.61 ppm. NOESY spectra of both complexes showed exchange peaks corresponding to olefin rotation. Strong interactions were observed for 37 between the olefinic proton and a methylene proton, between the hydroxy protons and the protons in the 3 position of the heterocyclic ring, and between a methylene proton and the o-protons in the phenyl ring. Since only weak interactions were observed between the methylene protons and the protons in the heterocyclic rings, hydrogen bonding to the metal was probably absent or present only in a minor conformer. The situation in 36 was similar to that in 37. We wished to further characterize the complexes by X-ray diffraction studies. Suitable crystals of 37 were obtained by allowing diethyl ether to slowly diffuse into a concentrated THF solution. To facilitate the process, the THF solution was seeded with microcrystals obtained by layering a THF solution of 37 with

CH2Cl2. The crystals contained molecules of 37 and THF in a 1:1 ratio (Figure 15). The OH groups were not found to be hydrogen bonded to palladium but

20 instead involved in intermolecular hydrogen bonds, one to the THF oxygen atom and the other possibly to N(4) in another complex (not shown). The coordination around Pd was trigonal planar and the olefin was bent, evidently as a result of rehybridization towards sp3. The fourteen phenanthroline ring atoms were co- planar within 0.032 Å.

Figure 15. The crystallographic asymmetric unit with the crystallographic labelling of the non-hydrogen atoms. The non-hydrogen positions and disorder sites are represented by their atomic displacement ellipsoids, drawn at a 30% probability level.

2.3.2 Computational Studies In order to gain further information about the requirements necessary for OH–M hydrogen bonding to occur, 36, 37, and additional π-olefin complexes containing 2,9-bis(hydroxymethyl)phenanthroline were subjected to computational studies using the B3LYP functional42 in Jaguar v4.0.43 The complexes were optimized using the lacvp**/6-31G(d,p) basis set.44,45 The most stable conformation of 36 (36´) had both its hydroxy groups involved in hydrogen bonding, one to palladium and the other to the nitro group (Figure 16). Complex 36´´, lacking the bond to the metal, was found to be of higher energy (1.6 kcal mol–1).

36´ 36´´

Figure 16. Two conformational minima of complex 36.

The difference in energy between the two analogous complexes of 37 was found to be 0.1 kcal mol–1 in favor of the conformation lacking an OH–Pd bond, which explains the experimental results. In 36´ the O–Pd and H–Pd distances were 3.47 and 2.66 Å and the O–H–Pd bond angle was 141°. The O–H bond was slightly longer than in 36´´ (0.972 Å as compared to 0.966). These values all fulfill the criteria of an OH–Pd hydrogen bond,10c although considerably weaker than the O–H...O bond (O...H 1.90 Å, O–H 0.974 Å).

Removal of the electron-withdrawing substituents on the olefins was expected to result in a stronger hydrogen bond to palladium due to higher electron density at the metal center. To test this assumption, computations were performed on a complex containing ethene (38) in place of substituted olefins. The conformation having the hydroxy groups hydrogen-bonded to the metal was found to be 5.7 kcal mol–1 more stable than one having both groups anti to the metal. The H–Pd distances for this complex were 2.41 and 2.42 Å and the O–H bonds were 0.977 Å. The conformations of the corresponding platinum complex were also computed and a similar energy difference was found (6.0 kcal mol–1).

N N F N N F Pd F Pd F OH HO OH HO

38 39

22 Another factor affecting the strength of the hydrogen bond is the acidity of the hydroxy protons. A profoundly stronger hydrogen bond was indeed observed when computations were performed on 39, having CF2OH substituents. The energy difference between the conformers was 14.3 kcal mol–1 and the H–Pd distances in the most stable complex were 2.24 and 2.25 Å. As expected, the stronger hydrogen bond resulted in profoundly elongated O–H bonds (0.995 and

0.996 Å, as compared to 0.973 Å in the other conformer). Since CF2OH and CFOH groups are known to be unstable and decompose into hydrogen fluoride and fluorinated carbonyl compounds,49 experimental studies using this ligand were not possible. The computational results showed, however, that these hydrogen bonds can be fairly strong.

2.4 Application of Hydroxy- and Methoxy-Substituted Phosphinooxazoline Ligands in Asymmetric Allylic Alkylations We were interested to see if the results obtained with pyridinooxazolines and bisoxazolines (vide supra) also could be observed with other more versatile catalytic systems. For this purpose we chose phosphinooxazolines (PHOX), initially prepared independently by the groups of Helmchen,50 Pfaltz,51 and Williams52 in 1993. PHOX ligands have proven to be highly versatile ligands which have found use in a whole range of catalytic processes like allylic substitutions, Heck reactions, conjugate additions, and hydrogenations, to mention only a few.53 A series of PHOX ligands carrying either hydroxy or methoxy substituents were synthesized and their complexes were used in the asymmetric allylic alkylation reaction.

2.4.1 Ligand Synthesis To allow a thorough investigation, we desired access to PHOX ligands with different substitution patterns on the oxazoline ring. We envisioned two kinds of ligands, either with a 4,5-disubstituted oxazoline ring (40–43), or a large substituent in the 4 position (44–47). These types of ligands were known to be accessible from 2-halobenzonitriles and 2-halobenzoic acid chlorides, respectively.54

O Ph O O O

N PPh2 N PPh2 N PPh2 N PPh2 Ph R R R R

40 R = OH 42 R = OH 44 R = OH 46 R = OH 41 R=OMe 43 R=OMe 45 R=OMe 47 R= OMe

Ligand 40 was prepared from threoninol and 2-fluorobenzonitrile in the presence of cadmium acetate. Protection of the alcohol function followed by nucleophilic aromatic substitution using lithium diphenylphosphide and subsequent deprotection gave 40. To avoid protection/deprotection of the alcohol function, a different route was employed for the syntheses of 41–43 (Scheme 7). Intermediate 48 was prepared by reacting threoninol and 2-iodobenzonitrile. O-methylation to give 49, followed by palladium-catalyzed coupling with diphenylphosphine afforded ligand 41. A similar procedure was used to furnish ligands 4255 and 43 via intermediates 50 and 51, respectively.

OH R1 1 O R PHPh2, Et3N, H2N OH Pd(OAc) (cat) N I 2 NC 41, 42, 43 Cd(OAc)2 (cat) I OR2 48 R1 = Me, R2 = H 50 R1 = Ph, R2 = H NaH, dimethyl sulfate 49 R1 = Me, R2 = Me 51 R1 = Ph, R2 = Me

Scheme 7. Synthetic routes for ligands 41–43.

Ligands 44 and 45 were obtained by first reacting 2-iodobenzoyl chloride with threoninol to give 52 as depicted in Scheme 8. Palladium-catalyzed coupling with diphenylphosphine yielded 44 in 33% overall yield. O-methylation to give 53 and subsequent palladium-catalyzed coupling with diphenylphosphine gave

24 ligand 45 in 25% overall yield. With a bulky phenyl substituent, the syntheses worked better. Ligands 46 and 47 were both obtained in 44% overall yield via intermediates 54 and 55, respectively. Previously ent-46 had been synthesized by nucleophilic substitution of the aromatic fluoride by lithium diphenylphosphide in a lower overall yield than we obtained for 46.54

OH R1 O PHPh2, Et3N, H N OH Pd(OAc) (cat) 44, 45, Cl 2 2 N I 46, 47 TsCl, Et N R1 O I 3 OR2

52 R1 = Me, R2 = H 54 R1 = Ph, R2 = H NaH, MeI/ dimethyl sulfate 53 R1 = Me, R2 = Me 1 2 55 R = Ph, R = Me

Scheme 8. Synthetic routes for ligands 44–47.

2.4.2 Initial Computations To begin with, we were mainly interested in learning if a hydroxy–palladium hydrogen bond was to be found also for these ligands. In order to do so, the product Pd(0)–π-olefin complexes of ligand 40 were calculated using the B3LYP functional42 with the lacvp**/6-31G(d,p) basis set44,45 in Jaguar v4.0.43 Assuming that the nucleophilic attack occurs at the allyl group from the side opposite to the metal at the allylic position trans to phosphorus in accordance with experimental observations,35b two π-olefin complexes are of interest (Figure 17). Olefin complex 57a originates from the exo-π-allyl–palladium complex 56a and complex 57b from the endo isomer 56b. 57a and 57b lead to different product enantiomers. Syn–anti and anti–anti allyl complexes were ignored as such complexes have not been detected in solution or in the solid state.56

25 O O N P Ph N P Ph HO Pd Ph HO Pd Ph Ph Ph Ph Ph 56a 56b

O O N P Ph N P Ph Pd Pd Ph OH Ph OH Ph H Nu Ph Ph H Nu Ph 57a 57b Figure 17. Nucleophilic attack at exo- and endo-π-allyl–palladium complexes of ligand 40.

– To simplify the computations the nucleophile was replaced by NH2 and the substituents on the oxazoline ring, the phosphorus atom and the olefin were replaced by hydrogen atoms. For both olefin complexes (57a and 57b), the most stable conformations were found to have a hydroxy–palladium hydrogen bond (Figure 18). For the complex arising from attack at the exo-allyl complex, this conformation (57a´) was found to be 2.1 kcal mol–1 lower in energy than the most stable conformation having the hydroxy proton pointing away from palladium (57a´´). The computed bond distances in 57a´ together with an O–H– Pd bond angle of 145° are all in accordance with a weak hydrogen bond.10c A slightly shorter O–H bond (0.97 Å) was observed for complex 57a´´.

O–Pd: 3.3 Å O–H: 0.98 Å

57a´ 57a´´

Figure 18. The two lowest energy conformations of the product olefin complex 57a arising from nucleophilic attack at the exo-π-allyl complex.

26 Single point calculations, performed using the larger lacv3p**++/6-311+G(d,p) basis set, confirmed complex 57a´ to be of lower energy (1.3 kcal mol–1) than 57a´´. Single point calculations were also performed simulating THF solution. Again complex 57a´ was found to be the most stable conformation (0.8 kcal mol–1). The most stable conformation of 57b, attained after attack at the endo- allyl complex, was found to be 2.6 kcal mol–1 higher in energy than 57a´. Calculations were also performed with the hydroxy group replaced by a methoxy group. The resulting olefin complexes, derived from ligand 41, all had the methoxy group pointing away from palladium in their most stable conformations.

2.4.3 Palladium-Catalyzed Allylations of Linear Substrates Ligands 40–47 were first used as ligands for the palladium-catalyzed allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate. For ligands 40–45, the hydroxy/methoxy pairs showed only minor differences in enantioselectivity (Table 1), whereas 46 and 47 displayed a somewhat larger difference (88 and 99% ee, respectively). Larger differences were expected but we reasoned that even if a hydrogen bond was present in the Pd(0)–olefin complex, it might be absent in the transition state and therefore not affect the stereochemistry of the catalytic reaction. To test this hypothesis, we wished to use conditions favoring a later transition state. This can be accomplished by either using a less reactive nucleophile or by changing the solvent. We started with the latter. The reaction was performed in toluene using ligands 40, 41, 46, and 47. The difference for ligands 40 and 41 (entries 2 and 4) was still insignificant, but this was more or less expected considering the results for the nitrogen ligands with non-substituted arms (vide supra). On the other hand, a somewhat larger difference in enantioselectivity was observed between ligands 46 and 47 (76 and 97% ee, entries 10 and 12).

27 Table 1. Reactions of rac-(E)-1,3-diphenyl-2-propenyl acetate with dimethyl malonate OO [η3-(C H )PdCl] , OAc 3 5 2 ligand, NaH, DMM O O Ph Ph * Ph Ph entrya ligand conv (%)b ee (%)b abs confc 1 40 99 95 R 2d 40 100 93 R 3 41 100 95 R 4d 41 100 91 R 5 42 100 92 R 6 43 100 88 R 7 44 100 97 S 8 45 100 98 S 9 46 100 88 S 10d 46 100 76 S 11 47 100 99 S 12e 47 81 97 S a 3 Reaction conditions unless otherwise noted: [(η -C3H5)PdCl]2 (1.0 mol %), ligand (2.4 mol %), rac-(E)-1,3-diphenyl-2-propenyl acetate (0.50 mmol), DMM (0.70 mmol), NaH (0.60 mmol), THF (6 mL), 5 h reaction time, 0 °C. b Determined by HPLC (chiral OD-H column). c Assigned by comparing the sign of optical rotation with literature data. d Reaction performed in toluene at rt, 1 h reaction time. e Reaction performed in toluene at rt, 18 h reaction time.

Employing the less reactive nucleophile acetylacetone, a considerable difference in enantioselectivity between ligands 46 and 47 was observed in THF (30 and >99% ee, entries 3 and 5, Table 2) and toluene (35 and >99% ee, entries 4 and 6). At the same time, similar enantioselectivities were achieved with ligands 40 and 41 (80 and 84% ee, entries 1 and 2). The results suggest that the transition state conformations of the hydroxy ligands are different from those of the methoxy ligands and that a bulky substituent in the 4 position of the ring is essential for obtaining a noteworthy effect.

28 Table 2. Reactions of rac-(E)-1,3-diphenyl-2-propenyl acetate with acetylacetone at 25 °C 3 OO [η -(C3H5)PdCl]2, OAc ligand, NaH, acac Ph Ph * Ph Ph

entrya ligand conv (%)b ee (%)b abs confc 1 40 100 80 R 2 41 100 84 R 3d 46 94 30 S 4d,e 46 55 35 S 5 47 95 >99 S 6e 47 90 >99 S a 3 Reaction conditions unless otherwise noted: [(η -C3H5)PdCl]2 (1.0 mol %), ligand (2.4 mol %), rac-(E)-1,3-diphenyl-2-propenyl acetate (0.50 mmol), acac (0.70 mmol), NaH (0.60 mmol), THF (6 mL), 2 h reaction time, rt. b Determined by HPLC (chiral OJ column). c Assigned by comparing the sign of optical rotation with literature data. d 15 h reaction time. e Reaction performed in toluene.

2.4.4 Additional Computations We decided to penetrate the issue of enantioselection using ligand 46 by performing detailed calculations of the product olefin complexes that are arising from nucleophilic attack at the π-allyl complexes 58a and 58b (Figure 19). The – only simplification made was the replacement of the nucleophile for NH2 . By analogy with the computational results obtained for ligand 40, we found the Pd(0)–olefin complex 59a, arising from attack at the exo-allyl complex, to be of lower energy than 59b arising from attack at the endo isomer. This is in agreement with the experimental results, because 59a represents the (S)-product and 59b the (R)-product when dimethyl malonate or acetylacetone is the nucleophile. This is also in line with the results by Helmchen, who has shown experimentally that the exo-allyl complex is more stable than the endo isomer27 and also the complex leading to the major product.35b

29 Ph H Ph H HO O HO O N P Ph N P Ph Pd Ph Pd Ph Ph Ph Ph Ph 58a 58b

H OH H OH Ph O Ph O N P Ph N P Ph Pd Ph Pd Ph Ph Ph

Ph Ph H Nu H Nu 59a 59b

Figure 19. Nucleophilic attack at the exo- and endo-π-allyl–palladium complexes of ligand 46.

The lowest lying conformation of 59a (59a´) has its hydroxy group pointing towards Pd with a Pd–H bond length of 2.23 Å (Figure 20), in accordance with a weak hydrogen bond.10c 59a´ has a non-planar Pd–N–C–C–C–P ring and the phenyl rings on the phosphorus atom are essentially perpendicular to each other. The axial phenyl group has its edge and the equatorial its face towards the metal. The group of Helmchen has found that the ligand adopts a similar conformation in Pd–π-allyl complexes of other phosphinooxazolines.57 They explained the preferential reaction of the exo complex with an unfavorable interaction of the equatorial phenyl group with the allyl ligand in the endo isomer.

Several conformational minima were found for the Pd(0)–olefin complex 59b, originating from the endo-allyl–palladium complex 58b and having an olefin ligand of opposite absolute configuration compared to 59a. All conformational minima having the ligand backbone bent, and thus the phenyl groups arranged in a way similar to that in 59a´, were found to be of significantly higher energy (>2.7 kcal mol–1) than 59a´.

59a´ 59b´

Figure 20. Conformations of the Pd(0)–olefin complexes of ligand 46.

A conformational minimum 59b´ with a hydroxy–palladium interaction and the ligand backbone bent in another way and hence with differently oriented phenyl groups was found to be only 1.3 kcal mol–1 higher in energy than 59a´. Competition between reactions leading to 59a´ and 59b´ is probably the reason why low selectivity is obtained with ligand 46 under certain conditions. Similar calculations were performed on the Pd(0)–π-olefin complexes of ligand 47. A complex leading to the (S)-product was found to be the most stable and complexes leading to the (R)-product were found to have considerably higher energies (>3 kcal mol–1). This explains well the high enantioselectivities obtained with this ligand.

2.4.5 Palladium-Catalyzed Allylations of Cyclic Substrates Next, ligands 40, 41, 46, and 47 were studied in the reaction using rac-3- cyclohexenyl acetate as substrate. The obtained enantioselectivities (Table 3) were all lower than those observed using 1,3-diphenyl-2-propenyl acetate as substrate. This was expected since only a few ligands have been reported to induce high enantioselectivities for cyclic substrates.25,35c Considerable differences in ee were observed between the ligand pairs and use of the hydroxy- containing ligands resulted in higher enantioselectivites, in contrast to the reactions with 1,3-diphenyl-2-propenyl acetate.

31 Table 3. Reactions of 3-cyclohexenyl with dimethyl malonate

O O 3 OAc [η -(C3H5)PdCl]2, O O ligand, NaH, DMM *

entrya ligand conv (%)b ee (%)c abs confd 1 40 48 20 S 2 41 49 5 S 3e 46 95 59 R 4f 47 98 26 R a 3 Reaction conditions unless otherwise noted: [(η -C3H5)PdCl]2 (1.0 mol %), ligand (2.4 mol %), rac-3-cyclohexenyl (0.50 mmol), DMM (0.70 mmol), NaH (0.60 mmol), THF (6 mL), 15 h reaction time, 0 °C. b Determined by GC-MS. c Determined HPLC (chiral OD- H column). d Assigned by comparing the sign of optical rotation with literature data. e 20 h reaction time. f 10 h reaction time.

2.4.6 Iridium Catalysis Phosphinooxazolines have been found to induce high enantioselectivity in iridium-catalyzed allylic alkylations of mono-substituted substrates.22 The isomerization of the π-allyl–iridium intermediates has been found to be slower than that for allyl–Pd complexes and memory effects can be substantial.58 Although the mechanism is not known in detail, it has been established that the reaction proceeds via a double inversion process.59 The reaction rates as well as the regio- and enantioselectivities have all been shown to improve with electron- deficient substituents on the phosphorus atom and with increased temperature.60 Allyl carbonates generally give faster reactions than acetates but can provide lower enantioselectivities.60 Some allyl–Ir(III) complexes have been isolated and characterized, but it is unclear which ones are leading to product and by which path they do so.60 Ligands 46 and 47 were employed in the iridium-catalyzed allylation reaction using (E)-cinnamyl acetate (5) and (E)-cinnamyl methyl carbonate (60) as substrates (Table 4). The nucleophile was either prepared prior to the reaction using NaH, or generated in situ using Cs2CO3. The latter method had recently been used in Rh-catalyzed allylations resulting in high enantioselectivities.61

32 Table 4. Reactions of cinnamyl acetate and cinnamyl methyl carbonate with dimethyl malonate at 65 °C O O O O R2 ligand, [Ir(cod)Cl]2, O O O O DMM, base *

5 R = OAc 60 R = OCO2Me

entrya ligand substrate base time conv (%)b b/lb ee (%)c abs confd 1 46 5 NaH 5d 67 0.8 3 S 2 46 5 Cs2CO3 5d 14 0.6 12 R 3 46 60 NaH 5d 93 1.4 6 S 4 46 60 Cs2CO3 3d 92 0.5 1 S 5 47 5 NaH 2d 97 2.4 82 R 6 47 5 Cs2CO3 3d 98 0.6 90 R 7 47 60 NaH 2d 100 4.9 29 R 8 47 60 Cs2CO3 3d 98 4.7 68 R a Reaction conditions: [Ir(cod)Cl]2 (2.0 mol %), ligand (4.4 mol %), substrate (0.25 mmol), dimethyl malonate (0.55 mmol), base (0.50 mmol), THF (1 mL). b Determined by GC–MS. c Determined HPLC (chiral OD-H column). d Assigned by comparing the sign of optical rotation with literature data.

Comparing the results of the catalytic reaction for the two ligands, ligand 47 generally gave faster reactions, higher branched/linear ratios and considerably higher ee’s. Ligand 47 provided the product with an ee as high as 90% (R, entry 6), while ligand 46 afforded the product with the opposite absolute configuration with an ee of 6% (entry 3). Changing the solvent to toluene, gave comparable results. The reaction was also performed with substrate 61, having an electron donating substituent in the phenyl ring (Scheme 9). The product using ligands 46 and 47, was obtained with full conversions after 20 hours and had higher branched to linear ratios (1.7 and 7.5, respectively) and similar enantioselectivities [6% (R) and 73% (R)] as compared to the unsubstituted product.

33 O O O O OCO2Me ligand, [Ir(cod)Cl]2, O O O O DMM, Cs2CO3 * MeO 61 MeO MeO

Scheme 9. Reaction with an electron-rich substrate.

Although no safe conclusion can be drawn about the origin of these interesting observations, it is clear that the two types of ligands also in this reaction exhibit contrasting behavior.

2.5 Conclusions An OH–Pd hydrogen bond in Pd(0)–π-olefin complexes of hydroxy-containing pyridinooxazoline and bisoxazoline ligands has been identified by DFT computations. The presence of this hydrogen bond affects the stereochemistry of palladium-catalyzed allylic alkylations and thus explains the different behavior of hydroxy- and methoxy-containing ligands in the catalytic process. The hydrogen bond in phenanthroline metal complexes was studied in detail. As expected, the strength of the bond increases with increased electron density at the metal and with increased acidity of the hydroxy protons. The study was extended to the use of hydroxy- and methoxy-substituted phosphinooxazoline ligands. OH–Pd hydrogen bonds were also here predicted by DFT calculations for the Pd(0)–π-olefin complexes of the hydroxy-containing ligands. Under some conditions, the two types of ligands accordingly give rise to different enantioselectivities and these differences are explained in detail. Iridium-catalyzed allylic alkylations employing the two types of ligands also result in different enantioselectivities. Also here a hydrogen bond with Ir(I) serving as the proton acceptor is assumed to be involved.

34 3 Oxygen-Metal Coordination and its Consequences for Enantioselection Paper IV

3.1 Introduction This chapter deals with hydroxy- and methoxy-containing PHOX ligands and their application in the rhodium- and iridium-catalyzed asymmetric hydrosilylation reaction. A metal-oxygen interaction enhances the rigidity of the catalysts and lead to profoundly improved enantioselectivities.

3.1.1 Hydrosilylations The transition metal-catalyzed asymmetric hydrosilylation of ketones and imines is a powerful reaction, as it under very mild conditions provides enantioenriched alcohols and amines, respectively.62 Since the first report in 1973 by Kagan and coworkers,63 hydrosilylations of prochiral ketones and imines have been extensively examined with a variety of catalysts and substrates. From the start, the choice of metal was normally rhodium, but more recently the reaction has been catalyzed by a whole range of metals including iridium, titanium, zinc, and copper.62 Aryl alkyl ketones are commonly used as substrates and are often reduced with high enantioselectivity, while dialkyl ketones are more challenging substrates. The use of [Rh(cod)Cl]2 as the metal precursor, acetophenone as substrate, and diphenylsilane as reducing agent early evolved as the benchmark reaction and most ligands have been utilized for this process.62 Successful ligands for the rhodium-catalyzed reaction include thiazolidine ligand 62,64 the pyridinobisoxazoline ligands (63),65 pyridine ferrocene ligand 64,66 and P,S ligand 65.67 Ligands 64 and 65 also give good ee’s for dialkyl ketones. Titanium catalysts have been shown to be highly enantioselective for the reduction of ketones68 and imines.69 The search for a more economic hydrosilylation method has led to the development of a zinc-catalyzed hydrosilylation reaction.70 Recently copper catalysts have emerged as highly efficient catalysts for the reduction of ketones,71 imines,72 and electrophilic carbon–carbon double bonds.73

35 O H Ph2P S O O N Fe N N S NH N N PPh2 EtO2C RR

62 63 64 65

The rhodium-catalyzed hydrosilylation of acetophenone is believed to occur according to the catalytic cycle shown in Figure 21.65,74 The first step is the oxidative addition of the silane to form Rh(III) complex 66. In the second step, the ketone coordinates to form species 67. The third step is insertion of the carbonyl bond into the rhodium–silicon bond to give 68. Subsequent reductive elimination completes the cycle, releasing the silylalkyl ether and reforming the Rh(I) catalyst. To obtain the secondary alcohol, the silyl group is removed by hydrolysis. Depending on the ligand used, silyl enol ether 69 (which upon hydrolysis reverts back to the starting ketone) is a more or less common by- product.

OSiHPh2 L' Cl Ph2SiH2 Me Ph Rh L S

Reductive elimination Oxidativ addition S = solvent

H OSiHPh2 L' S H L' SiHPh2 Rh Rh 68 OSiHPh 66 Ph L Cl 2 L S 69 Cl Me Ph

Insertion H L' SiHPh2 O Rh O L Cl Me Ph Me Ph Association 67

Figure 21. Proposed catalytic cycle for the rhodium-catalyzed hydrosilylation of acetophenone.

PHOX ligands have previously been employed for the hydrosilylation of ketones and resulted in moderate to high enantioselectivities. Reduction of acetophenone

36 with diphenylsilane resulted in 73–82% ee using a Rh catalyst containing the i- Pr–PHOX (70).75 Improved selectivity was achieved using an aminoindanol- derived PHOX (71, 94% ee)76 and an oxazolylferrocene-phosphine ligand (72, 91% ee).77 The latter ligand also gave rise to 96% ee in the iridium-catalyzed reaction.78

O O O Fe N PPh2 N PPh2 N PPh2 Ph

7071 72

3.2 Hydroxy-Containing PHOX Ligands – Application in Rhodium- and Iridium-Catalyzed Hydrosilylations Having observed that ligands containing properly situated hydroxy or methoxy groups exhibited contrasting performances due to a hydroxy–metal hydrogen bond,I-III we were interested to see whether these ligands also could interact with high valent metal ions via oxygen coordination. Both types of interactions may be expected to have an influence on the stereochemistry of catalytic reactions. For this purpose, the rhodium-catalyzed hydrosilylation reaction attracted us, mainly because the enantiodetermining step involves Rh(III) species but also because there is a choice between using a neutral or a cationic complex.

3.2.1 Hydrosilylations of Prochiral Ketones Rhodium-catalyzed hydrosilylation of acetophenone was performed employing diphenylsilane together with [Rh(cod)Cl]2 and ligands 40, 41, 46, or 47. Moderate enantioselectivities were observed with all ligands (entries 1, 3, 5, and 8, Table 5), indeed lower than those reported using 70 and other standard PHOX ligands.75 In order to favor coordination of oxygen to the metal ion, the reactions were also run in the presence of AgBF4. By doing so we intended to obtain cationic rhodium complexes by abstraction of the chloride ions. We were pleased to find that under these conditions, the product was obtained with considerably higher enantioselectivities, the best result being achieved using ligand 46 (91% ee, entry

37 6). An even higher ee was obtained at 0 ºC under otherwise identical conditions (95% ee, entry 7). The counterion evidently had an effect since addition of other silver salts led to lower enantioselectivities (AgOTf: 79% ee, AgPF6: 80% ee). Other experimental details were also found to be important; employing only one equivalent of ligand gave 83% ee at room temperature and using the alternative

Rh precursor Rh(cod)2BF4 resulted in only 58% ee.

Table 5. Hydrosilylations of acetophenone using rhodium complexes of various PHOX ligands

O [Rh(cod)Cl]2, OSiHPh2 OH ligand TsOH (cat) Ph SiH 2 2 MeOH rt, 16 h entrya ligand conv (%)b ee (%)c abs confd 1 40 100 12 S 2e 40 100 63 S 3 41 100 70 S 4e 41 100 60 S 5 46 100 66 R 6e 46 97 91 R 7ef 46 100 95 R 8 47 100 56 R 9e 47 100 87 R 10 70 100 73 R 11e 70 91 69 R

a Reaction conditions unless otherwise noted: [Rh(cod)Cl]2 (0.5 mol %), ligand (2 mol %), acetophenone (1.0 mmol), diphenylsilane (1.2 mmol), THF (1 mL), 16 h reaction time, rt. b Determined by NMR. Yield of silyl enol ether: 2–10%. c Determined by chiral GC. d e Assigned by comparing the sign of optical rotation with literature data. AgBF4 (2 mol %) added. f Reaction performed at 0 ºC, yield of silyl enol ether: <4%.

In order to rule out the possiblity that these intriguing effects accompanying the addition of AgBF4 might be the result of a more general phenomenon, we subjected the i-Pr–PHOX (70) to the hydrosilylation of acetophenone. With the neutral rhodium complex the result achieved was in agreement with those 75 published (73% ee, entry 10). When AgBF4 was added to the reaction mixture a comparable ee was obtained (69%, entry 11),79 indicating that the ee enhancement using ligand 46 was somehow linked to the oxygen-containing substituents. A probable explanation for the observed results is that the oxygen atom coordinates to rhodium(III) and thereby increases the rigidity of the catalyst and enhances the enantiodiscriminating power.

38 To investigate if the effect seen for rhodium also could be observed for iridium, our ligands were subjected to the iridium-catalyzed hydrosilylation reaction. The use of our ligands together with [Ir(cod)Cl]2 for the hydrosilylation of acetophenone led to products with moderate ee’s (entries 1, 3, 5, and 8, Table 6).

Addition of AgBF4 substantially improved the enantioselectivities. The best result at room temperature was again obtained with ligand 46 (77% ee, entry 6). The product had opposite absolute configuration to that of the product obtained in the Rh-catalyzed process. The rhodium and iridium catalysts therefore nearly behave as pseudo-enantiomers. Such behavior has previously been observed for an oxazolylferrocene–phosphine77,78 as well as for a few other less selective ligands.80 No explanation for these contrasting results is available at present. By analogy with what was observed in the rhodium-catalyzed reactions, a less pronounced selectivity improvement was observed when AgOTf or AgPF6 was added in place of AgBF4. Using 70 as ligand for the reaction, the product was obtained with low enantioselectivity both in the presence and absence of AgBF4 (entries 10 and 11).

Table 6. Hydrosilylations of acetophenone using iridium complexes of various PHOX ligands O [Ir(cod)Cl]2, OSiHPh2 OH ligand TsOH (cat) Ph SiH 2 2 MeOH rt, 16 h entrya ligand conv (%)b ee (%)c abs confd 1 40 99 2 S 2e 40 99 22 R 3 41 100 8 S 4e 41 98 26 R 5 46 97 33 S 6e 46 98 77 S 7ef 46 97 78 S 8 47 100 16 R 9e 47 98 53 S 10 70 98 8 R 11e 70 99 32 S a Reaction conditions unless otherwise noted: [Ir(cod)Cl]2 (0.5 mol %), ligand (2 mol %), acetophenone (1.0 mmol), diphenylsilane (1.2 mmol), THF (1 mL), 16 h reaction time, rt. b Determined by NMR. Yield of silyl enol ether: 2–15%.c Determined by chiral GC. d e Assigned by comparing the sign of optical rotation with literature data. AgBF4 (2 mol %) added. f Reaction performed at 0 ºC, yield of silyl enol ether: <5%.

39 Encouraged by the results with acetophenone, we decided to subject a number of prochiral ketones to the hydrosilylation using 46, AgBF4, and either [Rh(cod)Cl]2 or [Ir(cod)Cl]2 (Table 7). We found that for all ketones, the two catalytic systems gave rise to products with different absolute configurations. For 4- bromoacetophenone and 4-methoxyacetophenone the ee’s were good but somewhat lower than for acetophenone (entries 1–4). For benzylacetone and 2- octanone good ee’s were observed in the rhodium catalyzed reactions, but low in the iridium system.

Table 7. Hydrosilylations of various ketones using [Rh(cod)Cl]2 or [Ir(cod)Cl]2 together with AgBF4 and 46

a b c d entry ketone M conv (%) ee (%) abs conf O 1 Rh 91 81 R

2 Br Ir 98 69 S O 3 Rh 100 85 R

4 MeO Ir 97 62 S O 5 Rh 95 67 R

6 Ir 98 13 S

7 Rh 94 55 R O 8 Ir 100 9 S a Reaction conditions unless otherwise noted: [M(cod)Cl]2 (0.5 mol %), ligand 3 (2 mol %), AgBF4 (2 mol %), ketone (1.0 mmol), diphenylsilane (1.2 mmol), THF (1 mL), 16 h reaction time, rt. b Determined by NMR. Yield of silyl enol ether entries 1–4: <6%, entries 5–8: <3%. c Determined by chiral GC or HPLC. d Assigned by comparing the sign of optical rotation with literature data.

3.2.2 Study of the Oxygen–Metal Coordination To find evidence for the assumption that the oxygen atom coordinates to the metal center, the Ir(I) complex 73 was prepared by stirring 46 with [Ir(cod)Cl]2 1 13 followed by anion exchange with AgBF4. In the H and C NMR spectra, large downfield shifts were observed for Ha (from 4.11 to 5.91 ppm) and Ca (from 77.4 to 84.0 ppm) in the complex compared to the free ligand. This is consistent with the proposed interaction of the hydroxy group with the cationic metal. A signal

40 for the hydroxy proton at 3.66 ppm (–40 °C) showed that the ligand was not deprotonated. In an analogous fashion, and for comparison, complex 74 was prepared from ligand 70, [Ir(cod)Cl]2, and AgBF4. A line broadening of the cod signals was observed in the 1H NMR spectrum of 73 at 25 °C as an indication of exchange between certain cod protons. This observation was confirmed by running a 2D EXSY experiment, in which the appearance of cross-peaks between the corresponding protons proved unambiguously the site exchange due to the internal rotation of the cod ligand in the complex. The signs of the same exchange could also be observed for 74 but only at a higher temperature. The chemical shift differences between the signals involved in the exchange process were large enough and allowed us to determine the exchange rate by magnetization transfer experiments by selective inversion of the corresponding signals.81 Simultaneous analysis of the data resulted in a rate constant of 0.630 (± 0.008) s-1 for the rotation of the cod ligand in 73 at 25 °C, while a much slower rate of 0.041 (± 0.001) s-1 could be calculated for 74 at 45 °C. The difference between the two complexes can probably be explained by the oxygen–metal coordination in 73, resulting in a pentacoordinated arrangement.

O O

N PPh2 N PPh2 Ph BF4 BF4 H Ir Ir a O H

73 74

3.3 Conclusions Phosphinooxazolines carrying a hydroxy or a methoxy group were found to provide moderate to excellent enantioselectivities in rhodium- and iridium- catalyzed hydrosilylations of acetophenone. The enantioselectivities were higher using cationic complexes as compared to neutral species. This phenomenon is explained by an oxygen–metal coordination in the former type of complexes, which is confirmed by NMR studies of an iridium complex. The rhodium and iridium catalysts give opposite enantiomers of the product, an interesting observation for which no explanation can be provided to date.

41 42 4 Bifunctional Lewis Acid – Lewis Base Catalysis Paper V

4.1 Introduction This chapter deals with chiral ditopic pybox ligands and the application of their metal complexes in the asymmetric addition of cyanide to benzaldehyde. These complexes, containing both Lewis acid and Lewis base moieties, are capable of dual activation of the substrate and the cyanation reagent, thus rendering it possible to use the convenient but fairly unreactive reagents ethyl cyanoformate and acetyl cyanide.

4.1.1 Asymmetric Addition of Cyanide to Carbonyl Compounds Asymmetric addition of cyanide to prochiral ketones and aldehydes is a fundamental chemical reaction since it produces cyanohydrins, which constitute important building blocks for the synthesis of a variety of chiral compounds.82 Since the first report of an enantioselective synthesis of cyanohydrins in 1908,83 numerous asymmetric reactions have been developed, most of which are based on Lewis acid catalysis.82b A commonly used cyanide source is trimethylsilyl cyanide, but the use of other cheaper and less toxic cyanide sources such as cyanoformic esters and acetyl cyanide are of high interest, giving direct access to O-alkoxycarbonylated and O-acetylated cyanohydrins, respectively. The combination of a Lewis acid and a Lewis base to activate both an electrophile and a nucleophile has been particularly well studied and applied to a variety of enantioselective catalytic processes.19 Ligands based on binol20a-d and glucose20e,f have been appropriately functionalized to achieve dual Lewis acid– Lewis base activation in additions of cyanide to prochiral aldehydes and ketones. Activation of the cyanide source, usually trimethylsilyl cyanide,20a,b,e,f cyanoformic esters20c or phosphonic esters,20d has most commonly been achieved by incorporating phosphine oxide or amine functions in the chiral catalyst.

43 4.2 Ditopic Pybox Ligands – Application in Cyanations of Aldehydes It was recently found in our group that tertiary amines in combination with Ti(IV)–salen complexes84 accelerate highly enantioselective reactions of cyanoformates with prochiral aldehydes, and allow the addition of acetyl cyanide.85 Since the use of a bifunctional catalyst has the advantage of avoiding undesired reactions of the Lewis acid and the Lewis base and possibly also enabling enhanced activation and enantioselectivity, we wished to have access to ligands equipped with substituents containing amino groups. As a suitable ligand class we chose the pyridinobisoxazolines (pybox), initially prepared by the group of Nishiyama in 1989.65 The first use of a pybox ligand for a metal catalyzed addition of cyanide to prochiral aldehydes was reported by the group of Iovel in 1997.86 An aluminum complex of the i-Pr–pybox (75) catalyzed the addition of trimethylsilyl cyanide to benzaldehyde with good enantioselectivity (90% ee). The group of Aspinall used lanthanide complexes of 75 and the phenyl–pybox (76) for the addition of trimethylsilyl cyanide to a 87 range of aldehydes. An ee of 91% was obtained with a combination of YbCl3 and 76 in the cyanation of benzaldehyde.

O O N O N O N N N N Ph Ph 75 76

4.2.1 Synthesis of Amino-Functionalized Pybox Ligands Compound 77 was selected as a suitable precursor for ditopic pybox ligands carrying the desired amine functionalities and was obtained in two steps in good overall yield from 2,6-dicyanopyridine and (1S,2S)-2-amino-1-phenylpropane- 1,3-diol according to Desimoni et al.88 From 77 we identified two ways of introducing the amine functionalities, either via modification of the hydroxy groups followed by nucleophilic substitution or via esterification with an amino acid. Following the first approach, the four secondary amines diethylamine, 1- methylpiperazine, dibenzylamine and pyrrolidine were selected as suitable nucleophiles, as they give rise to structurally different ligands. Inspection of

44 molecular models suggested that the introduced amino groups should not take part in coordination to the metal center bound in the usual tridentate manner. To allow for nucleophilic substitutions, transformation of the hydroxy groups into suitable leaving groups was required. First we tried a one-pot procedure involving initial formation of the bistriflate using triflic anhydride, followed by addition of the secondary amine. Product formation was observed, but yields were poor. Searching for a better method we discovered that by first converting 77 into the ditosylated compound 78 and then performing the nucleophilic substitution in a second step provided superior results. Compound 78 was thus obtained in 87% isolated yield from 77 using TsCl and Et3N (Scheme 10). Ligands 79–82 were then conveniently synthesised by reacting 78 with the appropriate amine in acetonitrile or DMF.

O O Ph N Ph Et2NH N N 44% NN79

O O N Ph N Ph N N

N 80 H NN O O Ph N Ph 51% N N N N

OR RO O O 77 R = H Ph N Ph TsCl 87% N N (PhCH ) NH Et3N 78 R = Ts 2 2 45% NN81 Ph Ph Ph Ph

H O O N Ph N Ph N N

40% NN82

Scheme 10. Synthesis of ligands 79–82.

45 Following the second approach, L-proline was chosen as a suitable amino acid 89 (Scheme 11). L-proline was first converted into N-methyl-L-proline (83) as secondary amines have been shown to be inferior as Lewis bases in a similar reaction.90 Coupling of compound 77 with 83 was achieved using EDC–HCl, HOBt and N-methylmorpholine to give ligand 84 in 67% yield.

O O Ph N Ph EDC-HCl N N COOH HOBt, NMM 77 N 67% OO 83 O O N 84 N

Scheme 11. Synthesis of ligand 84.

4.2.2 Cyanations of Benzaldehyde We started to investigate whether the standard pybox ligands 75 and 76 could be used together with YbCl3 in the catalytic additions of ethyl cyanoformate (86) and acetyl cyanide (87) to benzaldehyde (85). The results are presented in Table 8.

Pybox ligand 76 together with YbCl3 in acetonitrile did not catalyze the addition of ethyl cyanoformate to benzaldehyde (entry 1). However, in the presence of

Et3N or DMAP, the reaction ran smoothly to give the desired product (88, entries 2 and 3). Pybox ligand 75 also catalyzed the reaction under similar conditions in the presence of DMAP (entry 4). The enantioselectivities using both ligands were low to moderate.

46 Table 8. Addition of cyanide to benzaldehyde using YbCl3, a pybox ligand and an amine O O O Lewis acid, amine O R ∗ H R CN 75 or 76 CN

86 R = OEt 88 R = OEt 85 87 R=Me 89 R=Me entrya ligand amine CN agent time (h)conv (%)b ee (%)c abs confd 1 76 86 24 0 2 76 Et3N 86 1 76 28 R 3 76 DMAP 86 4 75 58 R 4 75 DMAP 86 4 90 38 S 5 76 87 24 0 6 76 Et3N 87 4 38 24 R 7 76 DMAP 87 24 0 a Reaction conditions: benzaldehyde (0.25 mmol), YbCl3 (5 mol %), ligand (10 mol %), amine (10 mol %), 86 or 87 (0.50 mmol), MeCN (1 mL), 0–25 °C. b Determined by GC– MS. c Determined by chiral GC. d Assigned by comparing the sign of optical rotation with literature data.

Changing the cyanation reagent to the less reactive acetyl cyanide resulted in no conversion without base (entry 5). The use of Et3N as base resulted in a moderate conversion to product (89, entry 6), whereas no product was obtained in the presence of DMAP (entry 7). Having demonstrated that cyanations take place employing pybox ligands 75 and 76 in the presence of Lewis bases, we moved on to the five ditopic pybox ligands

79, 80, 81, 82, and 84. The results obtained with YbCl3 in MeCN using ethyl cyanoformate as cyanation agent are shown in Table 9. The use of ligand 79 resulted in full conversion at room temperature in the absence of free base, although with poor enantioselectivity (entry 1). Employing ligand 80 also resulted in a smooth reaction affording the product with somewhat better enantioselectivity (entry 2). It is interesting to note, even though the effect is small, that the absolute configuration of the cyanation product employing ligand 80 is the opposite to that obtained when using ligand 79. The reactions were also run in DMF (racemic product) and CH2Cl2 (slower reaction and racemic product). The reaction using ligand 82 ran smoothly, whereas reactions using ligands 81 and 84 had to be run at 60 °C to give acceptable conversions (entries 3–5). The product was obtained with very low or no ee.

47 The addition of acetyl cyanide to benzaldehyde was also examined. The reaction proceeded using ligands 79 and 80 (entries 6 and 7), thus verifying that the amino substituents serve as Lewis basic sites. As expected,85 the addition of acetyl cyanide was much slower than that of ethyl cyanoformate.

Table 9. Addition of cyanide to benzaldehyde using YbCl3 and a ditopic pybox ligand O O O R O Lewis acid ∗ H R CN ligand CN

85 86 R = OEt 88 R = OEt 87 R=Me 89 R=Me entrya ligand CN agent T (°C) conv (%)b ee (%)c abs confd 1 79 86 25 100 9 S 2 80 86 25 96 28 R 3 81 86 60 100 2 R 4 82 86 25 99 4 S 5ef 84 86 60 100 0 6f 79 87 25 44 5 S 7f 80 87 25 74 1 S a Reaction conditions unless otherwise noted: benzaldehyde (0.25 mmol), YbCl3 (5 mol %), ligand (10 mol %), 86 or 87 (0.50 mmol), MeCN (1 mL), 16 h reaction time. b Determined by GC–MS. c Determined by chiral GC. d Assigned by comparing the sign of optical rotation with literature data. e 5 mol % ligand. f 72 h reaction time.

We also investigated the use of other lanthanide salts. Lutetium, which has a smaller atomic radius than ytterbium, has previously provided somewhat better 91 results than ytterbium. Both LuCl3 and CeCl3 were shown to catalyze additions of ethyl cyanoformate to benzaldehyde in the presence of ligands 79–82, although 60 °C was required for reactions using ligand 81 (80–100% conversions, <20% ee’s). Catalysts prepared from ytterbium triflate were shown to be less reactive than those prepared from YbCl3, requiring 60 °C also for reactions with 80 and providing moderate conversion even at that higher temperature for 81. The products obtained using ligands 80, 81, 82, and 84 were essentially racemic. Interestingly, the product obtained using 79 and ytterbium triflate had an absolute configuration (18% ee) opposite to that obtained using 79 and YbCl3.

48 Next, aluminum complexes were subjected to the catalytic addition of ethyl cyanoformate to benzaldehyde. Ligand 79 gave rise to a very slow reaction at room temperature, but full conversion was achieved at 60 °C, resulting in a racemic product. Use of the less sterically hindered pyrrolidine-containing ligand 82 gave the desired product within 16 hours at room temperature with 98% conversion and 16% ee (R). In contrast to the situation with YbCl3, AlCl3 together with pybox ligand 75 and triethylamine resulted in very low conversion (< 8%, 16 hours) at room temperature. When triethylamine was exchanged for N-methylpyrrolidine, full conversion was achieved after 16 hours resulting in a racemic product.

4.3 Conclusions Five ditopic pybox ligands, which upon complexation to metal centers provide catalysts with Lewis acidic and Lewis basic sites, were synthesized. Lanthanide complexes of the new ligands were found to catalyze the addition of cyanide to benzaldehyde using the cheap but normally unreactive cyanation reagents ethyl cyanoformate and acetyl cyanide. Full conversions but low to moderate enantioselectivities were obtained. In contrast, no reaction was observed when the ditopic ligands were replaced by conventional pybox ligands, demonstrating that the amino substituents in the ditopic ligands serve as Lewis basic sites. The addition of ethyl cyanoformate was also catalyzed by an aluminum complex of a ditopic ligand containing pyrrolidine rings. Interestingly, some ligands useful for the lanthanide-catalyzed reaction were found to give rise to rather inactive aluminum complexes. Modification of the catalysts is needed to obtain better enantioselectivities.

50 5 Concluding Remarks and Outlook

This thesis describes examples where secondary interactions have been shown to significantly affect the outcome of catalytic reactions. Considerable attention had been devoted to the effect of such interactions prior to this report, and most certainly continued studies will result in new useful examples. When examining Nature’s own catalysts, the enzymes, the advantages with catalysts containing more than one binding site become obvious. Weak hydrogen bonds with late transition metals serving as hydrogen bond acceptors were shown to affect the stereochemistry of metal-catalyzed allylic alkylations using hydroxy-containing ligands. Most probably additional examples will follow that will broaden the scope of this effect. A particular challenge consists of designing hydroxy-containing ligands which upon O- alkylation yield ligands serving as pseudo-enantiomers to the original ligands. Another potential application for these weak hydrogen bonds might be in the area of molecular switches. The conformational change accompanying the shift in oxidation state from Pd(II) to Pd(0) could probably be useful in applications far from catalysis. An oxygen–metal coordination was shown to improve the enantioselectivities obtained in rhodium- and iridium-catalyzed hydrosilylations of prochiral ketones. Such interactions could certainly also be useful in other catalytic processes and investigations of this kind are already underway. Finally, metal complexes of ditopic pybox ligands were shown to catalyze the asymmetric addition of ethyl cyanoformate and acetyl cyanide to benzaldehyde. Modifications of the catalysts are clearly needed to improve the enantioselectivities, but the results of such attempts may be rewarding.

52 6 Acknowledgements

First of all, I would like to acknowledge my supervisor Christina Moberg. Thank you very much for having accepted my as a PhD student, for sharing your knowledge in various fields and for always having time for interesting discussions. Secondly, I am grateful to the Swedish Research Council and KTH for financial support. Furthermore I would like to acknowledge Alliance Française and the Swedish Chemical Society for supporting my short research stay in Rouen, France, and to the Aulin-Erdtman Foundation, the Knut and Alice Wallenberg Foundation, and the Lars Gunnar Sillén Foundation for making it possible for me to present my work at various conferences. Vincent Levacher and all the members of his group are gratefully acknowledged for welcoming me at IRCOF in Rouen. Thank you very much for the inspiring research environment you presented me with. All the present and former colleagues at the Department of Organic Chemistry and especially in the Ki group are gratefully acknowledged for creating a good working atmosphere. Special thanks to Fredrik Rahm, Christian Linde, and others for initial guidance in the lab, Raivis Žalubovskis for always lending me a helping hand, and Erica Wingstrand for interesting office discussions. Also a big thank you to my diploma workers Mélanie Tilliet, Armen Panossian, and Christian Belger for having done a great job.

Ulla Jacobsson, Krister Zetterberg, Stina Lundgren, and Kurt Möller are acknowledged for valuable discussions and comments on this thesis, Ulla Jacobsson and Zoltan Szabo for helping me with NMR-related issues and Timofei Privalov for supervising my computations. I am also thankful to Ingeborg Csöregh for the X-ray analysis and Lena Skowron, Ann Ekqvist, and Henry Challis for help with practical matters.

Thank you Stina, Mélanie, Raivis, and Per Restorp for being good friends of mine. Finally, I would like to thank my family for having provided a stimulating environment for me during my younger years and Anna-Karin for her wonderful spirit and for being perfectly skilled for making me dedicated and happy.

54 7 References

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