University of Groningen

Copper-catalysed asymmetric carbon-carbon bond formation using Grignard reagentsGeurts, Koen

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Chapter 1 Introduction

2 // Chapter 1

1.1 Emergence of order at the origin of life “Life is a flow of energy, matter and information” according to one of the many definitions1,2 given to life. That incessant flow of energy and mass must obey the second law of thermodynamics3 which states that the overall entropy of an isolated system not in equilibrium must increase, with its peek entropy at the point of thermodynamic equilibrium. In this continuous flux of energy and matter toward thermodynamic equilibrium patterns may emerge (Fig. 1).4

Fig. 1: Ripples in the sand or more complex, termite hills and cities.

This emergence of patterns may seem counterintuitive in that the system appears to become more structured. But in fact these critically unstable ordered structures maximise the rate of energy dissipation toward thermodynamic equilibrium and therefore are not in contradiction with the second law of thermodynamics. If now such an emergence is able to convey information through time that emergence may be called life. Life thus, in all its abundance and splendour is ultimately nothing more then a physical phenomenon; an optimal route toward thermodynamic equilibrium.

1.2 Life, carbon and homochirality Life as we know it is carbon based.5 The complex biomolecules involved in primary metabolism including proteins, nucleic acids, enzymes, carbohydrates and fatty acids that constitute “our biology” are composed of carbon atoms connected to each other (the carbon backbone) and to, among others, oxygen, nitrogen, hydrogen, sulfur and phosphorus. Two of the most important characteristics that make carbon so suitable to sustain life are: the energy required to make and break a bond with carbon is just at the appropriate level for building molecules that are not only stable but also reactive and the ability of carbon to form 4 bonds.

The balance between stability and reactivity of molecules composed in large part from carbon can be illustrated by comparing the dominant chemical composition in which carbon is present on earth in respect to its group 14 cousin silicon.6 Even though carbon is estimated to be ten times more abundant in the universe and sixteen times more abundant in the solar system, the earth’s crust contains twenty times more silicon (Si) than carbon. This difference in relative abundance can be attributed to the reactivity of the two elements. Silicon, with a Pauling

Introduction // 3

electronnegativity of 1.9 (compared with carbon at 2.6)7 is an oxophilic element that forms very stable bonds with oxygen (eletronegativity: 3.4)7 to form SiO2 (silica), a white crystalline solid and a relative inert material, thus not very suitable to accommodate the complex and dynamic chemistry that we observe in living systems. Carbon on the other hand reacts with oxygen to form CO2, a gas. As such, carbon has a higher chemical mobility than silicon because the latter is chemically immobilized as its oxide, while CO2 can take part in dynamic chemical processes. Because of carbon’s chemical mobility it can accommodate the complex and dynamic chemistry of living systems.

Besides being available in large quantities and possessing the ability to form and break bonds with other elements rather easily, carbon has another feature that makes it excellently suited to be the chemical backbone of life. Carbon can form up to 4 bonds in a tetrahedral arrangement with other elements. When these four substituents are not identical, the carbon to which those substituents are bonded is a stereogenic centre and the molecule itself is chiral (Fig 2). An object or a system is denoted as chiral if its mirror image cannot be superimposed on the original (Greek: χειρ (cheir) = hand, your left and right hands are mirror images of each other and cannot be superimposed) as is the case with four different substituents attached to one carbon atom. A chiral object and its mirror images are called enantiomorphs (Greek for opposite forms). When referring to molecules containing one stereogenic centre, the original and its mirror image are called enantiomers. If multiple stereocentres are present in a molecule, they are called diastereoisomers; with the exception of chiral molecules that do not possess a stereogenic centre but nonetheless are chiral e.g. biaryls, allenes, and helixes.8

Alanine, a natural α-amino acid, possesses a central stereogenic carbon atom with 4 different substituents attached to it. Therefore this molecule is chiral since its mirror image cannot superimpose on the original (Fig 2).

CO2H

HNH2

Me

CO2H

HH2N

Me

D-Alanine L-Alanine

Fig. 2: Enantiomers of Alanine.

Even though alanine exists as a pair of enantiomers, D- and L-alanine, life uses only one of the two enantiomers, L-alanine. All the other 19 genetically encoded α-

4 // Chapter 1

amino acids that make up our proteins, display the same relative configuration at the stereogenic carbon α to the carbonyl. Life is therefore said to be homochiral. The origin of the homochirality of life has been and still remains subject of much debate in the scientific community.9 Even though chiral molecules are the rule and not the exception10 (there are more chiral molecules than achiral molecules within the organic chemical framework) a symmetry-breaking event must have taken place to explain the homochirality of the basic building blocks of life. Scientists have even resorted to explanations such as: imbalances in the energy of enantiomers due to a lack of antimatter parity11 or enantioselective decomposition of organic matter in meteorites by polarized radiation from distant galaxies.12 In general the debate can be divided into those who favour a symmetry-breaking event based on statistical arguments13 or those based on a physical chemical argument, e.g. sublimation of α-amino acids14 and attrition-enchanced Ostwald ripening of α-amino acid derivatives15, of either terrestrial or extraterrestrial organic material.16 Even though the origin of homochirality may still be under debate, it is clear that homochirality is quintessential for life since it ensures selective interaction between molecules and thus facilitates information transfer, storage and integrity in living systems through time.

1.3 Carbon−carbon bond formation Because life is built around the carbon backbone, C−C forming reactions are among the most important bond forming reactions in natural- and anthropogenic chemistry. The latter can roughly be divided in three main groups: pharmaceutical, agrochemical and petrochemistry. Within these groups a whole flotilla of C−C bond forming reactions has been developed. Among the most common used synthetic strategies are: carbanion alkylation, carbonyl addition, aldol and related condensations, conjugate addition reactions, reactions of alkenes and aromatics, cycloadditions and radical reactions (Scheme 1).

Introduction // 5

Carbanion Alkylation1) Alkylation of enolates

R

O

+ R1 X R

OR1

2) Organometallic alkylation

R MgXO

ROH

Carbonyl addition3) Aldol

O2

OH O

4) Organometallic reactionsO OH

RR MgX

+

Base

+

Reactions of alkenes and aromatics7) Cyclo additions: Diels-Alder

8) Friedel-Crafts acylation

R

O

RCO

9) Organometallic reactions:The Heck reaction

X *Pd0+

+

Conjugate addition reactions;Michael or 1,4 addition

O

+ CH(CO2Et)2

O

O ORMgXR2CuLi

5) Malonate addition

6) Organometallic addition

R

CH(CO2Et)2

+

R

*Ti3+

R R Rn

10) Polymerization reactions

Radical reactions

O2 Mg, H+ OH OH11) Pinacol formation

R3

R2

R

R1

R7

R6

R4

R5

R5

R4

R

R1

R7

R6

R2

R3

Olefin metathesis

*[Ru]

H+

H+

H+

H+

* Metals are surrounded by ligands Scheme 1: Carbon−carbon forming reactions.8a

1.4 Asymmetric C−C bond formation In view of the fact that receptors and enzymes are chiral there will be a difference in binding constant and reactivity between two enantiomers. Therefore, in order to make biologically relevant and selective molecules e.g. drugs, flavours, perfumes and agrochemicals, resolution and asymmetric synthesis methods (Scheme 1)17 were developed to gain access to enantiopure compounds that are able to convey the ‘right message’ to the ‘right place‘.

6 // Chapter 1

Chiral pool Racemate Prochiral substrate

synthesis resolution asymmetric synthesis

kineticand DKR crystallization auxiliary catalytic biocatalytic

Optically enriched compounds Scheme 2: Routes to enantioenriched compounds.

The simplest source of enantiomerically enriched compounds is biological systems. Biologically produced chiral molecules that are available in useful quantities are called the chiral pool (Scheme 2). For instance lactate, the ionic form of L-(+)-lactic acid18 (falsely believed to cause muscle soreness19) 1.1 is produced from pyruvate in a variety of microorganisms. Industrially, lactic acid 1.1 is produced by fermentation of glucose by Lactobacillus bacteria.20

OH

N

HO N

OOH

O

OH

1.1 L-Lactic acid 1.2 Quinine 1.3 L-menthol Fig. 2: Chiral pool compounds.

Quinine 1.2 and menthol 1.3 are two other widely known and used compounds from the chiral pool. Quinine 1.2 was isolated from the bark of the Cinchona tree in 1817 by French researchers Pierre Joseph Pelletier and Joseph Bienaimé Caventou. Quinine is most famous for its antimalarial properties. Cinchona trees remain the only practical source of quinine. Even though chemical synthesis routes are available, none can compete in economic terms with the isolation of quinine from the cinchona tree.21 L-(-)-Menthol was first isolated in 1771 by Hieronymous David Gaubius22, although Japanese culture reports the use of menthol containing plants for at least 2000 years. The use of menthol as a flavour additive in chewing gum is one the best known of its numerous applications. The extraction of menthol from plants does not meet the massive demand. Therefore an asymmetric synthetic route toward enantiomerically enriched menthol on an industrial scale was developed by Otsuka et al.23

Introduction // 7

Evidently, only one of any two enantiomers can be obtained from the chiral pool and therefore it is possible that the unwanted enantiomer is simply inaccessible.24 A different route that in potential provides access to both enantiomers starts with a racemic (Latin: racemus = a bunch of grapes) mixture and then resolves the two enantiomers. The first to resolve a racemic mixture through crystallisation (spontaneous resolution of the ammonium salt of tartaric acid) was Louis Pasteur in 1848.25 However, spontaneous resolution is not a common phenomenon and therefore not practical. The field further matured with the development of resolution techniques using chiral resolving agents e.g. menthol (classical resolution).8,26 Even though the maximum yield of this process is 50%, classical resolution is still the most used method to obtain enantiopure compounds in industry. Higher yields can be obtained in a process called dynamic kinetic resolution (DKR) during which the substrate racemises in situ.

A fundamentally different approach toward the synthesis of enantiomerically enriched compounds is to start with a prochiral substrate and then create the desired stereocentre by chemical transformations. There are three different techniques that achieve such asymmetric synthesis (Scheme 2). If a chiral auxiliary is used, a stoichiometric amount of an enantiopure reagent is attached to the prochiral substrate. The configuration of the stereogenic centre formed is being dictated by the configuration of the chiral auxiliary, making the overall transformation diastereoselective.27 A major drawback of this method is the use of stoichiometric amounts of chiral auxiliary and the 2 additional steps required for attachment and removal of the chiral auxiliary. In a similar fashion stoichiometric amounts of chiral reagents can be employed as well. Catalytic asymmetric catalysis however circumvents these disadvantages by making use of a chiral catalyst to transform a prochiral substrate into a chiral enantiopure product. The chiral catalysts employed are commonly based on (transition) metals complexed to enantiopure organic ligands. Both enantiomers of a product can be obtained by simply inverting the configuration of the ligand used. In the case of biocatalytic asymmetric synthesis enzymes or antibodies are being utilized as catalysts28 which can be highly selective for specific substrates. In this case however due to their natural homochirality, obtaining the non-natural enantiomer may prove to be a major hurdle, that may be solved by directed evolution methods.29 Finally, a renaissance of a field of research called organocatalysis30 provides a metal free entry into the catalytic production of enantiopure compounds.31

Of the most common C−C bond forming reactions (Scheme 1), our group has been intimately involved in developing catalysed asymmetric versions of a number of these reactions. Our research primarily focused on the asymmetric conjugate addition reaction and more recently on the asymmetric allylic alkylation reaction using organometallic reagents.

8 // Chapter 1

1.5 Conjugate addition reactions The conjugate addition or 1,4-addition refers to the addition of any nucleophile to an unsaturated system in conjugation with an activating group 1.4, usually an electron-withdrawing group (EWG = CHO, COR, CO2R, CONR2, CN, SO2R, NO2

etc, Scheme 3). After protonation of enolate intermediate 1.5 the conjugate addition product 1.6 can be obtained. Michael-addition strictly refers to the addition of induction- or resonance-stabilized carbanions to unsaturated systems in conjugation with an activating group.32

EWGR Nu

EWGR

Nu

EWGR

Nu

H+

EWGR

Nu

-

-

-

1.4

1.6

α

β

α

β

1.5 Scheme 3: The conjugate addition reaction.

The first example of a conjugate addition reaction, in this case a Michael addition, was reported by Kommenos in 1883.33 Since this early work the conjugate addition has developed into one of the most widely used methods for C−C bond formation reactions in organic chemistry. The development of catalysed asymmetric conjugate additions reactions using organometallic reagents in the past three decades has played a major role. Not surprisingly, they are frequently used as key transformations in the synthesis of complex biologically active molecules.34

1.5.1 Catalysed conjugate addition reactions using carbon nucleophiles For the conjugate addition with carbon nucleophiles a variety of organometallic reagents can be used.35 The carbon nucleophiles can be separated in two different types. First, hard carbon nucleophiles; organometallics with a strongly polarized C-M bond like LiR,36 NaR, MgR2 ZnR2. Second, soft carbon nucleophiles; organometallics with a weakly polarized C-M bond like some transition metal organometallic reagents37 or stabilized carbon nucleophiles like enolates (Michael-donors). The polarization of carbon nucleophiles has a significant impact on the regioselectivity of the addition (Scheme 4).

Introduction // 9

R R1

O 1

2

4

R3

R12

4 OH

3

Nu1

R R1

O 1

24

Nu

3

Soft Nu

1,4-addition

Hard Nu

1,2-addition

− −

+ H+H

1.7 1.8 1.9 Scheme 4: Regioselectivity of the conjugate addition.

Soft nucleophiles preferentially add to the 4-position of substrate 1.8, yielding after protonation the 1,4-addition product 1.9. If hard nucleophiles are used the regioselectivity of the reaction shifts from the 4 position toward the 2 position, giving after protonation the 1,2-addition product 1.7. Among organo-transition metal compounds, homocuprates, heterocuprates, and higher-order cuprates are now the most widely used reagents that show high 1,4-selectivity.38 Although these reagents can be used in a stoichiometric amount, already as early as 1941 Kharasch et al reported that the use of a catalytic amount of CuCl in the addition of MeMgBr to isophorone gave the 1,4-addition product selectively. If no copper was present the 1,2-addition product was obtained as the dominant product.39 This event led to an exhaustive investigation of a large variety of transition metals and organometallic reagents in the catalysed conjugate addition eg. Mn, Co, Ni, Pd, Cu or Zn catalysts with organometallic reagents containing Li, Na, Mg, B, Al, Zn, Sn, Ti, Zr and Mn atoms.40

1.5.2 Copper-catalysed asymmetric conjugate additions using Grignard reagents

Stereoselectivity in the catalysed conjugate addition can be achieved via several different routes. Diastereoselective conjugate additions, starting from enantioenriched starting materials, and stereoselective stoichiometric reactions as well as stereoselective Michael additions 41 have been developed but they are not subject of this introduction nor of this thesis.42 The catalysed enantioselective conjugate addition using enantiomerically pure ligands has been developed also.34c,43 Complexes derived from Cu salts and chiral ligands have provided the best results when using organometallic reagents. The most commonly used organometallic reagents for these transformations are organozinc, Grignard, organoaluminium, organolithium and cuprate reagents.44,45 The most successful have been the organozinc reagents (Scheme 5), however these transformations are not part of this introduction nor of this thesis. 42,44,46

10 // Chapter 1

O O

R1

Cu(OTf )2 (2 mol%)L1 (4 mol%)Toluene, −35 °C

R2Zn

OP

ON

L1 =1.101.11 (72%) >98% ee

1.12 (95%) 94% ee

1.13 (77%) 95% ee

R = Me

R = i -Pr

R = (CH2)5OAc

Scheme 5: Cu-catalysed asymmetric conjugate addition using organozinc reagents.

Although organomagnesium reagents were among the first organometallic compounds to be applied to synthetic organic chemistry, the discovery of the highly enantioselective Cu-catalysed conjugate addition of dialkylzinc reagents replaced the use of Grignard reagents in this asymmetric C−C bond forming reaction. Even though there are several advantages to the use of common mono-alkylMgX reagents in place of organozinc reagents, most importantly being their ready availability and the transfer of all of the alkyl groups of the organometallic compound, it is only recently that efficient Cu-catalysed enantioselective conjugate addition of Grignard reagents has been achieved. 47,48 For recent advances in the Cu-catalysed asymmetric conjugate addition of Grignard reagents, see chapter 2.

1.6 Tandem reactions Organic reactions are generally viewed as linear and stepwise processes, in which isolation and purification of key intermediates often lead to reduced yields. The search for economical and no less environmental more efficient synthetic pathways has led to the development of “tandem” processes that allow access to a myriad of complex molecules with high stereocontrol in an efficient, atom-economical manner. Before elaborating on tandem reactions, however, some discussion regarding the terminology and organization of this type of transformation is warranted. In the literature, different authors use varying definitions as to what constitutes a “tandem” process. As duly noted by Nicolaou, terms including “tandem”, “domino”, “cascade”, and “sequential”, are frequently used, apparently interchangeably.49

The dictionary definition of tandem as “one behind the other”50 is, in itself, inadequate since every reaction sequence would qualify as a tandem reaction. To restore order in the particular field of reaction terminology Tietze et al51 proposed the following, now widely used, definition for domino (cascade) reactions in their authorative review concerning domino reactions: a domino reaction is a process involving two or more bond-forming transformations (usually C−C bonds) which take place under the same reaction conditions without adding additional reagents and catalysts,

Introduction // 11

and in which the subsequent reactions result as a consequence of the functionality formed in the previous step.52 However, this strictest of definitions53 of a domino process would discount any example in which the reaction conditions are altered during the process or in which further reagents are added at various points (“one-pot” transformations). Therefore in this thesis the terminology as proposed by Denmark et al is being followed, wherein tandem reactions are being defined as: reactions that occur one after the other, and the modifiers, domino, consecutive, and sequential specify how the two (or more) reactions follow.54 Within this definition tandem reactions can be divided into three catagories:

Tandem domino reactions, wherein the reactions are intrinsically coupled, i.e. each subsequent stage can occur by virtue of the structural change brought about by the previous step under the same reaction conditions.

Tandem consecutive reactions, wherein the first step is necessary but not sufficient for the tandem process, i.e. external reagents or changes in reaction conditions are also required to facilitate propagation.

Tandem sequential reactions wherein the second stage requires the addition of one of the reaction partners.

The first reported tandem consecutive reaction is Robinson’s early (1917) one pot synthesis of the alkaloid tropinone as a precursor to the drug atropine and counts as the seminal work in the field of tandem reactions (Scheme 6). 55

O

O

OO

O

O

O

Ca2+ M eNH2H2O, rt

N

O

CO2H

CO2H

MeN

O

Me

HCl+ NaOH

1.14 1.15 1.16 1.17Tropinone

Scheme 6: Robinson’s one pot synthesis of tropinone 1.17.

The progress in the development of tandem reactions has been the subject of numerous excellent books56 and reviews. , ,49 52 54 Although tandem reactions have been divided into a wide range of subsets that describe the mode of action, nucleophilic (electrophilic, radical, pericyclic etc), the whole field can be divided based on two fundamentally distinct strategies. There are tandem reactions that are predicted and modelled based on biomimetic strategies like Johnson’s biomimetic synthesis of progesterone57 and on the other hand, there are transition metal mediated tandem reactions that do not have a direct parallel in nature, e.g. the asymmetric polyene Heck cyclization58 (Scheme 7).

12 // Chapter 1

Me

Me OH

Me

Me O O

O

TFA, 0 °CCl(CH2)2Cl

1.18

MeMe

Me

Me O O

O

1.19

cationπ -cyclization

OMe

M e

Me H

Me

H HK2CO3MeOH, H2O

1.20

H

(+/-)-progesterone

OO

OMe

OMe

X

Biomimetic polyene cyclization

[Pd2(dba)3] (2.5 mol%)(S)-BINAP (10 mol%)

OO

OMe

OMe

PdPP

* OTf

OMe

OMe O

PdP

P*

L

OTf

(+)-xestoquinone

1,2-insertion,6-exo

1,2-insertion,6-endo

N8 equiv

toluene, 110 °C1.21

Transition m etal basedpolyene Heck cyclization

1.22X = OTf , Br

O

1.23 Scheme 7: Biomimetic and transition-metal mediated tandem strategies.

1.6.1 Tandem reactions triggered by conjugate additions Conjugate addition reactions of nucleophiles or nucleophilic radicals to α,β-unsaturated carbonyl compounds, forming carbon–carbon bonds, belong to the central tenet of modern asymmetric synthesis (vide supra). Not surprisingly, considerable efforts have been made to develop tandem asymmetric transformations initiated by conjugate additions in the past decades. 59,60

Introduction // 13

O

O

OMLn

R*

LnM

O

R**

E

nucleophilic addition electrophilic trapping

[RmMLn]

*R

radical addition radical trapping

Scheme 8: Mechanistic pathways for tandem transformations triggered by conjugate additions.

According to the mechanism of the addition step, these tandem conversions can be divided into anionic and radical processes (Scheme 8). Only anionic processes will be discussed in this thesis. Stoichiometric (and/or diastereoselective) tandem conjugate additions followed by a functionalization have been known for a long time.61 The development of copper catalysed enantioselective conjugate additions using various organometallic reagents (vide supra) prompted asymmetric tandem protocols to be developed also. When alkylzinc reagents are employed, the sequence typically starts with the transfer of an alkyl ligand from the zinc reagent to the copper centre (Scheme 9). Complexation of the alkylzinc reagent to the enone carbonyl group 1.10 and formation of the π−complex of the alkylcopper species with the C−C double bond of the enone results in the formation of the heterobimetallic complex 1.23. Subsequent alkyl transfer from the copper species to the substrate generates the zinc enolate 1.24. The stereoselectivity of the overall transformation is determined by the stereoselectivity of the alkyl transfer. The resulting chiral zinc enolate 1.24 can be trapped by various electrophiles such as aldehydes, ketones, oxocarbenium ions (by way of acetal decomposition), carboxylates, nitriles, alkyl halides, tosylates and related electrophiles creating the second and, in case of a prochiral trapping reagent, third stereocentre (Scheme 9).59 Although copper is the most frequently used metal, other metals have been utilized including: Rh62, Al63, Ir64, Mg65 and Ru66 for these type of transformations. This thesis, however, takes tandem reactions triggered by copper-catalysed conjugate addition of Grignard reagents in account only (see chapter 3).

14 // Chapter 1

O

R2Zn

[L2CuX]

CuL

LR

XZnR

[L2CuR]+

RZnX

O

O

OZnR

R

E

R

( )n

( )n

( )n

( )n

E

1.10

1.24

1.25

1.23

R

Scheme 9: Mechanistic pathway for asymmetric tandem transformations triggered by

copper catalysed conjugate addition of zinc reagents.

1.7 The allylic alkylation The development of highly enantioselective transition metal-catalysed allylic alkylation reactions has enjoyed widespread attention in the past decades.43c,45f,,67 This can be attributed to the fact that the allylic alkylation reaction not only facilitates the formation of carbon-carbon bonds, but the allylated products can be easily transformed into organic molecules possessing a wide variety of functional groups due to the presence of a terminal double bond (Scheme 10). The allylic alkylation can give rise to two products via SN2 or SN2’ substitution pathways. In this way the allylic alkylation is akin to the conjugate addition (vide supra) which can give rise to 1,4-addition products in competition with 1,2-addition.

Nu

RRLG Nu+* LG+Nu

αγ

βδ αγ αγ

1.26 SN2' 1.27 SN2 1.28 Scheme 10: The allylic alkylation

Direct displacement of the leaving group of 1.26 by the nucleophile in an SN2 fashion yields linear achiral product 1.28. Displacement of the leaving group in a SN2’ fashion by attack of the nucleophile on the γ position of substrate 1.26 gives branched product 1.27 after the allylic shift of the double bond. Product 1.27 is chiral if the nucleophile ≠ R, ≠ vinyl or R ≠ H.

Introduction // 15

Tremendous progress has been made in developing methods that provide full control over the regio- and enantioselectivity of the allylic alkylation reaction. Firstly, asymmetric allylic alkylation of soft carbon nucleophiles67d-f, including enolates and later hard organometallic based carbon nucleophiles have emerged.68 Distinctly different mechanisms are proposed for the metal-catalysed allylic alkylation reactions with hard and soft nucleophiles. In palladium-catalysed reactions the soft nucleophile67g,69 will approach the allyl moiety from the opposite side of the coordinated metal ion (see intermediate I), where with hard nucleophiles reductive elimination (see intermediate II) results in C−C bond formation.

R

R1

L

L

* L

L

*

NuNu

R R1

OAcPdL*CH2(CO2CH3)2Base

R R1

CH3CO2 CO2CH3

R

CuL*R1MgBr

R

R1

Br

Soft nucleophile Hard nucleophile

I IIR

1.29 1.30 1.31 1.32

Scheme 11: Soft vs hard nucleophiles in allylic substitution reactions.

Although stabilized carbon nucleophiles like enolates or malonates are widely used as nucleophiles in the (Pd- or Ni-catalysed) allylic substitution reaction,70 these reactions are neither the subject of this introduction nor of this thesis.

1.7.1 Copper-catalysed allylic alkylation As with the copper-catalysed conjugate addition of organometallic reagents Kharasch carried out the initial experiments that proved to be seminal in this field.71 Based on these results efforts were made to combine Cu and Zn catalysts with organometallic reagents based on Mg, Zn, Al or Ti.32 The use of Grignard reagents in the allylic alkylation reaction generally provided products with only moderate regioselectivity due the presence of a background reaction between the substrate and the Grignard reagent. Better regioselectivity whilst using Grignard reagents could be obtained using sterically hindered catalysts72 and substrates73 or by slow addition of the substrate to the catalyst solution.74 Even though asymmetric versions of the allylic alkylation using stoichiometric organocuprates have been reported75, catalytic asymmetric allylic alkylations lagged behind due to the sensitivity of the reaction toward the coordinating ability of the leaving group, the temperature and the method of addition of the substrate and the organometallic reagent. Only as late as 1995 Bäckvall and Van Koten reported the

16 // Chapter 1

first breakthrough in copper-catalysed asymmetric allylic alkylation reactions showing an enantio-, regio- and chemo- selective copper-catalysed addition of Grignard reagents to allylic halide substrates reaching complete regioselectivity and enantioselectivities of up to 42%. The progress of copper-catalysed asymmetric addition of Grignard reagents and possible mechanisms are being described in Chapter 4 of this thesis.67i Parallel to using Grignard reagents, zinc reagents have been used in this type of transformation. The highlights of the copper-catalysed AAA using zinc reagents after 1995 are being summarized in the following paragraph.

1.7.2 Copper-catalysed asymmetric allylic alkylation with zinc reagents Although the first enantioselective copper catalysed allylic alkylation reaching enantioselectivities of up to 42% used Grignard reagents, a major step forward was made when Dübner en Knochel focused on the use of zinc reagents.76

Ph Cl

(neopentyl)2Zn

CuBr Me2S (1 mol%)Ph

L2/L3 (10 mol%)

1.33 1.34NH2

Fe

t-Bu

NH2

Fe

t-Bu

L2 , −90 °C, 82% ee L3, −30 °C, 96% ee Scheme 12: Zinc reagents in copper-catalysed AAA reactions.

When they reacted cinnamyl chloride 1.33 with dineopentylzinc in the presence of CuBr•Me2S/L2 at −90 °C product 1.34 was obtained with 82% ee. Later, the more bulky ligand L3 proved to be more effective providing 1.34 with 96% ee at higher temperatures. The use of linear dialkylzincs such as dipentylzinc and functionalized dialkylzinc reagents afforded the corresponding products in moderate 44–65% ee only. Enantioselective allylic substitutions with linear alkylzinc reagents remained a major challenge.

This issue was independently addressed by our group77 (Scheme 13, L1 and L4) and the Alexakis group, with the development of the copper/phosphoramidite based catalyst system. Alexakis et al used Grignard reagents; these systems will be discussed in Chapter 4.78 Treatment of cinnamyl bromide 1.35 with diethylzinc in the presence of CuBr•Me2S and phosphoramidite L1 in diglyme at −40 °C afforded 1.36 with 77% ee. Further extensive screening of chiral phosphoramidites, solvent and copper salts revealed that L4 with Cu(I)OTf in THF led to improved enantioselectivity. As noted by Bäckvall and Van Koten, the enantioselectivity and regioselectivity were sensitive to changes in reaction parameters such as: concentration, leaving group, order of addition, etc.79

Introduction // 17

OP

ON

OP

ON

O

OP N

Ph Br

Et2Zn

CuX, (1 mol%)L, (2 mol%)

Ph

Et

1.35 1.36

L =

L1, −40 °C, 77% eeX = Br

L4 , −60 °C, 86% eeX = OTf

L5 , −30 °C, 71% eeX = OTfMe2S

Scheme 13: Phosphoramidite ligands in AAA with Cu and zinc reagents.

Zhou and co-workers employed chiral spiro phosphoramidite and phosphite ligands L5 in asymmetric allylic substitution reactions.80 The enantiomeric excess of the products obtained was generally moderate.

Hoveyda and co-workers developed various peptide-based modular chiral ligands for copper-catalysed asymmetric allylic substitution reactions.81 The modularity of these ligands allowed for high-throughput screening of generic ligands leading to rapid improvement of the efficiency, regioselectivity, and stereoselectivity of the reaction with ee’s up to 97% for tertiary carbon atoms (Scheme 14, L6, 1.45→1.46). Moreover, ligands that facilitate the asymmetric syntheses of quaternary carbon atoms were identified providing products with ee’s up to 90%. Woodward and co-workers examined 2-halomethylcinnamate derivatives as substrates in AAA reactions using 2,2’-binaphthol L7 (BINOL) as ligand, providing the corresponding products with up to 64% ee. Other BINOL-type ligands exhibited lower enantioselectivities, and the system resisted further optimization.82 As alternative chiral secondary amines L8 ligands were tested as well (CuTC = copper thiocarboxylate). The C2-symmetric di(1-arylethyl)amine skeleton appeared crucial for efficient stereoselection.83 High-throughput screening identified 4-methoxy-substituted ligand L8 to be the optimal ligand reaching enantioselectivities of up to 87%. Free amines such as L8 were always superior to their corresponding hydrochloride salts. Moreover, kinetic studies revealed that the enantioselectivity of the reaction decreased as the reaction proceeded. Okamoto and co-workers used carbene–copper complexes of L9 for asymmetric allylic substitution reactions.84 Sterically demanding L9 gave the highest ee values. Parallel to their modular Schiff base ligands Hoveyda and co-workers have developed new bidentate carbene-ligands.

18 // Chapter 1

N N

SMe

OHOH

SMe

N N

AgO

2

L8, 64% ee

Et2Zn, L6 (10 mol%)CuOTf (10 mol%)

THF −30 °C

L6

L7

L9

O

L10

O

OP(OEt)2

t -Bu O

O

t-BuEt

O

N

TBSO n-C6H13MgBr

Et2O −20 °C TBSO

n-C6H13CuCl, L9

O O H

N

HN

O n-BuNH

On- Bu

R

Cl O

OMeCuTC (5 mol%), MAO

DME, −40 °CEt2Zn, L8 ( 10 m ol%) R

O

OMe

Et

Me

Me

Me OP(OEt)2O

[CuCl2 2H2O (2 mol%)THF, −15 °C

Et2Zn, L10 (1 mol%)

Me

Me

EtMe

1.37 1.38 (68%), 97% ee

R = Ph 1.39R = p-NO2Ph 1.40

R = Ph 1.41 (92%)

R = p -NO2Ph 1.42

1.43 1.44 70% ee

L7 , 87% ee

1.45 1.46 (54), 96% ee

MeO

NH

OMe

L8

[Cu(CH3CN)4BF4] (10 mol%)

THF, −40 °CEt2Zn, L7( 20 mol%)

Scheme 14: Ligands used in AAA with Cu and zinc reagents.

Dinuclear silver complex L10 underwent facile ligand exchange with copper salts to generate highly effective chiral copper complexes.85 Besides lower catalyst loading, higher stereoselectivities were obtained using L10 compared to Schiff base based catalysis.

Introduction // 19

1.8 Combining asymmetric allylic alkylation with ring closing metathesis

The asymmetric synthesis of chiral carbo- and heterocycles plays an important role in the total synthesis of many natural products. One of the routes toward chiral carbo- and heterocycles is based on asymmetric allylic alkylation followed by ring closing metathesis86 (RCM). There are two synthesis routes that allow an AAA reaction to be followed by RCM (Scheme 15). Firstly, if the substrate has an olefin moiety imbedded that can partake in an RCM reaction (route A), secondly if the nucleophile introduced via the AAA has olefin moiety imbedded that can participate in an RCM reaction (route B)

R LG[M]L*

RRCM

Nu

* R

Nu

*

R LG[M]L*, Nu

RRCM

Nu

* R

Nu

*

1.26 1.27 1.47

A

B

1.26 1.271.48

Nu

Scheme 15: Asymmetric allylic alkylation in combination with RCM.

This synthesis strategy was pioneered by Evans and co-workers using route B.87 When they used enantioenriched carbonate 1.49 as the substrate for a Rh-catalysed allylic amination with enantioenriched allylamide nucleophiles, followed by treatment with Grubbs’ catalyst, chiral azacycle 1.50 was obtained in good yield and excellent diastereoselectivity (Scheme 15).

BnONH

RhCl(PPh3)3 (cat)1) P(OMe)3, 30 °C

Ph

OCO2Me

2) Grubbs' Cat., PhHN

Ph

BnO

TsTs

1.49 1.50 (74%), ds = 22:1RuPhPCy3

PCy3

Cl

Cl

Scheme 16: Asymmetric allylic amination in combination with RCM.

After this seminal publication by Evans et al, this strategy has been employed to products of AAA reactions catalysed by Pd,88 Ir,67f and Cu.78b,c Pd and Ir based

20 // Chapter 1

methods are not part of this introduction or of this thesis since they make use of soft nucleophiles. However, the Cu-catalysed AAA followed by a RCM method developed by Alexakis et al makes use of Grignard reagents (Scheme 16).78b,c

R Cl

1) CuTC, L11MgBr

2) Cat. = Grubbs I R

( )n

OP

O

OMe

OMe

L11 =1.51 R = p-Me-Ph 1.52 (64%)n = 1, 93% ee1.53 (76%)n = 2, 94% ee

( )n

Scheme 17: Cu-catalysed asymmetric allylic alkylation in combination with RCM.

This tandem consecutive AAA-RCM reaction was equally successful with Grignard reagents (n = 1 or 2) affording, quantitatively, carbocycles 1.52 and 1.53 without loss of enantioselectivity.

Investigations into the construction of chiral butyrolactone building blocks via Cu-catalysed hetero-AAA with Grignard nucleophiles, followed by RCM are described in Chapter 6.

Introduction // 21

1.9 Aims and outline of this thesis The overall aim of this thesis is to extend the current operational window of asymmetric catalytic addition of Grignard reagents to electrophiles using chiral nonracemic copper complexes. Three asymmetric catalytic C−C bond formations with Grignard reagents have been investigated and are summarized in this thesis: the 1,4-addition, the tandem 1,4-addition-Ireland-Claisen reaction and the hetero-allylic asymmetric alkylation. In chapter 2 the development of the catalytic asymmetric 1,4-addition of aromatic and aliphatic thioesters using Grignard reagents is given. Chapter 3 describes the research conducted toward achieving a stereoselective tandem consecutive 1,4-addition-Ireland-Claisen reaction. Several different approaches are described including: steric control by substituents at the α position, stereocontrol with chelating substituents and steric control by substituents at the γ-position. An exhaustive review about asymmetric allylic alkylation reactions using Grignard reagents is given in chapter 4, followed by the proposition of a tentative reaction mechanism for the AAA using Grignard reagents based upon literature precedent. A novel regio and enantioselective synthesis of benzoate protected allylic alcohols is introduced in chapter 5 with the development of the hetero-allylic asymmetric alkylation reaction. The application of benzoate protected allylic alcohols as starting materials for the synthesis of the valuable versatile γ-butyrolactone subunit via ring closing metathesis is described in chapter 6. Finally the applicability of the h-AAA followed by metathesis was illustrated by the use the γ-butyrolactone subunit in the formal synthesis of the natural products whiskey and cognac lactone, nephrosteranic and roccellaric acid.

22 // Chapter 1

1.10 References and notes

1 Hazen, R. M.; Genesis: The Scientific Quest for Life’s Origin, Henry, Washington, 2005. 2 Cleland, C. E.; Chyba, C. F. Origin of life and evolution of the biosphere. 2002, 32, 387 and references therein. 3 (a) Carnot S. Réflexions sur la puissance motrice du feu et sur les machines propres à développer cette puissance, 1824, 1. (b) Clausius, R. The Mechanical Theory of Heat – with its Applications to the Steam Engine and to Physical Properties of Bodies, London: John van Voorst, 1 Paternoster Row. 1865−1867. 4 (a) Lewes, G. H., Problems of Life and Mind, First Series: The Foundations of a Creed, Volume II, (Third Edition), Trübner, and Co, London, 1875. (b) For a brief history on the term emergence see: Corning, P. A. Complexity, 2002, 7 (6), 18 and references therein. 5 Sagan, C. The Cosmic Connection, Cambridge University Press, 2000, 2 ed. 6 Emsley, J. The Elements 3th edition, Oxford University Press, Oxford UK, 1999. 7 Atkins, P. W.; Beran, J. A. General Chemistry, W.H. Freeman & Company 2 ed, New York, 1992. 8 (a) Fox, M. A.; Whitesell, J. K. Organic Chemistry, Jones & Bartlett publishers, Sudbury 1997, (2 Ed). (b) Eliel, E. L.; Wilen, S. H. Stereochemistry of organic compounds, Wiley, John& sons Inc., 1994, 1 ed. 9 (a) Feringa, B. L.; van Delden, R. A. Angew. Chem., Int. Ed. 1999, 38, 3418. (b) Kuhn. H. Curr. Opin. colloid. In. 2008, 13, 3 and references therein. 10 Mislow, K.; Bickart, P. Israel J. Chem. 1977, 15, 1. 11 (a) Mason, S. F. Nature 1984, 311, 19. (b) Mason, S.F.; Tranter, G. E. Proc. R. Soc. Lond. A. 1985, 397, 45. 12 (a) Bonner, W.A. Orig. Life Evol. Biosph. 1995, 25, 175. (b) Cronin, J.R.; Pizzarello, S. Science 1997, 275, 951. (c) Bada, J.L. Science, 1997, 275, 942. 13 Siegel, J. S. Chirality, 1998, 10, 24. 14 (a) Fletcher, S. P.; Jagt, R. B. C.; Feringa, B. L. Chem. Commun. 2007, 2578; (b) Flores, J. J.; Bonner, W. A; Massey, G. A. J. Am. Chem. Soc. 1977, 99, 3622; (c) Klussmann, M.; Iwamura, H.; Mathew, S. P.; Wells Jr, D. H.; Pandya, U.; Armstrong, A.; Blackmond, D. G. Nature, 2006, 441, 621. 15 Kaptein, B.; Noorduin, W. L.; Meekes, H.; Enckevort, W. J. P.; Kellogg, R. M.; Vlieg, E. Angew. Chem., Int. Ed. 2008, 47, 7226 and references therein. 16 Pizzarello, S. Acc. Chem. Res.2006, 39, 231 and references therein. 17 Duursma, A.; Asymmetric catalysis with chiral monodendate phosphoramidite ligands, Thesis, Groningen, 2004. 18 Stryer, L. Biochemistry, W. H. Freeman and company, New York, 1988, p. 362. 19 Robergs, R.; Ghiasvand, F.; Parker, D. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2004, 287(3), 502. 20 Reddy, G.; Altaf, Md.; Naveena, B. J.; Venkateshhwar, M.; Vijay Kumar, E. Biotechnology advances, 2008, 26, 22. 21 Kaufman, T.; Rúveda, E. A. Angew. Chem., Int. Ed. 2005, 44, 845 and references therein. 22 Gaubius, H. D. Adversoriorum varii argumentii, Liber unus, Leiden, 1771, p 99. 23 (a) Tani, K.; Yamagata, T.; Otsuka, S.; Akutagawa, S.; Kunobayashi, H.; Taketomi, T.; Takaya, H.; Miyashita, A.; Noyori, R. J. Am. Chem. Soc. 1982, 11, 600; (b) Noyori, R. In Asymmetric catalysis; science and oppertunities, Nobel lecture. 2001.

Introduction // 23

24 Hanessian, S. Total synthesis of natural products: the "Chiron" approach, Pergamon Press, Oxford, 1983. 25 Pasteur, L. Comp. Rend. Acad. Sci. 1848, 26, 535. 26 Oertling, H.; Reckziegel, A.; Surburg, H.; Bertram, H-J. Chem. Rev. 2007, 107, 2136. 27 Seyden-Penne, J. Chiral auxiliaries and ligands in asymmetric catalysis, Wiley, New York, 1995. 28 (a) Klibanov, A. M. Nature, 2001, 409, 241. (b) Wagner, J.; Lerner, R. A.; Barbas, C. F. Science, 1995, 270, 1797. 29 Reetz, M. T.; Kahakeaw, D.; Lohmer, R. ChemBioChem, 2008, 9, 1797 and references therein. 30 The term organocatalysis was coined by MacMillan in 2000: Ahrendt, A. K.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243. 31 (a) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis. Weinheim: Wiley-VCH, (2005). (b) Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108. (c) Wynberg, H. Top. Stereochem. 1986, 16, 87. 32 Arnold, A. E. Phosphoramidites as ligands for copper in catalytic asymmetric C−C bond formation reactions with organozinc reagents, Thesis, Groningen, 2002 and references therein. 33 Kommenos, T. Liebigs Ann. Chem. 1883, 218, 145. 34 (a) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis; Springer-Verlag: Berlin, 1999. (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley and Sons; New York, 1994. (c) Blaser, H.-U.; Schmidt, E. Asymmetric Catalysis on Industrial Scale: Challenges, Approaches and Solutions; Wiley-VCH; Weinheim, 2004. (d) F. López, A. J. Minnaard, B. L. Feringa. In Catalytic Asymmetric Conjugate Addition and Allylic Alkylation Reactions using Grignard Reagents, S. Rappoport, J. Marek (Eds.), The Chemistry of Organomagnesium Compounds, Wiley-VCH, New York 2008; (e) F. López, B. L. Feringa. In Catalytic Asymmetric Conjugate Addition Reactions of Organo- metallic Reagents, M. Christmann, S. Bräse (Eds.), p. 78, Asymmetric Synthesis: The Essentials, Wiley-VCH, New York (2007). 35 Schmalz, H. -G. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, Chapter 1.5. 36 For Li see: Wardell, J. L. Comprehensive Organometallic Chemistry; Wilkinson, G.; Stone, F. G. A.; Abel, E. W., Eds.; Pergamon: Oxford, 1982; Vol. 1; b) Beswick, M. A.; Wright, D. S.;Comprehensive Organometallic Chemistry II; Wilkinson, G.; Stone, F. G. A.; Abel, E. W., Eds.; Pergamon: Oxford, 1995; Vol. 1. 37 For Cu see: (a) van Koten, G.; Noltes, J. G.; Comprehensive Organometallic Chemistry; Wilkinson, G.; Stone, F. G. A.; Abel, E. W., Eds.; Pergamon: Oxford, 1982; Vol.2. (b) Wardell, J. L. Comprehensive Organometallic Chemistry II; Wilkinson, G.; Stone, F. G. A.; Abel, E. W., Eds.; Pergamon: Oxford, 1995; Vol. 3. 38 Reviews: (a) Yamamoto, Y. Formation of C−C-Bonds by Addition to α,β-unsaturated Carbonyl Compounds in Houben−Weyl, Methods of Organic Chemistry, ed by Helmchen, R.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E., Thieme, Stuttgart 1995, Vol. E21b, p. 2041. (b) Taylor, R. J. K. Organocopper Chemistry: An Overview, in Organocopper reagents ed by Taylor, R. J. K., Oxford University Press, Oxfort 1994. (c) Kozlowski, J. A. Organocuprates in the Conjugate Addition Reaction in Comprehensive Organic Synthesis ed by Trost, B. M.; Fleming, I., Pergamon Press. Oxfort 1991, Vol. 4, p.169. (d) Posner, G.

24 // Chapter 1

H., An Introduction to Synthesis Using Organocopper Reagents, John Wiley & Sohns, New York 1980. 39 Kharasch, M. S.; Tawney, P. O. J. Am. Chem. Soc. 1941, 63, 2308. 40 Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R. Bull. Chem. Soc. Jpn. 2000, 73, 999, and references therein. 41 For reviews on conjugate addition using soft carbon-nucleophiles see: (a) Berner, O.M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877. (b) Fleming, F. F.; Wang Q. Chem. Rev. 2003, 103, 2035. (c) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini M. Chem. Rev. 2005, 105, 933. (d) Sulzer-Mosse, S.; Alexakis, A. Chem. Commun. 2007, 3123. (e) Almasi, D.; Alonso, D. A.; Najera C. Tetrahedron: Asymmetry 2007, 18, 299. (f) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.(g) Vicario, J. L.; Badia, D.; Carrillo, L. Synthesis 2007, 2065. 42 (a) Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771. (b) Krause, N.; Gerold, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 186. (c) Jansen, J. F. G. A.; Feringa, B. L. in Houben- Weyl, Stereoselective Synthesis of Organic Compounds; Hoffmann, R. W.; Mulzer, J.; Schaumann, E. Eds.; Georg Thieme Verlag Stuttgart, 1995. (c) Nogradi, M.; Stereo- selective Synthesis; VCH Publ.; Weinheim, 1987. 43 (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon; Oxford, 1992. (b) Krause, N. Modern Organocopper Chemistry; Wiley-VCH, Verlag GmbH; Weinheim, 2002. (c) Feringa, B. L.; de Vries, A. H. M. in Advances in Catalytic Processes, Doyle, M. P. (Ed.); JAI Press Inc; Greenwich, 1995. 151. (d) Tomioka, K.; Nagaoka, Y. Conjugate Addition of Organometallic Reagents in Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. (Ed.); Springer-Verlag: Berlin, 1999; 1105. (e) Tomioka K. Conjugate Addition of Organometals to Activated Olefinics in Comprehensive Asymmetric Catalysis, Supplement 2; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. (Ed.); Springer-Verlag: Berlin, Heidelberg, 2004; 109. 44 (a) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. Chem., Int. Ed. 1996, 35, 2374. (b) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries, A. H. M. Angew. Chem., Int. Ed. 1997, 36, 2620. 45 For reviews on asymmetric conjugate addition see: (a) Sibi, M. P.; Manyem, S. Tetrahedron, 2000, 56, 8033. (b) Krause, N., Hoffmann-Röder, A. Synthesis 2001, 171. (c) Alexakis, A., Benhaim, C. Eur. J. Org. Chem. 2002, 3221. (d) Feringa, B. L.; Naasz, R.; Imbos, R.; Leggy, A. A. Copper-Catalysed Enantioselective Conjugate Addition Reactions of Organozinc Reagents in Modern Organocopper Chemistry, Krause, N. (Ed.); Wiley-VCH Verlag GmbH; Weinheim, 2002; 224. (e) Christoffers, J.; Koripelly, G.; Rosiak A.; Rössle, M. Synthesis 2007, 9, 1279. (f) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Feringa B. L.; Chem. Rev. 2008, 108, 2824. 46 (a) Krause, N. Angew. Chem., Int. Ed. 1998, 37, 283. (b) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346. 47 Feringa, B. L.; Badorrey, R.; Peña, D.; Harutyunyan, S. R.; Minnaard, A. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5834. 48 (a) Woodward, S. Angew. Chem., Int. Ed. 2005, 44, 5560. (b) Lόpez, F.; R.; Minnaard, A. J.; Feringa, B. L. Acc. Chem. Res. 2007, 40, 179. 49 Nicolaou, K.C.; Edmonds, D.J.; Bulger, P.G. Angew. Chem. Int. Ed. 2006, 45, 7134. 50 In Oxford English Dictionary, Oxford University Press: Oxford, http://www.askoxford.com/

Introduction // 25

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26 // Chapter 1

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