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University of Groningen

Enantioselective copper catalyzed allylic alkylation using Grignard reagents Applications insynthesisZijl Anthoni Wouter van

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Enantioselective copper catalyzed allylic alkylation using Grignard reagents

Applications in synthesis

Anthoni Wouter van Zijl

titelblad en franse pagina_final

The work described in this thesis was carried out at the Stratingh Institute for Chemistry University of Groningen The Netherlands

The work described in this thesis was financially supported by the NRSC-catalysis program

Cover design by AW van Zijl ant silhouette by Ismael Montero Verdu

Printed by PrintPartners Ipskamp BV Enschede The Netherlands

ISBN 978-90-367-3683-1 (printed version) ISBN 978-90-367-3684-8 (electronic version)


RIJKSUNIVERSITEIT GRONINGEN

Enantioselective copper catalyzed allylic alkylation using Grignard reagents Applications in synthesis

Proefschrift

ter verkrijging van het doctoraat in de Wiskunde en Natuurwetenschappen aan de Rijksuniversiteit Groningen

op gezag van de Rector Magnificus dr F Zwarts in het openbaar te verdedigen op

vrijdag 16 januari 2009 om 1615 uur

door


geboren op 13 september 1979 te Leiden


Promotores Prof dr B L Feringa

Prof dr ir A J Minnaard

Beoordelingscommissie Prof dr J B F N Engberts

Prof dr J G de Vries

Prof dr A S C Chan

ISBN 978-90-367-3683-1

Table of Contents

Chapter 1 The niche of copper in transition metal catalyzed asymmetric allylic substitution

11 Introduction to asymmetric catalysis 12 Transition metal catalyzed asymmetric allylic substitution

121 Palladium catalyzed asymmetric allylic substitution 122 Iridium catalyzed asymmetric allylic substitution 123 Asymmetric allylic alkylation with

stabilized nucleophiles catalyzed by other transition metals 124 The application of organometallic reagents in

the transition metal catalyzed asymmetric allylic alkylation 13 Copper catalyzed asymmetric allylic alkylation

131 Zinc reagents in Cu-catalyzed asymmetric allylic alkylation 132 Grignard reagents

in Cu-catalyzed asymmetric allylic alkylation 133 Other reagents

in Cu-catalyzed asymmetric allylic alkylation 14 Aim and Outline of this Thesis 15 Conclusions and Perspectives

References

Chapter 2 Enantioselective Cu-catalyzed allylic alkylation with Grignard reagents using ferrocenyl diphosphine ligands

21 Introduction 211 Ferrocenyl diphosphine ligands and Grignard reagents in

Cu-catalyzed conjugate addition reactions 212 The absolute and relative configuration of Taniaphos

22 Results and Discussion 221 Asymmetric allylic alkylations with Josiphos ligands 222 Asymmetric allylic alkylations with Taniaphos

23 Conclusions 24 Experimental Part

References Chapter 3 Synthesis of chiral bifunctional

building blocks through asymmetric allylic alkylation 31 Introduction

311 Functionalised substrates in the Cu-AAA 312 Heteroatoms at the γ-position the h-AAA

7 8

10 11 14

15

16 19 20

22

24 26 27 29

35 36

37 41 45 45 50 55 56 62

65 66 67 70

Table of Contents

4

Table of Contents

313 The relevance of bifunctionality in asymmetric allylic alkylation products in total synthesis

32 Results and Discussion 321 Asymmetric allylic alkylation on functionalised substrates 322 Derivatizations of the allylic alkylation products

3221 Synthesis of bifunctional building blocks containing a protected alcohol

3222 Synthesis of bifunctional building blocks containing a protected amine


References

Chapter 4 Catalytic enantioselective synthesis of vicinal dialkyl arrays

41 Introduction 411 The presence of vicinal dialkyl arrays in natural products 412 Methods previously reported

for the asymmetric synthesis of vicinal dialkyl arrays 4121 Stoichiometric methods 4122 Catalytic methods

413 Catalytic asymmetric protocols that provide independent control of arrays of chiral centers

414 Application of cross-metathesis to allylic alkylation products

42 Results and Discussion 421 Synthesis of chiral substrates for conjugate addition through

allylic alkylation and metathesis 422 Asymmetric conjugate addition reactions with Grignard

reagents on the chiral metathesis products 4221 Conjugate addition to chiral αβ-unsaturated esters 4222 Conjugate addition to chiral αβ-unsaturated ketones 4223 Conjugate addition to chiral αβ-unsaturated thioesters

423 Total synthesis of the ant pheromones (minus)-lasiol and (+)-faranal


References

71 75 75 77

77

78 81 82 97

101 102 103

105 105 107

108

112 114

114

116 116 117 118

120 124 125 147

Table of Contents

5

Table of Contents

Chapter 5 Straightforward synthesis of αβ-unsaturated thioesters via olefin cross-metathesis with thioacrylate

51 Introduction 511 Cross-metathesis with sulfur containing compounds

52 Results and Discussion 521 Optimization of metathesis reaction conditions


References

Chapter 6 Preparation of chiral heterocyclic compounds via enantioselective Cu-catalyzed allylic alkylation

61 Introduction 611 Application of Cu-AAA products in cyclization reactions

62 Results and Discussion 621 Application of Cu-AAA and ring-closing metathesis

6211 Chiral γ-substituted dihydropyranones 6212 Chiral 5-methyl-34-dehydropiperidines 6213 Chiral 36-dimethyl-2367-tetrahydroazepine

622 Application of Cu-AAA and the Heck reaction formation of chiral quinoline and chromane derivatives

623 Synthesis of a chiral oxazinanone through iodo-cyclocarbamation

624 Asymmetric synthesis of a motor upper half precursor 63 Conclusions 64 Experimental Part

References Nederlandse Samenvatting English Summary Dankwoord

ξ 153 154 155 157 157 162 163 170

173 174 175 178 178 178 181 184

185

186 188 190 191 206

209

215

221


The rapidly developing field of transition metal based asymmetric catalysis offers a powerful but elegant way of obtaining chiral compounds in enantiomerically pure form The highly versatile allylic substitution reaction can be catalyzed in an enantioselective way by chiral catalysts based on several transition metals Each metal offers distinct possibilities concerning the type of substrate or nucleophile employed This chapter aims to provide an overview of what is possible with these transition metal catalysts in enantioselective allylic substitution including highlights and the current state-of-the-art Specifically focus will be directed towards the use of copper based asymmetric catalyst systems and why this metal has filled an important niche in the field

Chapter 1

8

Chapter 1_final version_2

11 Introduction to asymmetric catalysis The synthesis of urea from inorganic compounds by Friedrich Woumlhler in

18281 is seen by many as the birth of synthetic organic chemistry Before this milestone a ldquovis vitalisrdquo was thought to be necessary to produce organic compounds which were deemed too complicated in structure to produce them through any other means than life itself Although this theory of vitalism was not abandoned immediately by the scientific community including Woumlhler himself his synthesis was the start of a new era in which chemists slowly learned how to harness the potential of synthetic organic chemistry by preparing more and more complex organic compounds

It is easy to understand the mystification of organic chemistry by the early 19th-century chemists The complexity found in naturally occurring organic compounds also called natural products can still baffle the modern organic chemist even with our current knowledge of molecular structure One of the aspects of this complexity is chirality Chirality is a property which renders something non-superimposable on its mirror image2 In organic chemistry this signifies that these two mirror-images of a chiral compound enantiomers have the same connections of atoms within the molecule and the same relative spatial orientation of these atoms but opposite absolute spatial orientation It is best understood when compared to objects in every-day life including our hands feet and ears (Figure 11) Our left hand is not the same as our right hand and similarly the D- and L-forms of our α-amino acids are not the same compounds

Figure 11 The two enantiomers of α-amino acids are non-superimposable as is the case with a right and a left hand3

The niche of copper in transition metal catalyzed asymmetric allylic substitution

9


The two enantiomers of chiral compounds have the same physical properties The main difference lies in their interaction with other chiral substances or physical forces eg circular polarized light To extend the analogy we can compare it to a right hand fitting quite well in a right handed glove and not so well in a left handed one This is an important difference since our surroundings are often chiral at the molecular level Life itself makes use of many chiral building blocks DNA is chiral for example and all our proteins and enzymes are primarily built up from L-amino acids

This means that our body can react in different ways to the two mirror images of chiral compounds For instance limonene is an organic chiral compound of which the natural D-enantiomer has a pleasant citrus-like smell The mirror image L-limonene on the other hand has a harsh turpentine odor The artificial sweetener aspartame is more than a hundred times sweeter than sucrose its mirror image has a bitter taste instead

Examples with more serious consequences can be found in the pharmaceutical industry Thalidomide was a drug marketed in the 50s and 60s for the prevention of morning sickness of pregnant women One of the enantiomers was discovered to be teratogenic but only after it had already caused serious birth defects in over 10000 children Nowadays governments have set strict regulations regarding the enantiomeric purity of chiral pharmaceutical compounds which are to be brought on the market As a consequence this has sparked a considerable interest in finding ways to obtain chiral compounds in enantiomerically pure form

In principle there are three basic ways of obtaining enantiopure compounds4 They can be isolated from natural sources which produce only one enantiomer this is called the chiral pool An obvious drawback is that if only one enantiomer is produced the other cannot be obtained in this way The second way is to take a 5050 mixture of enantiomers a so-called racemate and separate the two from each other This is called resolution of a racemate and a disadvantage here is that in this case half of the compound is worthless because it is the wrong enantiomer unless it is recycled through racemization The third option asymmetric synthesis is to prepare selectively one enantiomer of a chiral compound from an achiral starting material To be able to do this another source of chirality is needed usually

Chapter 1

10


in an equal or larger amount than the starting material A notable exception to that is asymmetric catalysis which is the subject of this thesis

12 Transition metal catalyzed asymmetric allylic substitution

A catalyst is by definition a substance which accelerates a reaction without being changed overall in the process itself A small amount of an asymmetric catalyst would therefore enable the asymmetric synthesis of a larger amount of an enantiomerically pure chiral compound which makes the process more ldquoatom economicalrdquo5 This powerful but elegant method has become a widespread research field in the past decades and three of its pioneers were awarded the Nobel prize in chemistry at the start of the new millennium6

The subject of this thesis is copper catalyzed asymmetric allylic substitution reactions Allylic substitution is a powerful carbon-carbon or carbon-heteroatom bond forming reaction in which an electrophile containing an allylic leaving group reacts with a nucleophile Two pathways are possible in allylic substitution (Scheme 11) the SN2 pathway which features direct substitution of the leaving group at the α-position or the SN2rsquo pathway where the nucleophile attacks the γ-position causing a migration of the double bond

Scheme 11 The two possible pathways in allylic substitution lead to the SN2-product through α-substitution and the SN2rsquo-product through γ-substitution LG = leaving group

A range of different substrate classes eg chiral racemic (Rrsquo ne H) and prochiral (Rrsquo = H) and a range of nucleophiles including stabilized carbanions (Michael donors) organometallic reagents and heteroatom nucleophiles has been applied in catalyzed asymmetric allylic substitution reactions The possibilities depend largely on the transition metal catalyst used in the allylic substitution reaction and a short overview of the literature presenting the key aspects will follow in this section


11


121 Palladium catalyzed asymmetric allylic substitution Among the transition metals used for catalyzing asymmetric allylic

substitution palladium is by far the most extensively studied and the subject has been thoroughly reviewed7 Traditionally these reactions are performed using stabilized carbanions as nucleophiles such as malonate esters and symmetrically 13-disubstituted allylic electrophiles ie bearing the same substituents on the α- or γ-position (Scheme 12 a) This is because Pd-catalyzed allylic substitution is a regioselective as opposed to a regiospecific reaction Regioselectivity means that one of the two possible products (if R ne Rrsquo in Scheme 11) is formed preferentially while regiospecificity is the preference for one of the two pathways (SN2 vs SN2rsquo) regardless of the substituents

Scheme 12 a) The benchmark reaction in Pd-catalyzed asymmetric allylic substitution and b) Examples of other substrates applied successfully LG = leaving group

Generally Pd-catalysis is regioselective for the least substituted position making many prochiral substrates unsuitable for the reaction Exceptions to this are for example cyclic meso-compounds bearing two enantiotopic leaving groups 113-trisubstituted allylic substrates and allylic gem-diacetates (Scheme 12 b)7 In these cases substitution at the least hindered position will still lead to a chiral product Excellent regio- and enantioselectivity has been achieved in many examples of the palladium catalyzed allylic substitution with several classes of chiral ligand and the reaction has been applied in the total syntheses of several natural products8

Only recently have catalysts been developed which can induce a regioselective formation of a branched product from monosubstituted allylic substrates9-12 It is straightforward to induce this formation in intramolecular

Chapter 1

12


reactions where formation of a five- or six-membered ring is strongly preferred over larger rings7 However preferred formation of a branched product over the linear product is more problematic in an intermolecular substitution reaction (Scheme 13) Nevertheless it has been achieved in high selectivity with a few catalysts Trost and co-workers have been able to perform these reactions with oxygen nucleophiles using their diphosphine ligand systems9 The selective formation of branched products with stabilized carbanions as nucleophiles was first accomplished by the groups of Hayashi10 and Pfaltz11 and following this other catalytic systems have been reported that can achieve high selectivities (up to bl = gt991 and 98 ee) in this difficult transformation12

Scheme 13 Pd-catalyzed allylic substitution of monosubstituted allylic substrates the linear product is usually the major product

Significant progress in the field of Pd-catalyzed allylic substitution has been made in the application of a range of nucleophiles As discussed above the conventional nucleophile is a stabilized carbanion such as a malonate ester However a carbanion with two different electron-withdrawing groups which is a prochiral nucleophile can be applied also78 In this case the regioselective formation of a linear product still leads to a chiral compound and even simple non-substituted allyl electrophiles can be applied in an enantioselective reaction A good example is the enantioselective formation of α-amino acid derivatives through Pd-catalyzed allylic alkylation (Scheme 14)13

Scheme 14 Enantioselective synthesis of an amino acid derivative through Pd-catalyzed allylic substitution with a prochiral nucleophile CinOAc = cinnamyl acetate


13


An important class from a synthetic perspective of prochiral nucleophiles is the enolate of a ketone In contrast to the nucleophiles employed traditionally these carbanions are not stabilized by an additional electron-withdrawing group and their use in Pd-catalyzed allylic alkylation has been reported only recently14 Initially ketones were used which have just one α-carbon with acidic protons (eg 2-methyl-1-tetralone)15 or two which were chemically equivalent (cyclohexanone)16

The development of the enantioselective Tsuji allylation which is a decarboxylative allylation by Stoltz and co-workers has enabled the application of ketones with inequivalent α-carbons both of which bear acidic protons17 The reaction can be performed with allyl enol carbonates silyl enol ethers and allyl β-ketoesters In general application of the same conditions to these different substrates provided products with the same enantioselectivity (Scheme 15)18 This seems to indicate that for the three substrate classes a part of the mechanism and in particular the stereoselective step is essentially the same Enantioselectivities of up to 99 ee have been achieved in some examples and the reaction has been applied in the total syntheses of a number of natural products19

Scheme 15 Enantioselective Tsuji allylation can be performed on three different classes of substrate with essentially the same result dba = dibenzylideneacetone

Chapter 1

14


122 Iridium catalyzed asymmetric allylic substitution As explained in the previous section it is difficult to obtain branched

chiral products from monosubstituted allylic substrates when using Pd-catalysts For this reason other transition metals have been explored as potential catalysts also Some of these metals were found to have a preference for the branched product One of the most widely studied transition metals that provides high enantioselectivity in addition to regioselectivity in these transformations is iridium20

The first asymmetric iridium catalyzed allylic substitution reaction was reported by the group of Helmchen in 199721 The reaction involved the substitution of cinnamyl acetate with a malonate ester using a chiral phosphinooxazoline ligand and provided the branched product selectively in high enantiomeric excess (Scheme 16) However the substrate scope was limited and aliphatic substrates did not give the same excellent results as aromatic substrates

Scheme 16 Iridium catalyzed asymmetric allylic substitution of cinnamylic substrate with dimethyl sodiomalonate

Following this first report several groups have investigated the optimization of Ir-catalyzed asymmetric allylic substitution and a number of important discoveries have been reported20 For example allylic carbonates provide better results than acetates and phosphoramidites are excellent chiral ligands22 Both the racemic branched isomer and the linear achiral


15


isomer of the substrate are viable starting materials and several types of stabilized carbanion can be employed as nucleophile

Another important aspect of iridium catalyzed asymmetric allylic substitution is the possibility of using heteroatom nucleophiles Among others aliphatic amines anilines amides and hydroxylamines (N-nucleophiles) and aliphatic alcohols phenols oxims and silanols (O-nucleophiles) have been applied successfully with high regio- and enantioselectivity (Scheme 17)23 Substantial effort has been directed to elucidate the mechanism of the reaction The information obtained has led to the discovery of an iridacycle as an actual catalytic species (Scheme 17) the development of improved reaction conditions more selective ligands and more convenient precatalyst systems24

Scheme 17 Allylic amines and allylic ethers can be obtained using N-nucleophiles [N] and O-nucleophiles [O] respectively the catalytic species is in many cases an iridacycle

It should be noted that organometallic reagents have been applied in this reaction also The group of Alexakis reported an iridium catalyzed allylic substitution using aryl zinc reagents25 The enantioselectivities are moderate to excellent (up to 99) and although the regioselectivity was not good (up to 7327 bl ca 5050 typically) the asymmetric allylic substitution of monosubstituted allylic substrates with aromatic organometallic nucleophiles was unprecedented

123 Asymmetric allylic alkylation with stabilized nucleophiles catalyzed by other transition metals

The first metal other than Ir or Pd discovered to give high regioselectivity for the branched product (up to 964) in an asymmetric allylic substitution was tungsten26 The reaction was performed on prochiral

Chapter 1

16


linear allylic phosphates with dimethyl sodiomalonate as the nucleophile and a catalyst prepared from [W(CO)3(MeCN)3] and the phosphino-oxazoline ligand shown in Scheme 16 However the report was not followed by many further studies on the use of tungsten-based catalysts in this reaction

In 1998 Trost et al reported studies on W and Mo-based catalysts in which they found that molybdenum was the more viable candidate27 A Mo-based catalyst bearing a dipyridyl ligand catalyzed the regioselective asymmetric allylic substitution in equally high regio- and enantioselectivity as the tungsten equivalent (982 99 ee) However the Mo-catalyst was far more active than the W-catalysts Several reports of Mo-catalyzed asymmetric allylic alkylation have followed28 including mechanistic studies that established a double retention pathway for the reaction29 Only stabilized carbanions have been applied as nucleophiles with Mo-based catalysts

Recently ruthenium based catalysts were reported to catalyze asymmetric allylic substitution reactions30 Reaction (a) in Scheme 12 could be performed with high enantioselectivity using malonate esters and with an amine with moderate enantioselectivity31 A reaction similar to the Tsuji allylation provided branched products through a Carroll-type rearrangement with excellent regioselectivity and moderate enantioselectivity32 Aromatic and aliphatic alcohols have been applied as nucleophiles with moderate to excellent selectivities using prochiral linear monosubstituted allylic substrates33

124 The application of organometallic reagents in the transition metal catalyzed asymmetric allylic alkylation

All of the transition metals discussed previously catalyze asymmetric allylic substitution reactions using either heteroatom nucleophiles stabilized carbanions or in a few cases unstabilized enolate nucleophiles The direct introduction of an alkyl or aryl group through the use of an organometallic reagent is generally not possible in an efficient regio- and enantioselective manner (the Ir-catalyzed substitution with arylzinc reagents reported by the group of Alexakis25 being a notable exception vide supra)

In the case of Pd-catalyzed allylic alkylation it is known that the reaction pathway for allylic substitution with soft stabilized carbanion


17


nucleophiles is different than with hard organometallic reagents7 This is possibly the reason why highly enantioselective Pd-catalyzed allylic substitution with organometallic reagents has not been accomplished34 A few other transition metals have been reported to catalyze asymmetric allylic alkylation using organometallic reagents of which copper has been the most widely studied The progress in the field of copper catalysis will be discussed in more detail in section 13 Here two other metals which have been applied successfully nickel and rhodium will be highlighted

At a very early stage nickel was discovered to enable asymmetric allylic alkylation of some allylic ethers and esters using Grignard reagents35 High enantioselectivity was attained occasionally in cyclic and acyclic substrates where regioselectivity was not an issue36 and regio- and enantioselective substitution on cyclic allylic acetals has been reported as well37 However the use of monosubstituted allylic electrophiles led to low regioselectivity

Recently Fu and co-workers reported a Ni-catalyzed asymmetric cross-coupling of secondary allylic chlorides and aliphatic zinc bromides (Scheme 18)38 Both symmetrically substituted (R1 = R2) and asymmetrically substituted allyl electrophiles can be applied and the products can be obtained with good to excellent enantiomeric excess Sufficient steric difference between R1 and R2 would lead to excellent regioselectivity even if mixtures of regioisomeric substrates were used

Scheme 18 Ni-catalyzed asymmetric allylic alkylation using aliphatic zinc bromides

Rhodium on the other hand has not been explored extensively as a potential catalyst for asymmetric allylic substitution The metal was instead reported to conserve the enantiomeric excess of non-racemic substrates39 and possibly therefore assumed to be unsuitable for an enantioselective version of the reaction Nevertheless Hayashi et al reported an asymmetric allylic alkylation catalyzed by rhodium which provided excellent regio- and enantioselectivity with malonate ester as the nucleophile40

Chapter 1

18


Interestingly this transition metal can be used as a catalyst in the asymmetric allylic substitution with boron reagents The reaction has been performed using arylboroxines on cis-allylic diols41 and using arylboronic acids on a cyclic allylic meso-dicarbonate42 In particular the latter example led to products in excellent enantiomeric excess (Scheme 19)

Scheme 19 Rh-catalyzed allylic substitution with aryl boronic acid nucleophiles


19


13 Copper catalyzed asymmetric allylic alkylation Within the spectrum of transition metals able to catalyze asymmetric

allylic substitution reactions copper holds a special position The metal owes this position to two important properties the general regioselectivity for the branched product in an allylic substitution reaction with a monosubstituted allylic substrate and its compatibility with organometallic reagents which enables the direct introduction of alkyl groups43 These characteristics make copper complementary to the other transition metals catalysts for asymmetric allylic substitution reactions In addition copper is not as expensive and less toxic than many of those metals

The area of copper-catalyzed asymmetric allylic alkylation although not as widely studied as the Pd-catalyzed reaction has been a focus of interest in asymmetric catalysis for some time and has been reviewed extensively44 This section will provide a comprehensive overview of the catalyst systems and the organometallic reagents that have been applied It will present the groundbreaking work of several groups including ours which preceded the investigation described in this thesis and discuss the results that have been reported in the course of the realization of this thesis The section will not review any applications in synthesis because those will be discussed in the introductions of following chapters

The first report in 1995 of a copper catalyzed enantioselective allylic alkylation resulted from a collaboration between the groups of Baumlckvall and van Koten45 A Grignard reagent was used with allylic acetates as the electrophilic substrates The best result at that time was an enantiomeric excess of 42 for the branched SN2rsquo product found exclusively using an arenethiolato copper complex as catalyst (Scheme 110) Screening of experimental parameters and ligands effected an increase in enantioselectivity to 64 after replacing the phenyl ring of the original ligand with a ferrocenyl group46

Scheme 110 The first copper catalyzed asymmetric allylic alkylation reported in 1995

Chapter 1

20


131 Zinc reagents in Cu-catalyzed asymmetric allylic alkylation Following the first report of Baumlckvall and van Koten Knochel and co-

workers reported a copper catalyzed asymmetric allylic alkylation using dialkylzinc reagents instead47 Dialkylzinc compounds are generally less reactive than Grignard reagents which facilitates the prevention of uncatalyzed side reactions In addition they exhibit a high functional group tolerance which enables the use of functionalized organometallic nucleophiles48

The group of Knochel reported the application of chiral ferrocenyl based amine ligands This enabled a highly selective allylic alkylation of allylic chlorides with the bulky dineopentylzinc reagent (bl = 982 96 ee Scheme 111) Sterically less hindered zinc reagents provided significantly lower enantioselectivities (eg 44 ee for Et2Zn)

Scheme 111 Copper catalyzed asymmetric allylic alkylation using a dineopentylzinc

This promising result sparked an interest in the application of zinc reagents in the enantioselective copper catalyzed allylic alkylation Several groups developed new catalytic systems to apply in the reaction with diorganozinc compounds The benchmark reaction by which these catalyst systems can be compared is the allylic substitution on a cinnamyl substrate using diethylzinc as the nucleophilic reagent (Figure 12)

Hoveyda and co-workers applied their modular peptide-based ligand system on this benchmark reaction using cinnamyl phosphate as the substrate and attained excellent regio- and enantioselectivity (bl = gt982 95 ee)49 A range of substrates and diorganozinc reagents could be applied with similar and even better results (up to 98 ee)50 Furthermore chiral quaternary carbon centers could be formed in excellent selectivity when using γ-disubstituted allylic phosphates


21


Figure 12 The benchmark copper catalyzed asymmetric allylic alkylation which uses a cinnamyl derivative and diethylzinc as the organometallic reagent and the ligands developed by several groups with the regioselectivity and enantiomeric excess LG = leaving group Mes = mesityl

Phosphoramidites were studied as ligands for the enantioselective copper catalyzed allylic alkylation in our laboratories51 The reaction proceeded with high selectivity when cinnamyl bromide was used as the substrate (bl = 937 86 ee) A range of dialkylzinc reagents and p-substituted cinnamyl bromides could be applied with similar results The use

Chapter 1

22


of non-cinnamyl substrates led to a significant decrease in selectivity though Zhou and co-workers applied phosphoramidite ligands with a spirocyclic backbone as opposed to the BINOL-based backbone in the Feringa ligand52 The selectivities attained with these ligands were slightly lower

Another modular ligand library was developed by the group of Gennari and applied in the copper catalyzed allylic alkylation of cinnamyl phosphate53 High selectivity was not attained with this substrate (up to 40 ee) However they were able to apply this catalyst system in the desymmetrizing allylic alkylation of cyclic meso-compounds with much better results54 The same group reported the use of phosphoramidite ligands with these meso-substrates (see section 311)54a55

In addition to their modular ligand library the group of Hoveyda recently reported a new catalyst system for asymmetric allylic alkylation based on NHC-ligands (Figure 12 shows the dimeric Ag(I) complex of the ligand)56 They achieved excellent regio- and enantioselectivies using allylic phosphates as substrates This catalyst system enabled the application of a wide range of substrates and diorganozinc reagents with similar and higher selectivity (up to bl = gt982 and 98 ee) It is important to note that they reported the only example so far of the use of an aromatic organometallic nucleophile in this case diarylzinc reagents in enantioselective copper catalyzed allylic alkylation and enantioselectivities of up to 92 were achieved with a ligand similar to that shown in Figure 1256a

One further example of the use of dialkylzinc reagents in Cu-AAA is that reported by Woodward and co-workers57 Enantioselectivities of up to 90 were attained using chiral amines as ligands and allylic chlorides derived from Baylis-Hillman products This reaction is described in more detail in section 311

132 Grignard reagents in Cu-catalyzed asymmetric allylic alkylation Initially the efforts to develop efficient catalyst systems for

enantioselective copper catalyzed allylic alkylation focused primarily on the use of diorganozinc compounds The Grignard reagents applied originally by the group of Baumlckvall were not left out of consideration though Grignard reagents are more reactive than their zinc counterparts and less tolerant to functional groups However they are readily obtained easy to


23


handle and cheap compared to dialkylzinc reagents and exhibit a better ldquoatom economyrdquo5 since they contain one alkyl group only

The group of Alexakis focused on Grignard reagents Their initial reports featured both phosphite and phosphoramidite ligands and moderate to high selectivities (up to 86 ee and generally bl = gt9010) were attained with a range of allylic chorides and several Grignard reagents58 They arrived at a breakthrough when they introduced a new phosphoramidite ligand in 2004 which enabled the copper catalyzed allylic alkylation using Grignard reagents with excellent regio- and enantioselectivity (Scheme 112)59

Scheme 112 Highly selective copper catalyzed allylic alkylation with Grignard reagent using a phosphoramidite ligand TC = 2-thiophenecarboxylate

The method was subsequently extended to different substrate classes including for example β-substituted allylic chlorides60 A major draw-back of the catalyst system was the inefficient introduction of a methyl group using methyl Grignard reagents particularly with regard to the regioselectivity However increase in catalyst loading and slow addition of the Grignard reagent (4 h) improved the selectivity of the reaction substantially allowing for example the methylation of cinnamyl chloride with 96 ee and a regioselectivity of 891161

Two groups reported the use of NHC-ligands in copper catalyzed asymmetric allylic alkylation with Grignard reagents (Figure 13) Okamoto et al reached an enantioselectivity of 70 and excellent regioselectivity using a chiral imidazolium carbene62 More recently Hong and co-workers applied a bisisoquinoline based carbene in copper catalyzed allylic alkylation and attained selectivities up to bl = 8812 and 77 ee63

Chapter 1

24


Figure 13 Chiral N-heterocyclic carbenes have been used in the catalytic asymmetric allylic alkylation often although not exclusively with copper

The contribution of our group to the field of copper catalyzed asymmetric allylic alkylation using Grignard reagents will be extensively discussed in the following chapters of this thesis

Although not a copper catalyzed allylic alkylation the allylic alkylation with Grignard reagents reported by the group of Hoveyda is certainly worth mentioning64 The substitution of γ-chloro-αβ-unsaturated esters is catalyzed with high selectivity (up to bl = 937 and 98 ee) through Lewis base activation by a chiral carbene alone (Figure 13)

133 Other reagents in Cu-catalyzed asymmetric allylic alkylation In addition to dialkylzinc compounds and Grignard reagents

trimethylaluminum has been applied in copper catalyzed allylic alkylation65 The reaction is a key step in the total synthesis of baconipyrone C and is discussed in more detail in section 313

Aluminum reagents have been employed in a copper catalyzed asymmetric allylic alkenylation by the group of Hoveyda also66 The catalyst system featured one of the NHC-ligands and the alkenylaluminum reagents were formed in situ from alkynes and DIBAL-H (Scheme 113) The allyl phosphate substrates were alkenylated exclusively and transfer of the iso-butyl group did not occur A range of substrates and alkynes could be applied in high to excellent regio- and enantioselectivity (up to gt98 ee and full regioselectivity) The E-isomer of the product was formed in all cases except when tert-butyl propargyl ether was used as the alkyne in which case the Z-isomer was formed exclusively


25


Scheme 113 An example of enantioselective copper catalyzed allylic alkenylation using aluminum reagents formed in situ from DIBAL-H and an alkyne

Very recently an enantioselective copper catalyzed allylic substitution was reported which employed a diboron reagent as nucleophile67 The reaction enables the synthesis of allylboronates in high optical purity and is to the best of my knowledge the only example of a copper catalyzed asymmetric allylic substitution which does not make use of an organometallic nucleophile

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14 Aim and Outline of this Thesis The aim of the research presented in this thesis was the development of

a new catalyst system for copper catalyzed asymmetric allylic substitution The system should enable highly regio- and enantioselective reactions with a broad substrate and reagent scope In particular the focus is on reactions that remained challenging with the catalyst systems available so far (described in this chapter) for instance the introduction of a methyl substituent through allylic alkylation using Grignard reagents

In addition the versatility of the copper catalyzed asymmetric allylic alkylation was to be highlighted The intention was to demonstrate several routes by which the products of the reaction can be applied in a synthetically useful manner

Chapter 2 describes the development of a new method which uses a copper catalyst system based on the ferrocenyl diphosphine ligand Taniaphos Allylic bromides and Grignard reagents are employed providing excellent regio- and enantioselectivity In particular the high selectivity using methylmagnesium bromide makes the system complementary to the existing methods

In chapter 3 the application of the new catalyst system to functionalized substrates is described The versatility of the terminal olefinic double bond is highlighted through several derivatization reactions of the products obtained in the asymmetric allylic alkylation of these substrates Multiple chiral bifunctional building blocks which had shown their merit in total synthesis already were synthesized in this manner

Chapter 4 describes the development of a new protocol for the asymmetric synthesis of vicinal dialkyl arrays The method is based on copper catalyzed allylic alkylation cross-metathesis and copper catalyzed asymmetric conjugate addition Two pheromones of two species of ants were prepared using this route demonstrating the applicability of the protocol in the total synthesis of natural products

The total syntheses of the pheromones required a cross-metathesis reaction of a terminal olefin with a thioacrylate This reaction had not been reported previously and chapter 5 describes a new and efficient route to


27


obtain S-ethyl thioacrylate and its application in cross-metathesis with a range of olefins

Chapter 6 describes the application of copper catalyzed allylic alkylation to the preparation of chiral heterocyclic compounds The products of Cu-AAA are subjected to a range of cyclization reactions providing valuable heterocyclic building blocks in high optical purity

15 Conclusions and Perspectives In summary the highly versatile asymmetric allylic substitution reaction

is an important tool for synthetic organic chemists The reaction can be catalyzed by several transition metals of which palladium has proven the most widely applicable so far Most of these transition metal catalysts can be applied with stabilized carbanions and heteroatomic nucleophiles albeit not with organometallic reagents

Copper holds a special position among these transition metals one might even say an important niche It is the only metal so far that can both be applied to prochiral linear allylic substrates with a general regioselectivity for the branched product and be used efficiently with a wide range of organometallic reagents These qualities allow for the synthesis of versatile chiral compounds containing a terminal olefin which is a useful functional group for further transformations and a new stereogenic center with a simple alkyl substituent

Over the last decade several efficient catalyst systems for copper catalyzed asymmetric allylic alkylation have been developed Particularly effective for the application of dialkylzinc reagents are the systems based on the modular peptide ligands and the NHC-ligands both originating from Hoveydarsquos group In the case of Grignard reagents the most effective systems are based on phosphoramidites as reported by Alexakisrsquogroup or the diphosphine ligand Taniaphos which is further described in the following chapters of this thesis

Considering the impressive results reported in the field already it seems that the area is no longer in its infancy but has reached adolescence The focus of current research has shifted from development of more selective

Chapter 1

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procedures to broadening the scope of these procedures and applications in synthesis Nevertheless before the area can reach maturity ie the reaction becomes a standard tool in industrial as well as laboratory chemistry major hurdles remain to be overcome

In many cases catalyst loadings remain too high 1 mol is still considered high by industrial standards In addition the reaction temperature is often too low the reactions with Grignard reagents are all performed at around minus78 degC Some of the reactions reported by Hoveydarsquos group can be performed at minus15 degC however his use of dialkylzinc compounds is not as atom economical as the use of Grignard reagents A solution could be the use of monoalkylzinc compounds (RZnX) The low reactivity of these compounds should allow their use at higher temperatures however it seems to have precluded the development of an efficient catalyst system thus far68

In addition little is known about the mechanism of the reaction In general hypothetical models extrapolated from the knowledge of copper catalyzed conjugate addition are used Definitive information on the catalytic species and cycles is still unavailable More insight into the mechanism would help substantially in the amelioration of the reaction as has been seen in other catalyzed processes


29


References 1 Woumlhler F Ann Phys Chem 1828 88 253-256 2 Eliel E L Wilen S H Stereochemistry of Organic Compounds 1994 Wiley New York 3 Artwork from httpweb99arcnasagov~astrochmaachiralhtml 4 Sheldon R A Chirotechnology 1993 Dekker New York 5 a) Trost B M Angew Chem Int Ed Engl 1995 34 259-281 b) Trost B M Science 1991 254 1471-1477 6 httpnobelprizeorgnobel_prizeschemistrylaureates2001indexhtml 7 a) Ma S Lu Z Angew Chem Int Ed 2008 47 258-297 b) Pfaltz A Lautens M in Comprehensive Asymmetric Catalysis Jacobsen E N Pfaltz A Yamamoto H Eds Springer Heidelberg 1999 Vol 2 Chapter 24 c) Helmchen G J Organomet Chem 1999 576 203-214 d) Trost B M Van Vranken D L Chem Rev 1996 96 395-422 8 a) Trost B M J Org Chem 2004 69 5813-5837 b) Trost B M Crawley M L Chem Rev 2003 103 2921-2943 9 See for example a) Trost B M Schroeder G M J Am Chem Soc 2000 122 3785-3786 b) Trost B M Tsui H-C Toste F D J Am Chem Soc 2000 122 3534-3535 c) Trost B M Toste F D J Am Chem Soc 1998 120 9074-9075 10 a) Hayashi T Acc Chem Res 2000 33 354-362 and references therein b) Hayashi T Kawatsura M Uozumi Y Chem Commun 1997 561-562 11 a) Hilgraf R Pfaltz A Adv Synth Cat 2005 347 61-77 and references therein b) Preacutetocirct R Pfaltz A Angew Chem Int Ed 1998 37 323-325 12 a) Zheng W-H Sun N Hou X-L Org Lett 2005 7 5151-5154 b) Pagravemies O Dieacuteguez M Claver C J Am Chem Soc 2005 127 3646-3647 c) You S-L Zhu X-Z Luo Y-M Hou X-L Dai L-X J Am Chem Soc 2001 123 7471-7472 13 Trost B M Ariza X J Am Chem Soc 1999 121 10727-10737 14 For a review of the method in an achiral fashion see Kazmaier U Curr Org Chem 2003 7 317-328 15 a) Trost B M Schroeder G M Chem Eur J 2005 11 174-184 b) You S-L Hou X-L Dai L-X Zhu X-Z Org Lett 2001 3 149-151 c) Trost B M Schroeder G M J Am Chem Soc 1999 121 6759-6760 16 Braun M Laicher F Meier T Angew Chem Int Ed 2000 39 3494-3497 17 Behenna D C Stoltz B M J Am Chem Soc 2004 126 15044-15045

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18 For comprehensive reviews see a) Mohr J T Stoltz B M Chem Asian J 2007 2 1476-1491 b) You S-L Dai L-X Angew Chem Int Ed 2006 45 5246-5248 19 a) Enquist J A Jr Stoltz B M Nature 2008 453 1228-1231 b) White D E Stewart I C Grubbs R H Stoltz B M J Am Chem Soc 2008 130 810-811 see also references cited in ref 18 20 For reviews see a) Helmchen G Dahnz A Duumlbon P Schelwies M Weihofen R Chem Commun 2007 675-691 b) Takeuchi R Kezuka S Synthesis 2006 3349-3366 c) Miyabe H Takemoto Y Synlett 2005 1641-1655 21 Janssen J P Helmchen G Tetrahedron Lett 1997 38 8025-8026 22 a) Polet D Alexakis A Tissot-Croset K Corminboeuf C Ditrich K Chem Eur J 2006 12 3596-3609 b) Alexakis A Polet D Org Lett 2004 6 3529-3532 c) Bartels B Garciacutea-Yebra C Helmchen G Eur J Org Chem 2003 1097-1103 23 See for example a) Singh O V Han H J Am Chem Soc 2007 129 774-775 b) Lyothier I Defieber C Carreira E M Angew Chem Int Ed 2006 45 6204-6207 c) Shu C Hartwig J F Angew Chem Int Ed 2004 43 4794-4797 d) Ohmura T Hartwig J F J Am Chem Soc 2002 124 15164-15165 24 a) Marković D Hartwig J F J Am Chem Soc 2007 129 11680-11681 b) Polet D Alexakis A Org Lett 2005 7 1621-1624 c) Kiener C A Shu C Incarvito C Hartwig J F J Am Chem Soc 2003 125 14272-14273 d) Bartels B Garciacutea-Yebra C Rominger F Helmchen G Eur J Inorg Chem 2002 2569-2586 25 Alexakis A El Hajjaji S Polet D Rathgeb X Org Lett 2007 9 3393-3395 26 Lloyd-Jones G C Pfaltz A Angew Chem Int Ed Engl 1995 34 462-464 27 Trost B M Hachiya I J Am Chem Soc 1998 120 1104-1105 28 For a review see Belda O Moberg C Acc Chem Res 2004 37 159-167 29 a) Hughes D L Lloyd-Jones G C Krska S W Gouriou L Bonnet V D Jack K Sun Y Mathre D J Reamer R A Proc Nat Acad Sci USA 2004 101 5379-5384 b) Lloyd-Jones G C Krska S W Hughes D L Gouriou L Bonnet V D Jack K Sun Y Reamer R A J Am Chem Soc 2004 126 702-703 30 For reviews see a) Bruneau C Renaud J-L Demerseman B Pure Appl Chem 2008 80 861-871 b) Bruneau C Renaud J-L Demerseman B Chem Eur J 2006 12 5178-5187 31 Matsushima Y Onitsuka K Kondo T Mitsudo T Takahashi S J Am Chem Soc 2001 123 10405-10406 32 Constant S Tortoioli S Muumlller J Lacour J Angew Chem Int Ed 2007 46 2082-2085


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33 a) Onitsuka K Okuda H Sasai H Angew Chem Int Ed 2008 47 1454-1457 b) Mbaye M D Renaud J-L Demerseman B Bruneau C Chem Commun 2004 1870-1871 34 One example of Pd-catalyzed enantioelective allylic alkylation with an organometallic reagent has been reported Fotiadu F Cros P Faure B Buono G Tetrahedron Lett 1990 31 77-80 35 Consiglio G Morandini F Piccolo O J Chem Soc Chem Commun 1983 112-114 36 a) Nomura N RajanBabu T V Tetrahedron Lett 1997 38 1713-1716 b) Indolese A F Consiglio G Organometallics 1994 13 2230-2234 and references therein c) Hiyama T Wakasa N Tetrahedron Lett 1985 26 3259-3262 37 Gomez-Bengoa E Heron N M Didiuk M T Luchaco C A Hoveyda A H J Am Chem Soc 1998 120 7649-7650 38 Son S Fu G C J Am Chem Soc 2008 130 2756-2757 39 Evans P A Nelson J D J Am Chem Soc 1998 120 5581-5582 40 Hayashi T Okada A Suzuka T Kawatsura M Org Lett 2003 5 1713-1715 41 Miura T Takahashi Y Murakami M Chem Commun 2007 595-597 42 Menard F Chapman T M Dockendorff C Lautens M Org Lett 2006 8 4569-4572 43 For reviews on the general reactivity of copper-based reagents and catalysts in allylic alkylation see a) Breit B Demel P in Modern Organocopper Chemistry Krause N (Ed) Wiley-VCH Weinheim 2002 Chapter 6 b) Karlstroumlm A S E Baumlckvall J-E in Modern Organocopper Chemistry Krause N (Ed) Wiley-VCH Weinheim 2002 Chapter 8 c) Magid R M Tetrahedron 1980 36 1901-1930 44 a) Geurts K Fletcher S P van Zijl A W Minnaard A J Feringa B L Pure Appl Chem 2008 80 1025-1037 b) Falciola C A Alexakis A Eur J Org Chem 2008 3765-3780 c) Harutyunyan S R den Hartog T Geurts K Minnaard A J Feringa B L Chem Rev 2008 108 2824-2852 d) Yorimitsu H Oshima K Angew Chem Int Ed 2005 44 4435-4439 e) Alexakis A Malan C Lea L Tissot-Croset K Polet D Falciola C Chimia 2006 60 124-130 45 van Klaveren M Persson E S M del Villar A Grove D M Baumlckvall J-E van Koten G Tetrahedron Lett 1995 36 3059-3062 46 a) Cotton H K Norinder J Baumlckvall J-E Tetrahedron 2006 62 5632-5640 b) Karlstroumlm A S E Huerta F F Meuzelaar G J Baumlckvall J-E Synlett 2001 923-926 c) Meuzelaar G J Karlstroumlm A S E van Klaveren M Persson E S M del Villar A van Koten G Baumlckvall J-E Tetrahedron 2000 56 2895-2903

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47 a) Duumlbner F Knochel P Tetrahedron Lett 2000 41 9233-9237 b) Duumlbner F Knochel P Angew Chem Int Ed 1999 38 379-381 48 a) von Wangelin A J Frederiksen M U in Transition Metals for Organic Synthesis 2nd Ed Vol 1 Beller M Bolm C (Eds) Wiley-VCH Weinheim 2004 Chapter 37 b) Knochel P Almena Perea J J Jones P Tetrahedron 1998 54 8275-8319 49 a) Kacprzynski M A Hoveyda A H J Am Chem Soc 2004 126 10676-10681 b) Luchaco-Cullis C A Mizutani H Murphy K E Hoveyda A H Angew Chem Int Ed 2001 40 1456-1460 50 a) Murphy K E Hoveyda A H Org Lett 2005 7 1255-1258 b) Hoveyda A H Hird A W Kacprzynski M A Chem Commun 2004 1779-1785 c) Murphy K E Hoveyda A H J Am Chem Soc 2003 125 4690-4691 51 a) van Zijl A W Arnold L A Minnaard A J Feringa B L Adv Synth Catal 2004 346 413-420 b) Malda H van Zijl A W Arnold L A Feringa B L Org Lett 2001 3 1169-1171 52 Shi W-J Wang L-X Fu Y Zhu S-F Zhou Q-L Tetrahedron Asymm 2003 14 3867-3872 53 Ongeri S Piarulli U Roux M Monti C Gennari C Helv Chim Acta 2002 85 3388-3399 54 a) Piarulli U Daubos P Claverie C Monti C Gennari C Eur J Org Chem 2005 895-906 b) Piarulli U Daubos P Claverie C Roux M Gennari C Angew Chem Int Ed 2003 42 234-236 55 Piarulli U Claverie C Daubos P Gennari C Minnaard A J Feringa B L Org Lett 2003 5 4493-4496 56 a) Kacprzynski M A May T L Kazane S A Hoveyda A H Angew Chem Int Ed 2007 46 4554-4558 b) Van Veldhuizen J J Campbell J E Giudici R E Hoveyda A H J Am Chem Soc 2005 127 6877-6882 c) Larsen A O Leu W Nieto Oberhuber C Campbell J E Hoveyda A H J Am Chem Soc 2004 126 11130-11131 57 a) Goldsmith P J Teat S J Woodward S Angew Chem Int Ed 2005 44 2235-2237 b) Boumlrner C Gimeno J Gladiali S Goldsmith P J Ramazzotti D Woodward S Chem Commun 2000 2433-2434 58 a) Alexakis A Croset K Org Lett 2002 4 4147-4149 b) Alexakis A Pure Appl Chem 2002 74 37-42 c) Alexakis A Malan C Lea L Benhaim C Fournioux X Synlett 2001 927-930 d) Alexakis A Croset K Org Lett 2003 5 4239 correction 58a 59 a) Tissot-Croset K Polet D Alexakis A Angew Chem Int Ed 2004 43 2426-2428 b) Tissot-Croset K Polet D Gille S Hawner C Alexakis A Synthesis 2004 2586-2590


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60 a) Falciola C A Tissot-Croset K Reyneri H Alexakis A Adv Synth Catal 2008 350 1090-1100 b) Falciola C A Alexakis A Angew Chem Int Ed 2007 46 2619-2622 c) Falciola C A Tissot-Croset K Alexakis A Angew Chem Int Ed 2006 45 5995-5998 61 Tissot-Croset K Alexakis A Tetrahedron Lett 2004 45 7375-7378 62 a) Okamoto S Tominaga S Saino N Kase K Shimoda K J Organomet Chem 2005 690 6001-6007 b) Tominaga S Oi Y Kato T An D K Okamoto S Tetrahedron Lett 2004 45 5585-5588 63 Seo H Hirsch-Weil D Abboud K A Hong S J Org Chem 2008 73 1983-1986 64 Lee Y Hoveyda A H J Am Chem Soc 2006 128 15604-15605 65 Gillingham D G Hoveyda A H Angew Chem Int Ed 2007 46 3860-3864 66 Lee Y Akiyama K Gillingham D G Brown M K Hoveyda A H J Am Chem Soc 2008 130 446-447 67 a) Ito H Ito S Sasaki Y Matsuura K Sawamura M Pure Appl Chem 2008 80 1039-1045 b) Ito H Ito S Sasaki Y Matsuura K Sawamura M J Am Chem Soc 2007 129 14856-14857 68 The use of RZnX nucleophiles in a highly regio- and stereospecific Cu-catalyzed allylic substitution at room temperature has been reported recently Nakata K Kiyotsuka Y Kitazume T Kobayashi Y Org Lett 2008 10 1345-1348


In this chapter the development of a new method for copper catalyzed enantioselective allylic alkylation with Grignard reagents is described The new catalyst system is based on ferrocenyl diphosphine ligands the application of which was demonstrated previously in enantioselective conjugate addition The ligand which gives the best results is Taniaphos (up to 98 ee) The use of this ligand results in a catalyst which is complementary to previously reported systems for copper catalyzed allylic alkylation with Grignard reagents in that it gives the best results obtained thus far with methyl Grignard reagents The scope of the reaction is explored and a range of aromatic and aliphatic substrates have been applied with excellent results

This chapter has been published in part Loacutepez F van Zijl A W Minnaard A J Feringa B L Chem Commun 2006 409-411

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21 Introduction Enantioselective copper catalyzed allylic alkylation (Figure 21) is a

powerful C-C bond forming reaction1 It allows the formation of stereogenic centers with simple alkyl substituents which are ubiquitous in natural products As discussed previously in chapter 1 several catalyst systems have been reported in recent years however most of them suffer serious drawbacks including low selectivity or limited substrate scope The exceptions which include the systems reported by the groups of Hoveyda23 and Alexakis4 have enabled the application of enantioselective copper catalyzed allylic alkylation with high selectivity and an appreciable substrate scope

Hoveyda and coworkers have in fact developed two different catalytic asymmetric systems both applicable to the allylic alkylation using dialkylzinc reagents one system based on modular peptidic Schiff base ligands (Figure 21a)2 and one based on chiral N-heterocyclic carbene ligands (Figure 21b)3 Both systems can catalyze the allylic alkylation efficiently providing a large range of chiral products with high selectivity

Figure 21 Asymmetric Cu-catalyzed allylic alkylation and the best chiral ligands so far a) modular peptidic Schiff base ligand (Hoveyda) b) Ag-dimer of a NHC-ligand (Hoveyda) c) phosphoramidite ligand (Alexakis) Mes = mesitylene

Enantioselective Cu-catalyzed allylic alkylation with Grignard reagents using ferrocenyl diphosphine ligands

37


The group of Alexakis in contrast has reported a catalyst system which is effective in the enantioselective allylic alkylation using Grignard reagents4 A phosphoramidite ligand was used which comprised a binaphthol-backbone and a bis(1-(o-methoxyphenyl)ethyl)amine moiety (Figure 21c) High selectivities were attained with several aromatic substrates and one aliphatic substrate The use of a methyl Grignard reagent proved to be problematic though especially with respect to the regioselectivity of the reaction5 This was unfortunate since the methyl group is the most common aliphatic moiety in natural products

Grignard reagents are in general cheaper and easier to handle than dialkylzinc reagents and this makes their use in enantioselective reactions attractive The fact that the introduction of a methyl group remained problematic was an incentive to develop a new catalyst system which could make efficient use of methyl Grignard reagent in the enantioselective copper catalyzed allylic alkylation The new catalyst system should have a high substrate and reagent scope excellent regio- and enantioselectivity and it should be convenient to use for synthetic chemists An additional advantage would be a catalyst based on a readily available ligand which in the aforementioned systems from the Hoveyda and Alexakis groups has to be synthesized in several steps

211 Ferrocenyl diphosphine ligands and Grignard reagents in Cu-catalyzed conjugate addition reactions

A commercially and hence readily available ligand class (Figure 22) was applied recently in the copper catalyzed enantioselective conjugate addition using Grignard reagents6 Prior to this achieving high chemo- regio- and enantioselectivity in the enantioselective conjugate addition of Grignard reagents presented a considerable challenge7 This was in contrast to major successes in the use of dialkylzinc reagents8 Application of Grignard reagents to Cu-catalyzed conjugate addition reactions suffered from several drawbacks Amongst these were low regio- and enantioselectivity and in cases where the enantioselectivity was appreciably high (up to 92 ee) there was usually a restricted scope in the Grignard reagents or substrates that could be employed and a large amount of catalyst (substoichiometric chiral ligand) had to be used

Chapter 2

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Figure 22 Bidentate ferrocenyl diphosphine ligands Taniaphos and Josiphos which were successfully applied in the enantioselective copper catalyzed conjugate addition

In 2004 Feringa and coworkers reported for the first time that ferrocenyl diphosphine ligands (Figure 22) could be employed in catalyst systems that provide for the conjugate addition of several Grignard reagents to cyclic αβ-unsaturated carbonyl substrates efficiently9 Unprecedented enantiomeric excesses of up to 96 and high regioselectivities were achieved with the Taniaphos ligand L1 (Scheme 21)

Scheme 21 Cu-catalyzed enantioselective conjugate addition reactions to cyclic and acyclic substrates using Grignard reagents

This first report was followed by several further studies demonstrating the use of these catalyst systems in the asymmetric conjugate addition to different classes of acyclic αβ-unsaturated carbonyl substrates Although a lower reaction temperature was necessary in the conjugate addition to these


39


acyclic substrates (Scheme 21) the selectivities were again excellent when using the ligand Josiphos L2 (Figure 21) Several distinct substrate classes including αβ-unsaturated ketones10 oxoesters11 and thioesters12 and a range of Grignard reagents could be applied with excellent results

Insight into the mechanism was gained through spectroscopic kinetic electrochemical and catalysis data A structure for the catalytically active species was proposed together with a catalytic cycle for the reaction13 It was found that the CuXligand complex forms a solvent dependent monomerdimer equilibrium in solution However the dimers are broken up after addition of the Grignard reagent to form a mononuclear species associated closely with the alkylmagnesium halide (Scheme 22) This mononuclear species is the active catalyst and it was proposed that the rate limiting step in the catalytic cycle is the reductive elimination of a Cu(III)-σ adduct in which a halogen bridges with the magnesium enolate

Scheme 22 Catalytic cycle proposed for the enantioselective copper catalyzed conjugate addition using Grignard reagents

The results obtained using ferrocenyl diphosphine ligands together with Grignard reagents and the wealth of information regarding the active species

Chapter 2

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and catalytic cycle prompted the application of these ligands to the enantioselective copper catalyzed allylic alkylation Although there are expected to be several differences in the mechanism of the two reactions there are many similarities also (Scheme 23) An alkyl substituent has to be transferred from the organometallic reagent to a carbon of an olefinic double bond thereby shifting this double bond In the case of a conjugate addition the formation of an enolate allows this double bond shift In the case of an allylic substitution reaction a leaving group has to be expelled In both cases another regiochemical outcome of the reaction is possible 12-addition is competing with the conjugate addition reactions and SN2-substitution with SN2rsquo-substitution in allylic alkylation In general although success of a catalyst system in one of these two reactions is no guarantee for success in the other many catalysts can be used in both reactions albeit with adapted conditions

Scheme 23 Related copper catalyzed reactions a) conjugate addition b) allylic alkylation


41


212 The absolute and relative configuration of Taniaphos Taniaphos L1 amongst others has become an important ligand in

enantioselective copper catalyzed allylic alkylation It is pertinent to discuss the structure of the compound This is necessary due to confusion regarding its configuration which arose due to an erroneous representation in the first report of its synthesis and use in asymmetric catalysis in 199914

Scheme 24 Original synthesis of Taniaphos where CBS-reduction and di-lithiation were key transformations Note the erroneous representation of the configuration of Taniaphos14

Knochel and coworkers reported the synthesis of the compound through an asymmetric CBS-reduction of o-bromophenyl(ferrocenyl)ketone followed by substitution di-lithiation and reaction with ClPPh2 (Scheme 24) The stereochemical outcome of the CBS-reduction was known15 and the diastereoselectivity of the o-lithiation on the ferrocene was predicted based on the work by Ugi and coworkers16 This led to the assumption that they had synthesised the (RSp)-stereoisomer of Taniaphos as shown in Scheme 24

In 2007 Fukuzawa et al reported the synthesis of a ligand assumed to be the diastereomer of Taniaphos with the configuration (RRp)17 Later however they reported that the configuration was in fact the same as for Taniaphos18 The X-ray structure of the ligand in the original report by Knochel and coworkers showed that the configuration of Taniaphos was (RRp) also14 nevertheless the stereochemistry of (+)-Taniaphos was assigned incorrectly In reaction to Fukuzawarsquos remarks Knochel published a corrigendum to correct the stereochemical assignment (Figure 23)19

Chapter 2

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Figure 23 The originally reported stereochemistry versus the corrected stereochemistry of the diphosphine ligand (+)-Taniaphos

The misassignment is of interest as initial lithiation of the arylbromide causes the amine moiety to complex the aryllithium thus diminishing its potential for directing the o-lithiation In my opinion the high selectivity for lithiation on the opposite position could be attributed to cluster formation of the lithium species20 which could turn the aryllithium moiety into a directing group in the o-lithiation

Figure 24 X-ray crystal structures of CuCl (left) and CuBr (right) complexes with the ferrocenyl diphosphine ligand Taniaphos

The correct stereochemistry of Taniaphos is visible also in the X-ray crystal structures of complexes of CuCl and CuBr with Taniaphos prepared in our laboratories (Figure 24) Remarkable is the close proximity of the


43


benzylic hydrogen (H41 and H23 respectively) to the metal center and the elongation of the benzylic CminusH bond in both complexes the interatomic distances (Aring) for CminusH are 11763(-) and 139(8) and for CuminusH they are 217(-) and 191(8) in the CuCl and CuBr complexes respectively The CuminusHminusC bond angles are 137(-) and 138(5) respectively This could indicate an agostic interaction between the copper atom and the benzylic CminusH bond of the ligand since the bond lengths and angles in these complexes are within the generally expected values for agostic interactions reported by Brookhart et al21

In summary in all publications between 1999 and 2008 where Taniaphos is represented as the (RSp)-stereoisomer the (+)-(RRp)-stereoisomer was used instead (Figure 23) This includes some of the work presented in this thesis which was published previously2223 and the publications from this group where Taniaphos was used in conjugate additions910 In addition in a recent report which described the use of Taniaphos in the synthesis of chiral allylic esters (minus)-(RS)-Taniaphos should be (+)-(RRp)-Taniaphos24

Scheme 25 Stereochemical outcome in copper catalyzed 14-addition and allylic alkylation using ligands a) (RRp)-Taniaphos or b) (RSp)-Josiphos

Chapter 2

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The misassignment of Taniaphos is relevant also because it can have important implications in models to predict enantioselectivity such as that presented by Harutyunyan et al13 The conjugate addition of EtMgBr to cyclohexenone and other cyclic substrates affords opposite enantiomers of the product using the ligands (RRp)-Taniaphos L1 and (RSp)-Josiphos L2 (Scheme 25)9 However conjugate addition to the acyclic enone 3-nonen-2-one results in the same enantiomer using the ligands L1 and L210

In the copper catalyzed allylic alkylation with Grignard reagents (vide infra) the same enantiomer is obtained with both ligands also Clearly the development of a general enantiodiscrimination model for these ferrocenyl diphosphine ligands in copper catalyzed reactions with Grignard reagents is not a trivial matter


45


22 Results and Discussion

221 Asymmetric allylic alkylations with Josiphos ligands As the best results in the conjugate addition to acyclic substrates were

obtained with the ligand Josiphos L2 (Figure 22 vide supra) the first attempts towards allylic alkylation were performed with this ligand Cinnamyl bromide 1a was chosen as the primary substrate and three solvents that had shown good results in conjugate addition reactions with Grignard reagents were tested (Table 21)

Table 21 Solvent dependence of the reaction with Josiphos L2 and cinnamyl bromidea

entry RMgBr solvent product 2 3b eeb

1 MeMgBr t-BuOMe 2a 85 15 85

2 MeMgBr Et2O 2a 78 22 76

3 MeMgBr CH2Cl2 2a 49 51 73

4c MeMgBr t-BuOMe 2a 50 50 82

5 EtMgBr t-BuOMe 2b 38 62 56 a Reaction conditions 1a (added after all other reagents 10 equiv) RMgBr (25 equiv) CuBrmiddotSMe2 (5 mol) L2 (6 mol) minus75 degC 12 h gt 98 conversion (GC) b Determined by GC-analysis c Reverse addition RMgBr added after all other reagents

The catalyst was formed in situ from 5 mol CuBrmiddotSMe2 and 6 mol of L2 The asymmetric allylic alkylations were performed with 25 equivalents of methyl Grignard at minus75 degC with 1a added after all other reagents Full conversion was reached in 12 h in all cases and it was found that t-BuOMe

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gave the best regio- and enantioselectivity the branched and linear products 2 and 3 respectively were obtained in a ratio of 85 15 and the enantiomeric excess for 2 was 85 (Table 21 entry 1) Both Et2O and CH2Cl2 gave lower regio- and enantioselectivity (Table 21 entries 2 and 3) The order of addition of the reagents was found to be critical Addition of the Grignard reagent after the substrate lowered the regioselectivity substantially (Table 21 entry 4) With ethyl Grignard reagent the results were less promising than with MeMgBr (Table 21 entry 5)

Table 22 Variation of the copper salt with Josiphos L2 and cinnamyl bromidea

entry RMgBr [Cu] product 2 3b eeb

1 MeMgBr CuBrmiddotSMe2 2a 85 15 85

2 MeMgBr CuCN 2a 85 15 86

3 MeMgBr CuCl 2a 85 15 84

4 MeMgBr [Cu(MeCN)4]PF6 2a 84 16 84

5 MeMgBr CuTC 2a 60 40 84

6c EtMgBr CuCN 2b 50 50 nd

7d EtMgBr [Cu(MeCN)4]PF6 2b 25 75 38 a Reaction conditions 1a (added as the last reagent 10 equiv) RMgBr (25 equiv) [Cu] (5 mol) L2 (6 mol) t-BuOMe minus75 degC 12 h gt 98 conversion (GC) b Determined by GC-analysis c Reaction time 2h lt10 conversion d EtMgBr (115 equiv) CH2Cl2 as solvent TC = 2-thiophenecarboxylate

Subsequently the dependence on the copper source was explored (Table 22) The counterion can influence the nature of the catalytically active species However copper salts other than CuBrmiddotSMe2 could be used in the allylic alkylation of 1a with MeMgBr without significant effect on the


47


selectivity with the exception of CuTC which provided lower regioselectivity (Table 22 entries 2-5 vs entry 1) The use of other copper salts in the allylic alkylation with EtMgBr led to a very low conversion in t-BuOMe and diminished selectivity in CH2Cl2 (Table 22 entries 6 and 7)

In contrast to conjugate addition reactions allylic alkylation involves the loss of a leaving group This leaving group is important in the reaction as it changes the activity and nature of the electrophile and can also have a pronounced effect on the active catalyst species after the cleavage For these reasons different leaving groups were explored (Table 23)

The use of less active electrophiles such as cinnamyl chloride 1b or cinnamyl acetate 1c in the allylic alkylation with MeMgBr slowed down the reaction substantially and gave only the linear product 3 (Table 23 entries 2 and 3) Both cinnamyl diethyl phosphate 1d and cinnamyl methyl carbonate 1e were very slow to react in t-BuOMe also and gave low regioselectivity in dichloromethane (Table 23 entries 4-7)

Table 23 The effect of different leaving groups on the allylic alkylation with Josiphos L2a

entry 1 RMgBr product conversion 2 3b eeb

1 1a MeMgBr (25 eq) 2a gt98 85 15 85

2 1b MeMgBr (25 eq) 2a 29 0 100 -

3c 1c MeMgBr (25 eq) 2a 22 0 100 -

4 1d MeMgBr (25 eq) 2a lt10 81 19 58

5de 1d MeMgBr (15 eq) 2a 75 36 64 58

Chapter 2

48


6e 1e MeMgBr (15 eq) 2a no reaction

7de 1e MeMgBr (15 eq) 2a 25 8 92 57

8 1b EtMgBr (115 eq) 2b 70 9 91 0

9d 1b EtMgBr (115 eq) 2b gt98 57 43 36

10de 1b EtMgBr (115 eq) 2b 96 74 26 40

11d 1d EtMgBr (15 eq) 2b gt98 13 87 20 a Reaction conditions 1 (added as the last reagent 10 equiv) RMgBr (25 equiv) CuBrmiddotSMe2 (5 mol) L2 (6 mol) t-BuOMe minus75 degC 12 h b Determined by GC-analysis c Reaction temperature minus75 degC rarr minus30 degC d CH2Cl2 as solvent e Copper source [Cu(MeCN)4]PF6

In the case of ethylmagnesium bromide although the regioselectivity

could be improved by using cinnamyl chloride in CH2Cl2 with [Cu(MeCN)4]PF6 the enantioselectivity remained low (Table 23 entries 8-10) With cinnamyl diethyl phosphate (Table 23 entry 11) lower selectivities were attained than with cinnamyl bromide 1a using EtMgBr (vide supra Table 21 entry 5)

Although the use of Josiphos L2 as a ligand in the allylic alkylation with MeMgBr provided acceptable regio- and enantioselectivity (85 15 86 ee) the use of EtMgBr resulted in mediocre selectivities at best In the conjugate addition with Grignard reagents the use of the ligand reverse-Josiphos L3 (Figure 25) occasionally affords better results than L2 (eg with aromatic and sterically demanding oxoesters)11 Cinnamyl bromide 1a is an aromatic substrate and consequently ligand L3 was tested in the allylic alkylation (Table 24)

Figure 25 (RSp)-reverse-Josiphos L3 (RRp)-Taniaphos L1 and a few Taniaphos derivatives L1b-d


49


The use of ligand L3 with EtMgBr as the Grignard reagent in t-BuOMe did not improve the regio- or enantioselectivity (Table 24 entry 1) However when the reaction was performed in CH2Cl2 with [Cu(MeCN)4]PF6 as the copper source the branched product 2b was obtained with the highest enantiomeric excess so far albeit with low regioselectivity (Table 24 entry 2) Finally the use of cinnamyl chloride 1b and L3 as a ligand gave higher regioselectivities but lower enantioselectivities (Table 24 entries 3 and 4)

Table 24 The use of reverse-Josiphos L3 in allylic alkylation with Grignard reagentsa

entry solvent RMgBr product 2 3b eeb

1 t-BuOMe EtMgBr 2b 30 70 40

2c CH2Cl2 EtMgBr 2b 16 84 75

3d CH2Cl2 EtMgBr 2b 45 55 33

4cd CH2Cl2 EtMgBr 2b 65 35 40

5e t-BuOMe MeMgBr 2a 66 34 80

6 CH2Cl2 MeMgBr 2a 20 80 40 a Reaction conditions 1a (added as the last reagent 10 equiv) RMgBr (115 equiv) CuBrmiddotSMe2 (5 mol) L3 (6 mol) minus75 degC 12 h conversion gt 98 b Determined by GC-analysis c Copper source [Cu(MeCN)4]PF6 d Substrate 1b was used e RMgBr (25 equiv)

The reaction with reverse-Josiphos L3 as a ligand and MeMgBr as the Grignard reagent proceeded with higher enantioselectivity in t-BuOMe than in dichloromethane (Table 24 entries 5 and 6) The use of L2 as a ligand generally provided higher selectivities than the use of L3 however

Chapter 2

50


222 Asymmetric allylic alkylations with Taniaphos As discussed in section 21 another ferrocenyldiphosphine ligand

which had performed well in conjugate addition reactions is Taniaphos L1 (Figure 25) This ligand was applied in the allylic alkylation with EtMgBr as the Grignard reagent as well (Table 25) When t-BuOMe was used as the solvent the ligand Taniaphos L1 afforded similar results to those obtained with the ligands L2 and L3 (Table 25 entry 1) A dramatic improvement was observed when the solvent was changed for dichloromethane though Under these conditions the branched product was obtained in good regioselectivity and excellent enantioselectivity (82 18 96 ee Table 25 entry 2) An equally remarkable improvement was observed when MeMgBr was used as the Grignard reagent the branched product 2a was obtained in excellent regioselectivity and enantiomeric excess (98 2 97 ee Table 25 entry 3)

It was found that various copper salts as well as EtMgCl as the Grignard reagent could be applied with the same high regio- and enantioselectivity (Table 25 entries 4-7) The use of different substrates such as cinnamyl chloride 1b or cinnamyl diethyl phosphate 1d gave slower reactions with lower selectivities however (Table 24 entries 8 and 9) Subsequently three other Taniaphos derivatives (L1b-d Figure 25) were applied under the same conditions These reactions gave similar results albeit with slightly lower selectivities (Table 25 entries 10-12)

Table 25 Asymmetric allylic alkylations with Taniaphos derivatives as ligandsa

entry [Cu] L1 RMgBr product 2 3b eeb

1c CuBrmiddotSMe2 L1 EtMgBr 2b 31 69 32

2 CuBrmiddotSMe2 L1 EtMgBr 2b 82 18 96


51


3 CuBrmiddotSMe2 L1 MeMgBr 2a 98 2 97

4 CuTC L1 EtMgBr 2b 82 18 96

5 CuCl L1 EtMgBr 2b 82 18 95

6 Cu(MeCN)4PF6 L1 EtMgBr 2b 83 17 96

7 CuBrmiddotSMe2 L1 EtMgCl 2b 80 20 94

8d CuBrmiddotSMe2 L1 EtMgBr 2b 80 20 88

9e CuBrmiddotSMe2 L1 EtMgBr 2b 73 27 38

10 CuBrmiddotSMe2 L1b EtMgBr 2b 71 29 80

11 CuBrmiddotSMe2 L1c EtMgBr 2b 78 22 90

12 CuBrmiddotSMe2 L1d EtMgBr 2b 78 22 88 a Reaction conditions 1a (added as the last reagent 10 equiv) RMgBr (115 equiv) [Cu] (5 mol) L1 (6 mol) CH2Cl2 minus75 degC 12 h gt98 conversion b Determined by GC-analysis c t-BuOMe as solvent d Substrate 1b was used 45 conversion e Substrate 1d was used lt10 conversion TC = 2-thiophenecarboxylate

Having thus obtained excellent selectivities with Taniaphos as a ligand in the allylic alkylation of cinnamyl bromide with MeMgBr and EtMgBr an exploration of the scope of the reaction was undertaken (Table 26) The reactions were performed as specified previously in dichloromethane at minus75 degC and with 115 equiv of the Grignard reagent The catalyst loading however was lowered to 10 mol CuBrmiddotSMe2 and 11 mol L1 which did not have an adverse effect on the selectivity of the reaction with either MeMgBr or EtMgBr and the products 2a and 2b could be isolated in good yield high regioselectivity and excellent enantiomeric excess (Table 26 entries 1 and 2)

Other aliphatic Grignard reagents were found to be applicable in the asymmetric allylic alkylation (Table 26 entries 3-5) Reactions with n-butylmagnesium bromide and 3-buten-1-ylmagnesium bromide as the Grignard reagents yielded the products 2c and 2d in excellent regio- and enantioselectivity The use of the sterically more demanding Grignard reagent i-BuMgBr led to an incomplete reaction with very low selectivity

Chapter 2

52


though In enantioselective conjugate additions the catalyst systems described in this chapter were found to perform better with linear aliphatic Grignard reagents than with branched ones also910

Table 26 Exploration of the scope of the allylic alkylation with Taniaphos L1a

entry 1 Rrsquo product yieldb 2 3c eec

1 1a Me

2a 91 97 3 98 (S)

2 1a Et

2b 92 81 19 95 (S)

3 1a n-Bu ( )2

2c 92 87 13 94 (S)

4 1a ( )2 ( )2

2d 93 91 9 95 (S)

5de 1a i-Bu

2e 89f 42 58 6


53


6 1f Me Cl

2f 95 99 1 97

7 1f Et Cl

2g 80 82 18 96

8 1g Me MeO2C

2h 94 98 2 97

9 1h Me

2i 87 100 0 96 (S)

10 1h Et

2j 86 87 13 90

11d 1i Me ( )3 2k 99f 100 0 92

12d 1i Et ( )3

2l 99f 100 0 93

13deg 1j Et

2m 20f 25 75 22

a Reaction conditions 1a (added as the last reagent 10 equiv) RMgBr (115 equiv) CuBrmiddotSMe2 (10 mol) L1 (11 mol) CH2Cl2 minus75 degC 12 h gt98 conversion b Isolated yield of combined 2 and 3 c Determined by GC-analysis d 5 mol catalyst e RrsquoMgBr (25 equiv) f Conversion (GC) g Reaction performed at minus50 degC

A wide range of different substrates could be applied in the reaction In the case of other aromatic allyl bromides substitution at the p-position or the use of 1-naphthyl allyl bromide 1h did not have an adverse effect on the selectivity (Table 26 entries 6-10) The products 2f-j were all obtained in good yield and excellent regioselectivity and enantiomeric excess

Chapter 2

54


Gratifyingly the allylic alkylation of the aliphatic allyl bromide 1i with MeMgBr and EtMgBr proceeded in high selectivity when performed with 5 mol catalyst A catalyst loading of 1 mol resulted in a small but significant decrease of both the regioselectivity and the enantiomeric excess The substrate 1j which has R = t-Bu was unreactive under these conditions Although at an elevated reaction temperature of minus50 degC the products were observed the conversion was still low and both regio- and enantioselectivity were poor


55


23 Conclusions In summary a new catalyst system was developed for copper catalyzed

asymmetric allylic alkylation The catalyst system which can be formed in situ from CuBrmiddotSMe2 and Taniaphos L1 performs excellently with allylic bromides as substrates in dichloromethane at minus75 degC A diverse range of linear aliphatic Grignard reagents can be applied with equally high yields regioselectivities and enantiomeric excesses In particular the use of MeMgBr leads to very high selectivities and this is an important achievement since the majority of alkyl substituents at stereogenic centers in natural products are methyl groups It should not be forgotten that the introduction of a methyl group through asymmetric allylic alkylation either using methyl Grignard reagents or dimethylzinc has been challenging so far16

A series of aromatic allylic bromides are suitable substrates for the reaction and particularly noteworthy are the results obtained with n-heptenyl bromide since most catalysts previously reported do not give the same high selectivities in the asymmetric allylic alkylation of acyclic aliphatic electrophiles However using the ligand Taniaphos excellent enantioselectivity and full regioselectivity was achieved with this aliphatic substrate

Chapter 2

56


24 Experimental Part General Remarks 1H NMR spectra were recorded at 300 or 400 MHz with CDCl3 as solvent 13C NMR spectra were obtained at 754 or 10059 MHz in CDCl3 Chemical shifts were determined relative to the residual solvent peaks (CHCl3 δ = 726 ppm for hydrogen atoms δ = 770 for carbon atoms) The following abbreviations are used to indicate signal multiplicity s singlet d doublet t triplet q quartet m multiplet br broad Progress and conversion of the reaction was determined by GC-MS with HP1 or HP5 columns Enantiomeric excesses and regioselectivities were determined by capillary GC analysis using a flame ionization detector (in comparison with racemic products) Optical rotations were measured at ambient temperature in CHCl3 on a Schmidt + Haensdch polarimeter (Polartronic MH8) with a 10 cm cell (c given in g100 mL) Absolute configurations of the products were determined by comparison with compounds previously published Thin-layer chromatography (TLC) was performed on commercial Kieselgel 60F254 silica gel plates and components were visualized with KMnO4 reagent Flash chromatography was performed on silica gel Drying of solutions was performed with MgSO4 or Na2SO4 Concentrations were performed using a rotary evaporator

Ligands L1 L2 and L3 were generously donated by Solvias purchased from commercial sources or prepared according to literature procedures1425 Taniaphos derivatives L1b-d were prepared according to literature procedures1426 Copper sources were purchased from commercial sources and used without further purification CuTC refers to copper thiophene-2-carboxylate27 The substrates 1a-c were purchased from commercial sources The substrates 1d28 1e29 1f-h30 1i31 and 1j32 were prepared according to literature procedures Grignard reagents were purchased from commercial sources (EtMgBr MeMgBr) or prepared from the corresponding alkyl bromides and magnesium turnings in Et2O following standard procedures Grignard reagents were titrated using s-BuOH and catalytic amounts of 110-phenanthroline t-BuOMe was purchased as anhydrous grade stored over 4Aring mol sieves and used without further purification Et2O was distilled from Nabenzophenone CH2Cl2 was


57


distilled from CaH2 All reactions were conducted under an argon atmosphere using standard Schlenk techniques

Racemic products 2 and regioisomers 3 were obtained by reaction of the bromides 1 with the corresponding Grignard reagent (50 equiv) at minus25 oC in CH2Cl2 in the presence of CuCN (100 mol ) In some cases the racemic products were also obtained by using racemic-L1 ligand following the general procedure described below Spectroscopic and analytical data of products 2b-d 2g 2j were obtained from their mixtures with the corresponding compounds 3 due to inseparability by flash chromatography

General Procedure for the Enantioselective Cu-catalyzed Allylic Alkylation with Grignard Reagents In a Schlenk tube equipped with septum and stirring bar CuBrmiddotSMe2 (150 μmol 308 mg) and ligand L1 (18 μmol 124 mg) were dissolved in CH2Cl2 (30 mL) and stirred under argon at room temperature for 10 min The mixture was cooled to ndash 75 oC and the corresponding Grignard reagent (solution in Et2O 173 mmol) was added dropwise Allylic bromide 1 (150 mmol) was then added dropwise as a solution in CH2Cl2 over 15 min via a syringe pump Once the addition was complete the resulting mixture was further stirred at ndash 75 oC for 4-12 h The reaction was quenched by addition of MeOH (05 mL) and the mixture was allowed to reach rt Then aqueous NH4Cl solution (1M 2 mL) was added to the mixture The organic phase was separated and the resulting aqueous layer was extracted with Et2O (05 mL 3x) The combined organic phases were dried and concentrated to a yellow oil which was purified by flash chromatography to yield the corresponding products as a mixture of SN2rsquo (2) and SN2 (3) regioisomers Note GC analysis was carried out on a sample obtained after aqueous extraction with Et2O which has been passed through a short plug of silica gel to remove transition metal residues

(+)-1-((S)-But-3-en-2-yl)benzene (2a)33

Reaction time 4h Purification by column chromatography (2 98 Et2On-pentane) afforded a 97 3 mixture of 2a and 3a as a colorless oil [91 yield 2a 98 ee [α]D = +54 (c 12 CHCl3) lit33a (81 ee) [α]D = + 48 (neat) lit33b for

(R)-2a (60 ee) [α]D = minus22 (c 07 CHCl3)] 2a 1H-NMR δ 728-714 (m 5H) 602-593 (m 1H) 504-498 (m 2H) 347-340 (m 1H) 133 (d J =

Chapter 2

58


70 Hz 3H) 13C-NMR δ 1455 1432 1283 1272 1260 1130 431 207 Enantioselectivity determined by chiral GC analysis CP-Chiralsil-Dex-CB (25 m x 025 mm) initial temp 75 ordmC retention times (min) 156 (minor) and 158 (major) Retention time 3a 237 min

(+)-1-((S)-Pent-1-en-3-yl)benzene (2b) 2430

Reaction time 4h Purification by column chromatography (2 98 Et2On-pentane) afforded a 81 19 mixture of 2b and 3b as a colorless oil [92 yield 2b 95 ee [α]D = +47 (c 10 CHCl3) lit4 (96 ee) [α]D = + 55 (c 11 CHCl3) lit2

for (R)-2b (95 ee) [α]D = minus 51 (c 05 CHCl3)] 2b 1H-NMR δ 732-712 (m 5H) 591 (m 1H) 501-497 (m 2H) 311 (q J = 74 Hz 1H) 174-164 (m 2H) 083 (t J = 731 Hz 3H) 13C-NMR δ 1444 1422 1284 1276 1261 1140 517 283 121 MS (EI) mz 146 (M+ 32) 128 (10) 117 (100) 91 (62) Enantioselectivity determined by chiral GC analysis CP-Chiralsil-Dex-CB (25 m x 025 mm) initial temp 75 degC for 30 min then 5 degCmin to 100 degC (final temp) retention times (min) 260 (minor) and 262 (major) Retention time 3b 380 min

(+)-1-((S)-Hept-1-en-3-yl)benzene (2c)33034

Reaction time 4h Purification by column chromatography (2 98 Et2On-pentane) afforded a 87 13 mixture of 2c and 3c as a colorless oil [92 yield 94 ee [α]D = +47 (c 05 CHCl3) lit30 (88 ee) [α]D = + 44 (c 01 CHCl3)] 2c 1H-

NMR δ 721 (m 5H) 595 (m 1H) 502 (m 2H) 332 (q J = 75 Hz 1H) 170 (q J = 74 Hz 2H) 139-102 (m 4H) 087 (t J = 70 Hz 3H) 13C-NMR δ 1447 1425 1284 1276 1260 1138 499 351 297 226 140 Enantioselectivity determined by chiral GC analysis CP-Chiralsil-Dex-CB (25 m x 025 mm) initial temp 80 degC for 60 min then 10 degCmin to 140 degC (final temp) retention times (min) 537 (minor) and 542 (major) retention time 3c 704 min

(+)-1-((S)-Hepta-16-dien-3-yl)benzene (2d)24

Reaction time 4h Purification by column chromatography (2 98 Et2On-pentane) afforded a 91 9 mixture of 2d and

( )2

( )2


59


3d as a colorless oil [93 yield 95 ee [α]D = +36 (c 15 CHCl3) lit4 (92 ee) [α]D = + 33 (c 10 CHCl3)] 2d 1H-NMR δ 730-716 (m 5H) 595 (m 1H) 579 (m 1H) 503-492 (m 4H) 326 (q J = 75 Hz 1H) 210-194 (m 2H) 181-175 (m 2H) 13C-NMR δ 1441 1421 1384 1284 1276 1261 1146 1141 491 344 315 MS (EI) mz 172 (M+ 13) 159 (6) 130 (33) 117 (100) 115 (41) 91 (48) HRMS Calcd for C13H16 1721252 found 1721255 Enantioselectivity determined by chiral GC analysis CP-Chiralsil-Dex-CB (25 m x 025 mm) initial temp 90degC for 45 min then 5 degCmin to 140 degC (final temp) retention times (min) 300 (minor) and 303 (major) retention time 3d 560 min

(+)-1-(-But-3-en-2-yl)-4-chlorobenzene (2f)535

Reaction time 4h Purification by column chromatography (2 98 Et2On-pentane) afforded a 99 1 mixture of 2f and 3f as a colorless oil [95 yield 97 ee [α]D = + 12 (c 16 CHCl3)] 2f 1H-NMR δ

729 (d J = 85 Hz 2H) 707 (d J = 85 Hz 2H) 600-590 (m 1H) 506-497 (m 2H) 344-336 (m 1H) 132 (d J = 70 Hz 3H) MS (EI) mz 166 (M+ 47) 165 (9) 151 (46) 139 (10) 131 (68) 91 (100) HRMS Calcd for C10H11Cl 1660549 found 1660557 Enantioselectivity determined by chiral GC analysis CP-Chiralsil-Dex-CB (25 m x 025 mm) initial temp 95degC for 45 min then 2ordmCmin to 140 ordmC (final temp) retention times (min) 258 (minor) and 261 (major) retention time 3f 408 min

1-Chloro-4-(pent-1-en-3-yl)benzene (2g)30

Reaction time 4h Purification by column chromatography (2 98 Et2On-pentane) afforded a 82 18 mixture of 2g and 3g as a colorless oil [80 yield 96 ee] 2g 1H-NMR δ 725 (d J = 84 Hz 2H) 709 (d J = 84 Hz 2H) 588 (m 1H) 500 (m 2H) 310

(dt J = 77 and 73 Hz 1H) 169 (m 2H) 083 (t J = 73 Hz 3H) Enantioselectivity determined by chiral GC analysis CP-Chiralsil-Dex-CB (25 m x 025 mm) initial temp 50degC then 10ordmCmin to 120 ordmC (final temp) for 30 min retention times (min) 197 (minor) and 201 (major)

Cl

Cl

Chapter 2

60


(+)-Methyl 4-(-but-3-en-2-yl)benzoate (2h)36

Reaction time 4h Purification by column chromatography (2 98 Et2On-pentane) afforded a 98 2 mixture of 2h and 3h as a colorless oil [94 yield 97 ee [α]D = +12 (c 09 CHCl3)] 2h 1H-

NMR δ 791 (d J = 830 Hz 2H) 722 (d J = 830 Hz 2H) 597-590 (m 1H) 503-498 (m 2H) 384 (s 3H) 349-344 (m 1H) 132 (d J = 70 Hz 3H) 13C-NMR δ 1670 1509 1422 1297 1280 1272 1138 519 431 205 MS (EI) mz 190 (M+ 44) 159 (33) 131 (100) 115 (25) 91 (22) 59 (8) HRMS Calcd for C12H14O2 1900994 found 1900997 Enantioselectivity determined by chiral GC analysis CP-Chiralsil-Dex-CB (25 m x 025 mm) initial temp 105 degC for 70 min then 1ordmCmin to 140 ordmC (final temp) retention times (min) 717 (minor) and 721 (major) retention time 3h 938 min

(minus)-1-((S)-But-3-en-2-yl)naphthalene (2i)33b3738

Reaction time 4h Purification by column chromatography (2 98 Et2On-pentane) afforded 2i (3i was not observed) as a colorless oil [87 yield 96 ee [α]D = - 298 (c 11 CHCl3) lit37 [α]D = minus 29 (c 10

CHCl3) lit38a [α]D = minus 37 (neat) lit33b for (R)-2i (90 ee) +163 (c 04 CHCl3)] 2i 1H-NMR δ 815 (d J = 83 Hz 1H) 787 (d J = 78 Hz 1H) 774 (d J = 80 Hz 1H) 754-741 (m 4H) 623-615 (m 1H) 517-513 (m 2H) 436-429 (m 1H) 154 (d J = 70 Hz 3H) 13C-NMR δ 1429 1414 1340 1314 1289 1268 1257 1256 1253 1236 1235 1136 378 202 MS (EI) mz 182 (M+ 50) 167 (100) 165 (31) 152 (24) 84 (27) 51 (11) HRMS Calcd for C14H14 1821096 found 1821107 Enantioselectivity determined by chiral GC analysis CP-Chiralsil-Dex-CB (25 m x 025 mm) initial temp 120degC for 60 min retention times (min) 358 (minor) and 363 (major) retention time 3i 563 min

(minus)-1-(Pent-1-en-3-yl)naphthalene (2j)3037

Reaction time 4h Purification by column chromatography (2 98 Et2On-pentane) afforded a 87 13 mixture of 2j and 3j as a colorless oil [86 yield

MeO2C


61


90 ee [α]D = minus 26 (c 10 CHCl3)] 2j 1H-NMR δ 812 (d J = 81 Hz 1H) 784 (d J = 79 Hz 1H) 770 (d J = 79 Hz 1H) 751-736 (m 4H) 611-602 (m 1H) 511-507 (m 2H) 401 (q J = 71 Hz 1H) 195-188 (m 2H) 095 (t J = 74 Hz 3H) 13C-NMR δ 1428 1415 1353 1329 1300 1277 1267 1266 1264 1250 1245 1157 471 291 135 MS (EI) mz 196 (M+ 26) 152 (42) 139 (11) 115 (14) Enantioselectivity determined by chiral HPLC analysis Chiralcel OD-H (9975 heptaneiPrOH) 40ordmC retention times (min) 204 (major) and 232 (minor) retention time 3j 321 min

3-Methylhept-1-ene (2k)39

Reaction carried out using 50 mol CuBrmiddotSMe2 and 60 mol L140 Reaction time 12 h Purification by column chromatography (2 98 Et2On-pentane) afforded 2k (3k

was not observed) as a colorless oil [99 conversion41 92 ee] 2k 1H-NMR δ 567-558 (m 1H) 483 (dd J = 104 and 73 Hz 2H) 205-201 (m 1H) 128-119 (m 6H) 091 (d J = 67 Hz 3H) 082 (t J = 70 Hz 3H) 13C-NMR δ 1449 1121 377 363 294 228 201 140 Enantioselectivity determined by chiral GC analysis CP-Chiralsil-Dex-CB (25 m x 025 mm) initial temp 55degC for 20 min retention times (min) 54 (minor) and 55 (major)

3-Ethylhept-1-ene (2l)42

Reaction carried out using 50 mol CuBrmiddotSMe2 and 60 mol L143 Reaction time 12 h Purification by column chromatography (2 98 Et2On-pentane) afforded 2l (3l

was not observed) as a colorless oil [99 conversion41 93 ee] 2l 1H-NMR δ 551-542 (m 1H) 492-486 (m 2H) 180-177 (m 1H) 137-115 (m 8H) 085-078 (m 6H) 13C-NMR δ 1434 1139 458 344 294 277 228 141 116 MS (EI) mz 126 (M+ 3) 97 (18) 84 (72) 69 (81) 55 (100) Enantioselectivity determined by chiral GC analysis CP-Chiralsil-Dex-CB (25 m x 025 mm) initial temp 55degC for 20 min retention times (min) 98 (minor) and 99 (major)

Chapter 2

62


References 1 For reviews on this subject see a) Geurts K Fletcher S P van Zijl A W Minnaard A J Feringa B L Pure Appl Chem 2008 80 1025-1037 b) Falciola C A Alexakis A Eur J Org Chem 2008 3765-3780 c) Yorimitsu H Oshima K Angew Chem Int Ed 2005 44 4435-4439 d) Alexakis A Malan C Lea L Tissot-Croset K Polet D Falciola C Chimia 2006 60 124-130 2 Kacprzynski M A Hoveyda A H J Am Chem Soc 2004 126 10676-10681 3 Van Veldhuizen J J Campbell J E Giudici R E Hoveyda A H J Am Chem Soc 2005 127 6877-6882 4 Tissot-Croset K Polet D Alexakis A Angew Chem Int Ed 2004 43 2426-2428 5 Tissot-Croset K Alexakis A Tetrahedron Lett 2004 45 7375-7378 6 Loacutepez F Minnaard A J Feringa B L Acc Chem Res 2007 40 179-188 7 a) Harutyunyan S R den Hartog T Geurts K Minnaard A J Feringa B L Chem Rev 2008 108 2824-2852 b) Loacutepez F Minnaard A J Feringa B L Catalytic enantioselective conjugate addition and allylic alkylation reactions using Grignard reagents in The Chemistry of Organomagnesium Compounds Eds Rappoport Z Marek I 2008 Wiley Chichester Part 2 Chapter 17 8 a) Christoffers J Koripelly G Rosiak A Roumlssle M Synthesis 2007 1279-1300 b) Alexakis A Benhaim C Eur J Org Chem 2002 3221-3236 c) Feringa B L Naasz R Imbos R Arnold L A Copper-catalysed Enantioselective Conjugate Addition Reactions of Organozinc Reagents in Modern Organocopper Chemistry Krause N (Ed) Wiley-VCH Weinheim 2002 Chapter 7 9 Feringa B L Badorrey R Pentildea D Harutyunyan S R Minnaard A J Proc Nat Acad Sci USA 2004 101 5834-5838 10 Loacutepez F Harutyunyan S R Minnaard A J Feringa B L J Am Chem Soc 2004 126 12784-12785 11 Loacutepez F Harutyunyan S R Meetsma A Minnaard A J Feringa B L Angew Chem Int Ed 2005 44 2752-2756 12 Des Mazery R Pullez M Loacutepez F Harutyunyan S R Minnaard A J Feringa B L J Am Chem Soc 2005 127 9966-9967 13 Harutyunyan S R Loacutepez F Browne W R Correa A Pentildea D Badorrey R Meetsma A Minnaard A J Feringa B L J Am Chem Soc 2006 128 9103-9118


63


14 Ireland T Grossheimann G Wieser-Jeunesse C Knochel P Angew Chem Int Ed 1999 38 3212-3215 15 Wright J Frambes L Reeves P J Organomet Chem 1994 476 215-217 16 Marquarding D Klusacek H Gokel G Hoffmann P Ugi I J Am Chem Soc 1970 92 5389-5393 17 Fukuzawa S-i Yamamoto M Kikuchi S J Org Chem 2007 72 1514-1517 18 Fukuzawa S-i Yamamoto M Hosaka M Kikuchi S Eur J Org Chem 2007 5540-5545 19 Ireland T Grossheimann G Wieser-Jeunesse C Knochel P Angew Chem Int Ed 2008 47 3666 20 Pratt L M Mini-Rev Org Chem 2004 1 209-217 21 Brookhart M Green M L H Parkin G Proc Nat Acad Sci USA 2007 104 6908-6914 22 Loacutepez F van Zijl A W Minnaard A J Feringa B L Chem Commun 2006 409-411 23 van Zijl A W Loacutepez F Minnaard A J Feringa B L J Org Chem 2007 72 2558-2563 24 Geurts K Fletcher S P Feringa B L J Am Chem Soc 2006 128 15572-15573 25 Togni A Breutel C Schnyder A Spindler F Landert H Tijani A J Am Chem Soc 1994 116 4062-4066 26 Ireland T Tappe K Grossheimann G Knochel P Chem Eur J 2002 8 843-852 27 Allred G D Liebeskind L S J Am Chem Soc 1996 118 2748-2749 28 Luchaco-Cullis C A Mizutani H Murphy K E Hoveyda A H Angew Chem Int Ed 2001 40 1456-1460 29 Lehmann J Lloyd-Jones G C Tetrahedron 1995 51 8863-8874 30 van Zijl A W Arnold L A Minnaard A J Feringa B L Adv Synth Catal 2004 346 413-420 and references therein 31 a) Watanabe Y Iida H Kibayashi C J Org Chem 1989 54 4088-4097 b) Bonini C Federici C Rossi L Righi G J Org Chem 1995 60 4803-4812 c) Binns M R Haynes R K Lambert D E Schober P A Turner S G Aust J Chem 1987 40 281-290

Chapter 2

64


32 a) Hoffmann R W Brinkmann H Frenking G Chem Ber 1990 123 2387-2394 b) Midland M M Koops R W J Org Chem 1990 55 5058-5065 33 a) Hayashi T Konishi M Fukushima M Kanehira K Hioki T Kumada M J Org Chem 1983 48 2195-2202 b) Kawatsura M Uozumi Y Ogasawara M Hayashi T Tetrahedron 2000 56 2247-2257 34 Yanagisawa A Nomura N Yamamoto H Tetrahedron 1994 50 6017-6028 35 Franciograve G Faraone F Leitner W J Am Chem Soc 2002 124 736-737 36 Gomes P Gosmini C Peacuterichon J J Org Chem 2003 68 1142-1145 37 Larsen A O Leu W Nieto Oberhuber C Campbell J E Hoveyda A H J Am Chem Soc 2004 126 11130-11131 38 a) Menicagli R Piccolo O Lardicci L Wis M L Tetrahedron 1979 35 1301-1306 b) Obora Y Tsuji Y Kobayashi M Kawamura T J Org Chem 1995 60 4647-4649 39 Underiner T L Paisley S D Schmitter J Lesheski L Goering H L J Org Chem 1989 54 2369-2374 40 With 10 mol CuBrmiddotSMe2 and 11 mol L1 the product 2k was obtained with 99 conversion a regioselectivity of 100 0 and 84 ee 41 Conversion based on GC The high volatility of the products 2k and 2l did not allow to completely remove the solvents after the chromatography impeding the determination of an accurate isolated yield 42 Pelter A Smith K Elgendy S Rowlands M Tetrahedron Lett 1989 30 5647-5650 43 With 10 mol CuBrmiddotSMe2 and 11 mol L1 the product 2l was obtained with 99 conversion a regioselectivity of 97 3 and 88 ee

Chapter 3 Synthesis of chiral bifunctional building blocks through asymmetric allylic alkylation

In this chapter the application of the enantioselective copper catalyzed allylic alkylation (Cu-AAA) with Taniaphos L1 as a ligand in the synthesis of chiral bifunctional building blocks is described Utility of an asymmetric catalytic reaction depends in part on the applicability of more complex substrates The reaction was performed on allylic bromides with a protected hydroxyl or amine functional group using a range of Grignard reagents High regio- and enantioselectivities were obtained with these functionalized substrates The terminal olefin moiety in the products was transformed into a diverse range of functional groups without racemisation providing facile access to a variety of versatile bifunctional chiral building blocks

This chapter has been published in part van Zijl A W Loacutepez F Minnaard A J Feringa B L J Org Chem 2007 72 2558-2563

Chapter 3

66


31 Introduction The complexity of natural products and pharmaceutical compounds

which is currently a major challenge to synthetic chemists provides a strong incentive toward the design of catalytic methods which enable access to versatile multifunctional enantioenriched building blocks and chiral starting materials also Retrosynthetic analysis of natural products frequently leads to bifunctional synthons which contain a single stereogenic centre1 Among the methods available to prepare these synthons enantioselective catalysis2 is particularly attractive due to the ready accessibility of both enantiomers the potential atom efficiency of such reactions and the ease with which small variations in the product can be introduced However resolution chiral pool or auxiliary based asymmetric syntheses are still the most widely applied approaches That the more widespread use of catalytic approaches the so called ldquocatalytic switchrdquo over non-catalytic syntheses has not yet happened is due in part to the fact that new enantioselective catalytic methods are developed using benchmark substrates and not the building blocks required in eg total synthesis The organic chemistsrsquo familiarity with chiral pool strategies and aversion to synthesizing chiral ligands which must themselves be prepared enantiomerically pure in case they are expensive or not commercially available may be another reason that catalytic asymmetric methods are not routinely used

Scheme 31 Concept of the stereoselective synthesis of chiral bifunctional building blocks via Cu-catalyzed asymmetric allylic alkylation FG = functional group LG = leaving group

As discussed in chapter 1 copper catalyzed asymmetric allylic alkylation presents an opportunity to use hard organometallic-based nucleophiles thus enabling the introduction of simple alkyl fragments at the γ-position This provides branched chiral products that contain a terminal olefin functionality which can be transformed subsequently into a broad

Synthesis of chiral bifunctional building blocks through asymmetric allylic alkylation

67


range of functional groups derived from prochiral monosubstituted allylic substrates (Scheme 31) The inclusion of a functional group in the allylic precursor would offer access to a broad range of synthetically valuable bifunctional chiral building blocks

311 Functionalised substrates in the Cu-AAA In general catalytic asymmetric reactions are developed using

benchmark substrates This is perhaps primarily due to their commercial availability and their supposed ldquowell-behavednessrdquo ie ready enantiodiscrimination and inertness of the substituents on the reactive moiety The preferred benchmark substrates for the copper catalyzed allylic alkylation have been cinnamyl or cyclohexyl based allylic compounds (Figure 31) After the development of conditions which catalyze efficiently the allylic alkylation of for instance cinnamyl bromide a broad substrate scope of other aromatic substrates can usually be applied (see for example chapter 2) although different types of substrate might not behave similarly

Figure 31 Typical allylic benchmark substrates for the copper catalyzed asymmetric allylic alkylation cinnamyl- 1 and cyclohexyl-based 2 allylic electrophiles

If an enantioselectively catalyzed reaction is suggested to be applicable in total synthesis it is necessary to prove the applicability of the reaction to more complex systems The introduction of functionality in the substrate can easily interfere with catalysis either showing lability of the functional group under the reaction conditions or through complexation of the catalyst to the functional group

A good example of a functionalised substrate where interference or lability of the functional group is imagined easily is the allylic phosphate 3 which Hoveyda and co-workers have used successfully on several occasions (Scheme 32)3 The ester group at the γ-position can allow 12-addition or conjugate addition among other possibilities Using their copper catalyst system with modular peptidic Schiff base ligands they were able to obtain

Chapter 3

68


products 4 in good yield and excellent selectivity though The reaction could be performed on allylic phosphates bearing a disubstituted (Rrsquo = H) as well as a trisubstituted (Rrsquo = Me Ph) olefin allowing the formation of both tertiary and quaternary stereocenters4

Scheme 32 Cu-catalyzed asymmetric allylic alkylation with allylic phosphates bearing an ester functionality at the γ-position

Woodward and coworkers employed substrates 5 which are derived readily from Baylis-Hillman products (Scheme 33)5 These substrates have an ester group at the β-position and could be alkylated with full chemo- and regioselectivity using chiral secondary amines as ligands EtZnCl which is produced during the reaction has a detrimental effect on the selectivity Addition of MAO biased the Schlenk equilibrium of the organozinc compounds in favour of the dialkylzinc species and thus enantioselectivities up to 90 were attained However it is possible that this is not an allylic alkylation A conjugate addition elimination mechanism cannot be excluded The absence of the other regioisomer the SN2-product even under conditions that provide a less active and selective reaction indicates that this is a distinct possibility

Scheme 33 Cu-catalyzed asymmetric allylic alkylation with allylic chlorides bearing an ester functionality at the β-position

Linear aliphatic substrates 6 which contain a TBS-protected hydroxyl group at the δ-position have been used by the group of Okamoto (Scheme 34)6 The enantioselectivity they achieved in the allylic alkylation using


69


Grignard reagents with a carbene-CuCl complex as the catalyst was modest though It was interesting to note that the E and Z isomers of the substrate yielded opposite enantiomers of the product

Scheme 34 Cu-AAA with allylic substrates bearing a protected alcohol at the δ-position

Substrates bearing two enantiotopic leaving groups at an allylic position at either side of the alkene double bond are especially interesting targets After SN2rsquo substitution the unreacted leaving group becomes unreactive to allylic alkylation although it can be a versatile handle for subsequent transformations For example 14-dihalobut-2-enes 8 which were applied in the Cu-AAA by Alexakis and coworkers furnish chiral homoallylic halides in excellent enantioselectivity (Scheme 35)7

Scheme 35 Cu-AAA with substrates containing enantiotopic allylic leaving groups

Complete regioselectivity was reported However SN2-substitution would produce a compound which is still an allylic electrophile and the presence or absence of dialkylated products was not noted by the authors

Chapter 3

70


The versatile compounds 9 can serve as electrophiles and (through umpolung) as nucleophiles in subsequent reactions

The cyclic meso-diphosphates 10 were applied successfully in copper catalyzed allylic alkylations with dialkylzinc reagents by the group of Gennari8 These desymmetrisation reactions yield cyclic products with two stereogenic centers and a phosphate protected alcohol group The particularly interesting product 12 could be obtained in an enantiomeric excess of up to 86 in this case four new stereogenic centers have been formed in one step from an achiral precursor

312 Heteroatoms at the γ-position the h-AAA Recently a completely new type of substrate for the copper catalyzed

allylic alkylation was introduced Compounds with a heteroatom substituent at the γ-position had been deemed too unstable under the reaction conditions of allylic alkylation However in 2006 Geurts et al reported the synthesis of chiral allylic esters through asymmetric allylic alkylation of 3-bromopropenyl benzoate 13 (Scheme 36)9 This transformation was coined hetero-allylic asymmetric alkylation h-AAA

Scheme 36 The first example of a copper catalyzed enantioselective allylic alkylation on a substrate bearing a heteroatom substituent on the γ-position (h-AAA)

The reasons for the perception of instability were primarily that ester groups can undergo 12-addition vinyl esters are well-known acyl transfer agents and finally an oxygen atom at the γ-position might perturb the electronic properties of the allyl electrophile substantially Nevertheless substrate 13 was applied in the allylic alkylation under the conditions described previously in chapter 2 Using Taniaphos L1 as a ligand various alkyl Grignard reagents and substrates were applied successfully the desired allylic esters were obtained in excellent regio- and enantioselectivity


71


Following this first example of a Cu-catalyzed h-AAA allylic alkylations on compounds with silicon or boron substituents at the γ-position were reported thus enabling the synthesis of chiral allyl silanes and boronates respectively (Figure 32)10 This clearly demonstrates that the functional group tolerance and the generality of the asymmetric allylic alkylation is much larger than was envisioned previously

Figure 32 Chiral allylsilanes and allylboronates obtained through h-AAA


Despite the recent demonstration of the high functional group tolerance of copper catalyzed asymmetric allylic alkylation reactions (vide supra) it has not yet found widespread application in synthesis The preparation of building blocks which can be used for total synthesis usually relies on the presence of two or more functional groups as handles for further transformation The functionality embedded in the substrate for the allylic alkylation can serve as one handle the terminal olefin as another since there are many transformations which render a range of other functional groups from terminal alkenes

In some cases it is not necessary to obtain bi- or multifunctional building blocks from the enantioselective reaction ie when the synthesized building block already approaches the structure of the target close enough For example this is the case with natural compounds which have a terminal olefin next to a stereogenic center One such compound is sporochnol 18 a fish deterrent (a fish-repelling agent) which was synthesized by Hoveyda and coworkers in two steps from allylic substrate 17 using a Cu-catalyzed enantioselective allylic alkylation and a deprotection of the tosylated alcohol (Scheme 37)11

Chapter 3

72


Scheme 37 Enantioselective catalytic total synthesis of the fish deterrent sporochnol

Another exception is when only the olefin needs to be transformed and the rest of the structure was already present in the substrate Alexakis and coworkers used their copper catalyzed allylic alkylation to synthesize 20 a potential precursor to naproxen which is a well-known anti-inflammatory drug (Scheme 38)12 The authors claimed its formal total synthesis the last step being an oxidation of the double bond to a carboxylic acid which was apparently deemed obvious Despite the fact that several methods exist to accomplish such a transformation the oxidation was not reported by the authors nor did they refer to one in the literature The incompatibility of many of these well-known methods with naphthyl groups renders the transformation not that obvious though Although this cannot be found using conventional databases the intended reaction has been accomplished with NaIO4 and KMnO413

Scheme 38 Enantioselective catalytic synthesis of a potential precursor for naproxen


73


Other examples of formal total syntheses are those of two cyclic chiral imides reported by the group of Hoveyda ethosuximide an anti-convulsant and aminoglutethimide which has been used effectively against breast cancer3a In these cases the necessity of bifunctionality in the building blocks obtained is clear Transformation of the terminal olefin of the product affords the intermediates needed to synthesize the target compounds (Scheme 39) The functionality which was embedded in the substrate is converted either in the same step (as in the case of ethosuximide) or at a later stage in the synthesis route (aminoglutethimide)

Scheme 39 Formal total syntheses of chiral cyclic imides through copper catalyzed enantioselective allylic alkylation

The total synthesis of (+)-baconipyrone C performed by Hoveyda and coworkers14 is the last example of the application of copper catalyzed enantioselective allylic alkylation in total synthesis in this section It contains an elegant double allylic alkylation of compound 25 using trimethylaluminum and a N-heterocyclic carbene as the ligand (Scheme 310)

The general selectivity of the reaction is not particularly high because in the second alkylation catalyst control has to overcome substrate control This led to substantial amounts of the meso-diastereomer (8) and the regioisomer (27) which underwent a sequential SN2rsquoSN2 substitution The desired stereoisomer 26 separable from its byproducts by chromatography could be obtained in 61 yield though Since two

Chapter 3

74


enantioselective reactions have taken place the enantiomeric excess of the product is excellent The two geminally disubstituted alkenes are converted into ketones through ozonolysis and the alcohol is deprotected to yield the intermediate which can be coupled to the other part of the target molecule

Scheme 310 Double copper catalyzed allylic alkylation step using trimethyl aluminum in the total synthesis of baconipyrone C


75



321 Asymmetric allylic alkylation on functionalised substrates The compatibility of substrates containing either a protected hydroxyl or

amine moiety with the reaction conditions of the allylic alkylation using Grignard reagents and the ligand Taniaphos L1 was demonstrated using allylic bromides 28-30 (Table 31) The substrates 2815 and 2916 were synthesized in one step from 14-dibromobut-2-ene (Scheme 311) Substrate 3017 was prepared in three steps from 2-butyne-14-diol

Scheme 311 Synthesis of allylic bromides bearing functional groups at the δ-position i) BnOH 10 mol n-Bu4NHSO4 CH2Cl2 aq NaOH rt 44 ii) Ts(Boc)NH K2CO3 MeCN reflux 54 based on amide iii) LiAlH4 THF reflux 69 iv) TBDPSCl n-BuLi THF reflux 24 v) NBS Me2S CH2Cl2 rt 57

Compounds 28 and 29 subjected to methylmagnesium bromide in CH2Cl2 at minus75degC in the presence of 1 mol of the chiral Cu-catalyst undergo substitution to provide the products 31 and 32 respectively in high yields and excellent regioselectivities (Table 31 entries 1 and 2) The reactions were performed on a preparative scale (75 mmol) to demonstrate their potential synthetic utility The enantiomeric excesses of 31 and 32 were found to be 92 and 95 respectively after derivatization18 The other allylic alkylations were performed on a smaller scale and with 5 mol catalyst loading for synthetic convenience For example substrate 30

Chapter 3

76


containing a tert-butyldiphenylsilyl ether could be methylated in high yield excellent regioselectivity and with an enantiomeric excess of 94 (entry 3)

Table 31 Cu-catalyzed allylic alkylation with Grignard reagents of allylic bromides containing protected hydroxyl and amine functional groupsa

entry

substrate

FG

RMgBr

product

yieldb

() b lc

eed ()

1ef 28 BnO MeMgBr 31 94 1000 92

2ef 29 Boc(Ts)N MeMgBr 32 96 gt955 95

3 30 TBDPSO MeMgBr 33 72 gt955 94

4f 28 BnO EtMgBr 34 98 982 94

5 29 Boc(Ts)N EtMgBr 35 83 gt955 90

6 28 BnO n-BuMgBr 36 93 1000 94

7 28 BnO n-PentMgBr 37 87 1000 94

8 28 BnO 3-butenylMgBr 38 89 gt955 90

9 28 BnO Ph(CH2)2MgBr 39 86 gt955 92 a Reagents and conditions RMgBr (15 equiv) CuBrmiddotSMe2 (5 mol) L1 (6 mol) CH2Cl2 -75degC b Isolated yield c Established by GC or NMR d Established by chiral GC or HPLC e Reaction performed on preparative scale (75 mmol substrate) f Reaction performed with 1 mol cat and 12 equiv RMgBr

Other linear alkyl Grignard reagents could also be applied to these functionalized substrates all with similar results Substrates 28 and 29 can be ethylated efficiently providing products 34 and 35 with high regioselectivity and excellent enantioselectivity (Table 31 entries 4 and 5)


77


The use of the other Grignard reagents with substrate 28 gave products 36-39 with excellent regio- and enantioselectivities also (entries 6-9)

322 Derivatizations of the allylic alkylation products A range of derivatisation reactions of 31 and 32 were performed to

demonstrate their versatility providing a family of optically active bifunctional synthons (Schemes 312ndash314) The enantiomeric purity of all bifunctional synthons was determined independently by GC or HPLC-analysis to ensure that racemisation during the derivatisation did not occur


Hydroboration of 31 and subsequent treatment with H2O2 provides the mono-protected diol 40 (Scheme 312)1920 This compound has been used before in the total syntheses of (E)-vitamin K121 vitamin E22 and cylindrocyclophane F23

Scheme 312 Synthesis of bifunctional chiral building blocks 40-43 containing a benzyl protected alcohol group from allylic alkylation product 31

Chapter 3

78


The olefin 31 was converted to methyl ketone 41 using a catalytic Wacker oxidation24 Thus treatment of olefin 31 with PdCl2 (5 mol) and CuCl (2 equiv) under an O2-atmosphere provided β-hydroxyketone 41 in 86 yield This ketone has been applied in the total syntheses of the C1-C25 segment of spirastrellolide A25 the octalactins A and B26 (+)-miyakolide27 (minus)-botryococcene28 and also (+)-phyllanthocin and (+)-phyllanthocindiol29

By carrying out an ozonolysis NaBH4 reduction protocol 31 was converted into the mono-protected 13-diol 4230 This simple building block has been applied in numerous total syntheses Amongst the many recent examples are syntheses of potential antitumor agents31 antibiotics32 matrix metalloproteinase inhibitors33 and tetrahydrocannabinol analogues34

The β-hydroxyacid 43 which has been used in the synthesis of clasto-lactacystin β-lactone35 was obtained in 52 yield through Ru-catalyzed oxidation of the terminal olefin with NaIO436 From the representative examples shown in Scheme 312 it is evident that the catalytic asymmetric allylic alkylation of 28 can provide a variety of important difunctionalized synthons in a few steps All products were shown by chiral GC or HPLC analysis to have retained the high ee (92) of the original allylic alkylation product 31


Compound 32 was detosylated by treatment with magnesium in methanol under sonication37 to yield Boc-protected amine 44 (Scheme 313) As for 41 the β-aminoketone 45 was obtained in 82 yield using the same procedure for a catalytic Wacker oxidation

In an analogous fashion to 42 compound 32 could be transformed using the ozonolysis reduction protocol into either 13-aminoalcohol 46 or compound 47 depending on the work-up procedure Direct quenching of the reaction with 1M aq HCl gave exclusively compound 46 In contrast prior concentration of the reaction mixture at 50degC (eg by removal of solvent in vacuo) led to a [15]-migration of the Boc-group to the newly formed alcohol38 thus yielding compound 47 which contains a tosyl-protected amine and an alcohol with a Boc-protecting group The full


79


selectivity of either method increases significantly the versatility of this building block precursor

Scheme 313 Synthesis of bifunctional chiral building blocks 44-47 containing a protected amine functional group from allylic alkylation product 32

The β 2-amino acid 48 could be synthesized in 79 yield (Scheme 314) using the same Ru-catalyzed oxidation that furnished 43 This is especially noteworthy as β 2-amino acids are in general difficult to obtain39 The latter product was converted to the respective methyl ester 49 using TMSCHN2 and MeOH and consecutively detosylated with Mg-powder and sonication to obtain N-Boc-protected β 2-amino acid 50 This compound has been applied in the total synthesis of the potent antitumor macrolides cryptophycin A B and C40

The transformations described in schemes 313 and 314 show that the allylic alkylation product 32 is an attractive precursor for (protected) amino

Chapter 3

80


alcohols amino ketones and β 2-amino acids Similar transformations are readily accomplished with allylic alkylation products (eg compound 35) obtained with other Grignard reagents All derivatives shown in schemes 313 and 314 were obtained with the same high enantiomeric excess (95) as product 32 This was determined by GC or HPLC analysis

Scheme 314 Synthesis of β 2-amino acid building blocks from product 32


81


33 Conclusions In conclusion it has been demonstrated that the Cu-catalyzed allylic

alkylation with Grignard reagents can be performed with excellent yield regioselectivity and enantioselectivity on allylic bromides bearing protected functional groups on the δ-position In addition two of the reactions have been performed on a preparative scale (more than 1 gram) showing their versatility in synthetic organic chemistry

The products obtained were shown to be suitable precursors in the synthesis of optically active bifunctional building blocks within one or two steps Many of these bifunctional building blocks have demonstrated their value already through multiple applications in the total synthesis of natural products This catalytic protocol makes use of a commercially available chiral ligand and is thus easily applicable for practicing organic chemists This access to a wide variety of versatile bifunctional building blocks provides an important alternative to common approaches using chiral synthons derived from the chiral pool

Chapter 3

82


34 Experimental Part General Remarks For general remarks see the experimental part of chapter 2 In addition the following remarks should be taken into account

The substrates 2815 2916 and 3017 were prepared according to literature procedures THF was distilled from Nabenzophenone and CH2Cl2 was distilled from CaH2 All other solvents were used as purchased

Racemic products of derivatization reactions were obtained through the transformations described vide infra on the racemic allylic alkylation products The products 31 33 36 40 41 42 43 and 50 have been previously described elsewhere (for appropriate references vide infra)

General Procedure for the Preparative Enantioselective Cu-catalyzed Allylic Alkylation with Methyl Grignard In a Schlenk tube equipped with septum and stirring bar CuBrmiddotSMe2 (75 μmol 154 mg) and ligand L1 (90 μmol 619 mg) were dissolved in CH2Cl2 (15 mL) and stirred under an argon atmosphere at room temperature for 10 min The mixture was cooled to ndash75 oC and the methyl Grignard reagent (90 mmol 3M solution in Et2O 30 mL) was added dropwise Allylic bromide 28 or 29 (75 mmol) was added dropwise as a solution in 25 mL CH2Cl2 at that temperature over 60 min via a syringe pump Once the addition was complete the resulting mixture was stirred at ndash75 oC for a further 24 h The reaction was quenched by addition of MeOH (25 mL) and the mixture was allowed to reach rt Subsequently aqueous NH4Cl solution (1M 30 mL) and 50 mL Et2O were added the organic phase was separated and the resulting aqueous layer was extracted with Et2O (2x 25 mL) The combined organic phases were dried and concentrated to yield a yellow oil which was purified by flash chromatography

(minus)-(S)-((2-Methylbut-3-enyloxy)methyl)benzene (31)41

Purification by column chromatography (SiO2 199 Et2On-pentane Rf = 035) afforded 31 (124 g) as a colourless oil [94 yield 92 ee [α]D = minus 54 (c 13 CHCl3) lit41a [α]D = minus 3 (c 10 CHCl3)] 1H-

NMR δ 732-721 (m 5H) 581 (ddd J = 69 104 and 173 Hz 1H) 511-500 (m 2H) 453 (s 2H) 335 (ddd J = 67 91 and 239 Hz 2H) 254-

O


83


249 (m 1H) 105 (d J = 68 Hz 3H) 13C-NMR δ 1413 1386 1283 1275 1274 1140 750 729 378 166 MS (EI) mz 176 (M+ 16) 175 (6) 92 (11) 91 (100) 65 (6) HRMS Calcd for C12H16O 1761201 found 1761207 Enantiomeric excess determined for derivatized product 40

(minus)-(S)-(N-2-Methylbut-3-enyl)(N-t-butoxycarbonyl)p-toluene sulfonamide (32)

Purification by column chromatography (SiO2 1090 Et2On-pentane Rf = 030) afforded 32 (245 g) as a colourless oil [96 yield 95 ee [α]D = minus 77 (c 14 CHCl3)] 1H-NMR δ 778 (d J = 84 Hz 2H) 729 (d J = 84 Hz 2H) 573 (ddd J = 81 102 and 173 Hz 1H) 510-500 (m 2H) 382-372

(m 2H) 278-266 (m 1H) 243 (s 3H) 132 (s 9H) 107 (d J = 68 Hz 3H) 13C-NMR δ 1510 1440 1407 1375 1291 1279 1153 840 519 387 278 215 173 MS (EI) mz 283 (9) 216 (20) 185 (6) 184 (64) 155 (42) 91 (39) 68 (7) 65 (11) 57 (100) 56 (5) 55 (13) MS (CI) mz 359 (8) 358 (20) 357 ([M+NH4]+100) 302 (7) 301 (40) 284 (6) HRMS Calcd for [M-Me2C=CH2]+ C13H17NO4S 2830878 found 2830887 Enantiomeric excess determined for derivatized product 44 The absolute configuration was assigned by comparison of the sign of the optical rotation of derivatized product 50 with the literature value (vide infra)

General Procedure for the Enantioselective Cu-catalyzed Allylic Alkylations In a Schlenk tube equipped with septum and stirring bar CuBrmiddotSMe2 (15 μmol 31 mg) and ligand L1 (18 μmol 124 mg) were dissolved in CH2Cl2 (25 mL) and stirred under argon at room temperature for 10 min The mixture was cooled to ndash75 oC and the Grignard reagent (045 mmol solution in Et2O) was added dropwise The allylic bromide (03 mmol) was then added dropwise as a solution in 05 mL CH2Cl2 at ndash75 oC over 15 min Once the addition was complete the resulting mixture was further stirred at ndash75 oC After full conversion was established by TLC the reaction was quenched by addition of MeOH (05 mL) and the mixture was allowed to reach rt Then sat aqueous NH4Cl solution (15 mL) was added the organic phase was separated and the aqueous phase was extracted with Et2O (2x 25 mL) The combined organic phases were dried and

SN

OO

O

O

Chapter 3

84


concentrated to yield a yellow oil which was purified by flash chromatography

(minus)-(S)-4-[(tert-Butyldiphenylsilyl)oxy]-3-methylbut-1-ene (33)41a

Purification by column chromatography (SiO2 02998 Et2On-pentane Rf = 025) afforded 33 (703 mg) as a colourless oil [72 yield 94 ee [α]D = minus 27 (c 13 CHCl3) lit41a [α]D = minus 318 (94 ee c 071 CHCl3)] 1H-NMR δ 768 (dd J = 77 and 16

Hz 4H) 745-736 (m 6H) 581 (ddd J = 69 104 and 174 Hz 1H) 506-498 (m 2H) 358 (dd J = 97 and 62 Hz 1H) 350 (dd J = 97 and 67 Hz 1H) 244-237 (m 1H) 106 (s 9H) 104 (d J = 68 Hz 3H) 13C-NMR δ 1413 1356 1339 1295 1276 1140 685 402 269 193 162 MS (EI) mz 268 (24) 267 ([M-tBu]+ 100) 240 (17) 239 (80) 237 (12) 211(9) 199 (15) 197 (14) 190 (7) 189 (36) 183 (23) 182 (7) 181 (19) 159 (19) 135 (18) 121 (10) 105 (11) 77 (7) MS (CI) mz 344 (8) 343 (28) 342 ([M+NH4]+ 100) 325 ([M+H]+ 14) HRMS Calcd for [M-tBu]+ C17H19OSi 2671205 found 2671197 Enantiomeric excess determined for derivatized product 42 (Scheme 315 vide infra)

(+)-1-((2-ethylbut-3-enyloxy)methyl)benzene (34)42

Purification by column chromatography (SiO2 298 Et2On-pentane) afforded a 98 2 mixture of 34 and and its regioisomer as a colorless oil [97 yield

94 ee [α]D = + 19 (c 11 CHCl3)] 1H-NMR δ 730-721 (m 5H) 566-557 (m 1H) 506-501 (m 2H) 447 (s 2H) 335 (d J = 65 Hz 2H) 222 (m 1H) 156-147 (m 1H) 127-120 (m 1H) 083 (t J = 75 Hz 3H) 13C-NMR δ 1400 1386 1283 1275 1274 1156 736 730 457 240 114 MS (EI) mz 190 (M+ 11) 189 (11) 123 (21) 105 (100) 91 (79) 77 (30) HRMS Calcd for C13H18O 19013576 found 19013505 Enantiomeric excess determined by chiral HPLC analysis Chiralcel OD-H (9975 n-heptaneiPrOH) 40ordmC retention times (min) 99 (minor) and 109 (major) In accordance with the results obtained in the other allylic alkylations the absolute configuration of this compound is assumed to be (S) analogous to the other products

SiO

O


85


(minus)-(N-2-Ethylbut-3-enyl)(N-tert-butoxycarbonyl) p-toluenesulfonamide (35)

Purification by column chromatography (SiO2 595 Et2On-pentane Rf = 025) afforded 35 (875 mg) as a colourless oil [83 yield 91 ee [α]D = minus 04 (c 85 CHCl3)] 1H-NMR δ 775 (d J = 81Hz 2H) 726 (d J = 81Hz 2H) 559-549 (m 1H) 506-500 (m 2H) 378 (d J = 77Hz 2H) 249-240 (m

1H) 239 (s 3H) 155-144 (m 1H) 129 (s 9H) ppm 126-118 (m 1H) 088 (t J = 74Hz 3H) 13C-NMR δ 1510 1439 1393 1375 1290 1278 1172 839 508 467 277 248 215 115 MS (EI) mz 353 (M+ 01) 297 (15) 216 (10) 185 (9) 184 (88) 155 (49) 92 (5) 91 (39) 82 (39) 69 (7) 65 (9) 57 (100) MS (CI) mz 373 (9) 372 (20) 371 ([M+NH4]+ 100) 317 (6) 316 (12) 315 (75) 298 (8) 271 (8) HRMS Calcd for [M-Me2C=CH2]+ C14H19NO4S 2971035 found 2971027 Enantiomeric excess determined for derivatized product 51 In accordance with the results obtained in the other allylic alkylations the absolute configuration of this compound is assumed to be (S) analogous to the other products

(+)-(S)-((2-n-Butylbut-3-enyloxy)methyl)benzene (36)42

Purification by column chromatography (SiO2 199 Et2On-pentane Rf = 050) afforded 36 (605 mg) as a colorless oil [93 yield 94 ee [α]D =

+ 185 (c 22 CHCl3)] 1H-NMR δ 738-727 (m 5H) 570 (ddd J = 84 106 and 170Hz 1H) 513-507 (m 2H) 454 (s 2H) 342 (d J = 64Hz 2H) 242-232 (m 1H) 160-148 (m 1H) 140-120 (m 5H) 092 (t J = 70Hz 3H) 13C-NMR δ 1404 1386 1283 1275 1274 1154 738 729 441 309 291 228 140 MS (EI) mz 218 (M+ 11) 107 (13) 105 (6) 104 (7) 97 (8) 96 (6) 92 (15) 91 (100) 85 (11) 83 (16) 69 (6) 65 (8) 57 (8) 55 (21) HRMS Calcd for C15H22O 2181671 found 2181665 Enantiomeric excess determined by chiral HPLC analysis Chiralcel OD-H (100 n-heptane) 40ordmC retention times (min) 116 (minor) and 136 (major) The absolute configuration was assigned by comparison of the sign of optical rotation of the hydrogenated product 2-ethylhexan-1-ol (PdC H2 in MeOH) with the literature value43

O

SN

OO

O

O

Chapter 3

86


(+)-(S)-((2-n-Pentylbut-3-enyloxy)methyl)benzene (37)

Purification by column chromatography (SiO2 199 Et2On-pentane Rf = 050) afforded 37 (604 mg) as a colorless oil [87 yield 94

ee [α]D = + 144 (c 24 CHCl3)] 1H-NMR δ 738-728 (m 5H) 570 (ddd J = 84 106 and 170Hz 1H) 514-507 (m 2H) 455 (s 2H) 342 (d J = 65Hz 2H) 242-232 (m 1H) 159-146 (m 1H) 140-121 (m 7H) 091 (t J = 69Hz 3H) 13C-NMR δ 1404 1386 1282 1275 1274 1154 738 729 441 319 312 266 226 141 LRMS (EI) mz 232 (M+ 24) 231 (6) 161 (7) 107 (8) 105 (5) 104 (11) 92 (14) 91 (100) 69 (14) 65 (5) 55 (8) HRMS Calcd for C16H24O 2321827 found 2321835 Enantiomeric excess determined by chiral HPLC analysis Chiralcel OD-H (100 n-heptane) 40ordmC retention times (min) 115 (minor) and 133 (major) The absolute configuration was assigned by comparison of the sign of optical rotation of the hydrogenated product 2-ethylheptan-1-ol (PdC H2 in MeOH) with the literature value44

(+)-(S)-(2-Vinyl-hex-5-enyloxymethyl)-benzene (38)


+ 100 (c 25 CHCl3)] 1H-NMR δ 740-727 (m 5H) 582 (tdd J = 66 102 and 169 Hz 1H) 574-564 (m 1H) 514-494 (m 4H) 453 (s 2H) 346-338 (m 2H) 245-236 (m 1H) 218-197 (m 2H) 170-160 (m 1H) 144-134 (m 1H) 13C-NMR δ 1399 1387 1385 1283 1275 1274 1158 1145 737 729 435 311 304 MS (EI) mz 216 (M+ 04) 173 (6) 95 (6) 92 (11) 91 (100) 79 (6) 67 (8) 65 (11) 55 (5) HRMS Calcd for C15H20O 2161514 found 2161513 Enantiomeric excess determined by chiral HPLC analysis Chiralcel OD (100 n-heptane) 40ordmC retention times (min) 75 (minor) and 85 (major) The absolute configuration was assigned by comparison of the sign of optical rotation of the hydrogenated product 2-ethylhexan-1-ol (PdC H2 in MeOH) with the literature value43

O

O


87


(+)-(2-Vinyl-4-phenyl-butyloxymethyl)-benzene (39)

Purification by column chromatography (SiO2 199 Et2On-pentane Rf = 050) afforded 39 (690 mg) as a colorless oil [86 yield 92 ee [α]D = + 38 (c 22 CHCl3)] 1H-NMR δ

742-735 (m 4H) 735-729 (m 3H) 725-720 (m 3H) 578 (ddd J = 85 110 and 165Hz 1H) 521-515 (m 2H) 455 (s 2H) 351-343 (m 2H) 278-269 (m 1H) 259 (ddd J = 66 102 and 138Hz 1H) 251-241 (m 1H) 193 (dddd J = 46 66 111 and 134Hz 1H) 170-160 (m 1H) 13C-NMR δ 1424 1398 1385 1284 1283 1282 1275 1274 1256 1161 737 729 437 332 330 MS (EI) mz 266 (M+ 3) 162 (5) 157 (10) 129 (6) 104 (5) 92 (10) 91 (100) 65 (10) HRMS Calcd for C19H22O 2661671 found 2661682 Enantiomeric excess determined by chiral HPLC analysis Chiralcel OD (995 n-heptanei-PrOH) 40ordmC retention times (min) 81 (minor) and 100 (major) In accordance with the results obtained in the other allylic alkylations the absolute configuration of this compound is assumed to be (S) analogous to the other products

(+)-(S)-4-Benzyloxy-3-methylbutan-1-ol (40)23b

To a cooled solution (0 degC) of 31 (05 mmol 88 mg) in THF (35 mL) a solution of 9-BBN (075 mmol 05M in THF 15 mL) was added The reaction mixture was stirred for 3 h then it was

allowed to reach rt after which sequentially EtOH (25 mL) aq NaOH (1M 25 mL) and aq H2O2 (30 20 mL) were added The resulting mixture was stirred vigorously overnight at rt then quenched with aq Na2S2O3 (10 10 mL) CH2Cl2 (20 mL) was added the organic phase was separated and the aqueous phase was extracted with CH2Cl2 (20 mL) The combined organic layers were dried and concentrated in vacuo Purification by column chromatography (SiO2 4060 Et2On-pentane Rf = 025) afforded 40 (773 mg) as a colorless oil [80 yield 92 ee [α]D = + 18 (c 29 EtOH) minus 55 (c 27 CHCl3) lit 212245 [α]D = + 22 (c 11 EtOH) + 626 (c 55 CHCl3)46] 1H-NMR δ 739-726 (m 5H) 452 (s 2H) 375-361 (m 2H) 335 (ddd J = 62 91 and 165Hz 2H) 242 (bs 1H) 195 (tq J = 69 and 138Hz 1H) 169-151 (m 2H) 095 (d J = 69Hz 3H)

13C-NMR δ 1380 1284 1277 761 732 612 381 314 177 MS (EI)

O

OOH

Chapter 3

88


mz 194 (M+ 7) 108 (11) 107 (37) 105 (6) 92 (28) 91 (100) 85 (12) 79 (7) 77 (8) 65 (15) 55 (8) HRMS Calcd for C12H18O2 1941307 found 1941309 Enantiomeric excess determined by chiral HPLC analysis Chiralcel OD-H (99 n-heptanei-PrOH) 40ordmC retention times (min) 577 (major) and 649 (minor)

(minus)-(R)-4-Benzyloxy-3-methylbutan-2-one (41)2947

A suspension of PdCl2 (50 μmol 89 mg) and CuCl (10 mmol 99 mg) in DMFH2O (61 5 mL) was stirred vigorously under an O2-stream for 15 h at rt After addition of 31 (05 mmol 88 mg) vigorous

stirring was continued for 32 h under an O2-atmosphere at rt Then H2O (20 mL) was added and the mixture was extracted with Et2O pentane (11 3x 10 mL) The combined organic layers were washed with H2O (10 mL) dried and concentrated in vacuo Purification by flash chromatography (SiO2 1090 Et2O pentane Rf = 020) afforded 41 (824 mg) as a colorless oil [86 yield 92 ee [α]D = minus140 (c 40 CHCl3) lit29b [α]D = minus 167 (c 391 CHCl3)] 1H-NMR δ 737-726 (m 5H) 450 (d J = 18Hz 2H) 363 (dd J = 75 and 92Hz 1H) 349 (dd J = 55 and 92Hz 1H) 291-281 (m 1H) 218 (s 3H) 110 (d J = 71Hz 3H) 13C-NMR δ 2111 1380 1284 1276 1276 732 721 472 290 134 MS (EI) mz 192 (M+ 4) 134 (27) 108 (18) 107 (46) 105 (12) 92 (14) 91 (100) 86 (43) 85 (6) 79 (8) 77 (7) 71 (27) 65 (9) HRMS Calcd for C12H16O2 1921150 found 1921144 Enantiomeric excess determined by chiral HPLC analysis Chiralcel AS (995 n-heptanei-PrOH) 40ordmC retention times (min) 118 (minor) and 164 (major)

(minus)-(S)-3-Benzyloxy-2-methylpropan-1-ol (42)48

Ozone was bubbled for 10 min through a solution of 31 (05 mmol) in CH2Cl2MeOH (11 15mL) cooled to minus78degC NaBH4 (25 eq 25 mmol 95

mg) was added at minus78degC after which the cooling bath was removed and the reaction mixture was stirred at rt for 2 h The reaction was quenched by addition of aq HCl (1M 15 mL) The organic layer was separated and the resulting aqueous layer extracted with CH2Cl2 (2x 25 mL) the combined organic layers were dried (MgSO4) and concentrated in vacuo Purification

O

O

O OH


89


by flash chromatography (SiO2 3070 Et2Opentane Rf = 030) afforded 42 (470 mg) as a colorless oil [52 yield 92 ee [α]D = minus 130 (c 23 CHCl3) lit48 [α]D = minus 155 (c 18 CHCl3)] 1H-NMR δ 739-726 (m 5H) 452 (s 2H) 366-353 (m 3H) 343 (dd J = 80 and 90Hz 1H) 256 (bs 1H) 214-202 (m 1H) 089 (d J = 70Hz 3H) 13C-NMR δ 1380 1284 1276 1275 751 733 675 355 134 LRMS (EI) mz 180 (M+ 10) 108 (13) 107 (51) 105 (6) 92 (23) 91 (100) 89 (5) 79 (15) 78 (5) 77 (13) 65 (18) 51 (7) HRMS Calcd for C11H16O2 1801150 found 1801157 Enantiomeric excess determined by chiral HPLC analysis Chiralcel AS (985 n-heptanei-PrOH) 40ordmC retention times (min) 119 (minor) and 140 (major)

(minus)-(R)-3-Benzyloxy-2-methylpropionic acid (43)2947

To a biphasic system of 31 (05 mmol) and NaIO4 (205 mmol 438 mg) in CCl4MeCNH2O (1115 5 mL) RuCl3xH2O (25 μmol 52 mg) was added and the reaction was stirred vigorously overnight Afterwards 10 mL CH2Cl2 and 5 mL H2O were

added and the organic layer was separated the aqueous layer was further extracted with CH2Cl2 (3x 5mL) and the combined organic layers were dried (MgSO4) and concentrated in vacuo The residue was dissolved in Et2O (10 mL) and extracted with sat aq NaHCO3 (3x 5 mL) the combined aqueous layers were acidified and extracted with CH2Cl2 (3x 10 mL) Drying (MgSO4) and concentrating the combined CH2Cl2 layers in vacuo afforded 43 (503 mg) as a colorless oil [52 yield 92 ee [α]D = minus 67 (c 27 CHCl3) lit29b [α]D = minus 85 (c 37 CHCl3)] 1H-NMR δ 1078 (bs 1H) 740-727 (m 5H) 456 (s 2H) 366 (dd J = 75 and 90Hz 1H) 355 (dd J = 57 and 91Hz 1H) 288-278 (m 1H) 122 (d J = 71Hz 3H) 13C-NMR δ 1808 1378 1283 1276 1276 731 715 401 137 MS (EI) mz 194 (M+ 16) 108 (9) 107 (83) 105 (8) 92 (13) 91 (100) 89 (5) 79 (23) 77 (14) 73 (6) 65 (18) 51 (7) HRMS Calcd for C11H14O3 1940943 found 1940948 Enantiomeric excess determined by chiral GC analysis CP-Chiralsil-Dex-CB (25 m x 025 mm) isothermic 150 ordmC retention times (min) 415 (minor) and 429 (major)

O OH

O

Chapter 3

90


(minus)-(S)-(N-tert-Butoxycarbonyl)(2-methylbut-3-enyl)amine (44)

To a solution of 32 (05 mmol 170 mg) in MeOH (6 mL) Mg-powder (25 mmol 61 mg) was added and the mixture was sonicated for 60 min at rt The resulting suspension was diluted with CH2Cl2 (20

mL) and poured in aq HCl (05M 20 mL) The organic phase was separated and washed with aq sat NaHCO3 (2x 10 mL) dried and concentrated in vacuo affording 44 (833 mg) as a colorless oil [90 yield 95 ee [α]D = minus 161 (c 27 CHCl3)] 1H-NMR δ 567 (ddd J = 76 104 and 176Hz 1H) 509-502 (m 2H) 454 (bs 1H) 320-309 (m 1H) 295 (ddd J = 54 80 and 133Hz 1H) 237-226 (m 1H) 144 (s 9H) 101 (d J = 68Hz 3H) 13C-NMR δ 1559 1413 1149 789 456 383 283 173 MS (EI) mz 130 (6) 129 (17) 59 (19) 57 (100) 56 (7) 55 (11) MS (CI) mz 204 (13) 203 ([M+NH4]+ 100) 202 (5) 187 (7) 186 ([M+H]+ 58) 163 (9) 148 (5) 147 (63) 130 (33) 86 (7) HRMS Calcd for [M-Me2C=CH2]+ C6H11NO2 1290790 found 1290797 Enantiomeric excess determined by chiral GC analysis CP-Chiralsil-Dex-CB (25 m x 025 mm) initial temp 85 ordmC rate 10 degCmin fin temp 120 degC retention times (min) 614 (major) and 647 (minor)

(+)-(R)-4-((tert-Butoxycarbonyl)(p-toluenesulfonyl)amino)- 3-methyl-butan-2-one (45)

The title compound was prepared in an analogous way to 41 from 32 Purification by flash chromatography (SiO2 1090 Et2Opentane Rf = 005) afforded 45 (1453 mg) as a colorless oil [82 yield 95 ee [α]D = + 26 (c 71 CHCl3] 1H-NMR

δ 777 (d J = 82Hz 2H) 730 (d J = 80Hz 2H) 404 (dd J = 60 and 146Hz 1H) 390 (dd J = 80 and 146Hz 1H) 316-302 (m 1H) 243 (s 3H) 221 (s 3H) 131 (s 9H) 121 (d J = 72Hz 3H) 13C-NMR δ 2101 1508 1442 1369 1291 1277 844 485 471 286 276 214 142 MS (EI) mz 282 ([M-tBuO]+ 5) 200 (9) 198 (6) 191 (27) 184 (35) 156 (5) 155 (53) 144 (31) 120 (15) 108 (27) 102 (7) 100 (27) 91 (50) 72 (10) 65 (11) 61 (9) 58 (20) 57 (100) 56 (6) MS (CI) mz 375 (11) 374 (31) 373 ([M+NH4]+ 100) 317 (5) 219 (6) 69 (5) HRMS Calcd for [M-tBuO]+ C13H16NO4S 2820800 found 2820805 Enantiomeric excess

NH

O

O

SN

OO

O

O O


91


determined by chiral HPLC analysis Chiralcel AD (98 n-heptanei-PrOH) 40ordmC retention times (min) 168 (major) and 209 (minor)

(minus)-(R)-3-((tert-Butoxycarbonyl)(p-toluenesulfonyl)amino)- 2-methylpropan-1-ol (46)

The title compound was prepared in an analogous way to 42 from 32 Purification by flash chromatography (SiO2 5050 Et2Opentane Rf = 025) afforded 46 (1328 mg) as a colorless oil which crystallized upon standing [77 yield 95 ee [α]D = minus 33 (c 81 CHCl3) mp = 598-

604 degC] 1H-NMR δ 773 (d J = 82Hz 2H) 728 (d J = 85Hz 2H) 385 (dd J = 91 and 146Hz 1H) 372 (dd J = 53 and 146Hz 1H) 370-363 (m 1H) 351-343 (m 1H) 263 (bs 1H) 241 (s 3H) 216-204 (m 1H)m 129 (s 9H) 100 (d J = 70Hz 3H) 13C-NMR δ 1519 1443 1371 1292 1276 848 636 491 364 277 215 145 MS (EI) mz 270 ([M-tBuO]+ 5) 184 (47) 179 (28) 155 (48) 120 (14) 108 (26) 92 (8) 91 (52) 65 (12) 58 (6) 57 (100) 56 (6) MS (CI) mz 363 (8) 362 (22) 361 ([M+NH4]+ 100) 305 (11) HRMS Calcd for [M-tBuO]+ C12H16NO4S 2700800 found 2700787 Enantiomeric excess determined by chiral HPLC analysis Chiralcel AD (98 n-heptanei-PrOH) 40ordmC retention times (min) 386 (major) and 510 (minor)

(minus)-3-((tert-Butoxycarbonyl)(p-toluenesulfonyl)amino)- 2-ethylpropan-1-ol (46b)

The title compound was prepared in an analogous way to 42 from 35 Purification by flash chromatography (SiO2 5050 Et2Opentane Rf = 025) afforded 46b (1310 mg) as a colorless oil [74 yield 90 ee [α]D = minus 68 (c 58 CHCl3 ] 1H-NMR δ 773 (d J = 84Hz 2H) 729 (d J =

86Hz 2H) 387-374 (m 2H) 373-356 (m 2H) 269 (bs 1H) 242 (s 3H) 186-177 (m 1H) 156-144 (m 1H) 143-132 (m 1H) 130 (s 9H) 099 (t J = 75Hz 3H) 13C-NMR δ 1520 1443 1370 1292 1276 850 603 480 429 277 216 215 115 MS (EI) mz 284 ([M-tBuO]+ 2) 216 (5) 193 (15) 184 (25) 155 (29) 120 (5) 108 (14) 92 (9) 91 (49) 65 (14) 57 (100) 56 (8) 55 (7) MS (CI) mz 377 (10) 376 (27) 375

SN

OO

O

O

OH

SN

OO

O

O

OH

Chapter 3

92


([M+NH4]+ 100) 319 (47) HRMS Calcd for [M-tBuO]+ C13H18NO4S 2840956 found 2840973 Enantiomeric excess determined by chiral HPLC analysis Chiralcel AD (98 n-heptanei-PrOH) 40ordmC retention times (min) 352 (major) and 527 (minor)

(+)-(R)-3-(p-Toluenesulfonylamino)-1-(tert-butoxycarbonyloxy)- 2-methylpropane (47)

Ozone was bubbled for 10 min through a solution of 32 (05 mmol) in CH2Cl2MeOH (1115mL) cooled to -78degC NaBH4 (25 eq 25 mmol 95 mg) was added at -78degC after which the

cooling bath was removed and the reaction mixture was stirred at rt for 2 h The solvents were removed from the reaction mixture by rotavap (waterbath at 60 degC) followed by addition of aq HCl (1M 15 mL) and Et2O (25 mL) The organic layer was separated and the resulting aqueous layer extracted with Et2O (2x 25 mL) the combined organic layers were dried (MgSO4) and concentrated in vacuo Purification by flash chromatography (SiO2 3070 Et2Opentane Rf = 030) afforded 47 (1238 mg) as a colorless oil [69 yield 95 ee [α]D = + 06 (c 79 CHCl3)] 1H-NMR δ 774 (d J = 82Hz 2H) 729 (d J = 82Hz 2H) 522 (t J = 66Hz 1H) 400 (dd J = 47 and 112Hz 1H) 388 (dd J = 67 and 112Hz 1H) 295-279 (m 2H) 241 (s 3H) 206-190 (m 1H) 144 (s 9H) 093 (d J = 69Hz 3H) 13C-NMR δ 1536 1432 1369 1296 1269 822 688 456 332 276 214 144 MS (EI) mz 226 (25) 225 (6) 224 (23) 199 (7) 197 (8) 188 (9) 185 (9) 184 (88) 157 (6) 156 (9) 155 (100) 133 (8) 132 (25) 119 (6) 92 (12) 91 (80) 70 (73) 65 (17) 59 (6) 57 (71) 56 (12) MS (CI) mz 363 (7) 362 (19) 361 ([M+NH4]+ 100) 333 (14) 305 (6) 289 (14) HRMS Calcd for [M-tBuO]+ C12H16NO4S 2700800 found 2700795 Enantiomeric excess determined by chiral HPLC analysis Chiralcel AS-H (90 n-heptanei-PrOH) 40ordmC retention times (min) 403 (minor) and 430 (major)

(minus)-(R)-3-((tert-Butoxycarbonyl)(p-toluenesulfonyl)amino)-2-methylpropionic acid (48)

The title compound was prepared in an analogous way to 43 from 32 The product 48 (1409 mg) was obtained as a white crystalline solid [79 yield S

N

OO

O

O

OH

O

SNH

O O

O O O


93


95 ee [α]D = minus 95 (c 36 CHCl3) mp = 1144-1163 degC] 1H-NMR δ 1027 (bs 1H) 780 (d J = 84 Hz 2H) 731 (d J = 86 Hz 2H) 414 (dd J = 68 and 145 Hz 1H) 396 (dd J = 77 and 145 Hz 1H) 310-301 (m 1H) 244 (s 3H) 133 (s 9H) 129 (d J = 72 Hz 3H) 13C-NMR δ 1805 1509 1443 1370 1292 1279 847 487 397 277 216 145 MS (EI) mz 284 ([M-tBuO]+ 4) 194 (5) 193 (44) 185 (5) 184 (54) 156 (5) 155 (55) 120 (18) 112 (7) 108 (34) 102 (11) 92 (7) 91 (57) 65 (14) 57 (100) 56 (7) MS (CI) mz 377 (8) 376 (19) 375 ([M+NH4]+ 100) 319 (16) 275 (6) 174 (7) HRMS Calcd for [M-tBuO]+ C12H14NO5S 2840592 found 2840607 Enantiomeric excess determined on derivatized product 49

(minus)-(R)-Methyl 3-((tert-butoxycarbonyl)(p-toluenesulfonyl)amino)-2-methylpropionate (49)

To a solution of 48 (019 mmol 65 mg) and MeOH (1mL) in toluene (3mL) TMSCHN2 (10 mmol 10M in Et2O 05 mL) was added The reaction mixture was stirred at rt for 1 h then MeOH (2mL) was added and the excess TMSCHN2 was destroyed through addition of

AcOH (05 mL) The mixture was diluted with toluene (5mL) and washed with sat aq NaHCO3 (5 mL 2x) The organic layer was dried (MgSO4) and concentrated in vacuo to yield 49 (636 mg) as a colorless oil which crystallised upon standing [94 yield 95 ee [α]D = minus 208 (c 28 CHCl3) mp = 758-786 degC] 1H-NMR δ 777 (d J = 82 Hz 2H) 728 (d J = 83 Hz 2H) 408 (dd J = 73 and 144 Hz 1H) 389 (dd J = 72 and 144 Hz 1H) 365 (s 3H) 304-294 (m 1H) 241 (s 3H) 130 (s 9H) 122 (d J = 71 Hz 3H) 13C-NMR δ 1746 1509 1442 1372 1292 1278 844 518 491 398 277 215 146 MS (EI) mz 298 ([M-tBuO]+ 4) 284 (12) 208 (7) 207 (56) 185 (6) 184 (56) 160 (7) 156 (5) 155 (59) 120 (17) 116 (29) 112 (8) 108 (32) 92 (7) 91 (54) 88 (9) 84 (6) 65 (12) 57 (100) 56 (7) MS (CI) mz 391 (7) 390 (20) 389 ([M+NH4]+ 100) 333 (13) 289 (6) HRMS Calcd for [M-tBuO]+ C13H16NO5S 2980749 found 2980733 Enantiomeric excess determined by chiral HPLC analysis Chiralcel AD (99 n-heptanei-PrOH) 40ordmC retention times (min) 269 (major) and 352 (minor)

SN

OO

O

O

O

O

Chapter 3

94


(minus)-(R)-Methyl 3-t-butoxycarbonylamino-2-methyl-propionate (50)40b

The title compound was prepared in an analogous way to 44 from 49 (0104 mmol 388 mg) Work-up afforded compound 50 (205 mg) as a colorless oil [90 yield 95 ee [α]D = minus 218 (c 19

CHCl3) lit40b [α]D = minus 176 (c 274 CHCl3)] 1H-NMR 494 (bs 1H) 368 (s 3H) 335-319 (m 2H) 272-261 (m 1H) 141 (s 9H) 115 (d J = 72 Hz 3H) 13C-NMR δ 1758 1559 793 518 429 399 283 147 MS (EI) mz 217 (M+ 1) 161 (29) 160 (8) 144 (19) 130 (30) 116 (6) 112 (20) 101 (7) 88 (24) 84 (8) 59 (17) 58 (6) 57 (100) 56 (8) MS (CI) mz 452 ([2M+NH4]+ 10) 236 (12) 235 ([M+NH4]+ 100) 219 (6) 218 ([M+H]+ 45) 179 (16) 162 (11) 69 (9) HRMS Calcd for C10H19NO4 2171314 found 2171327 Enantiomeric excess determined by chiral GC analysis CP-Chiralsil-Dex-CB (25 m x 025 mm) isothermic 130 ordmC retention times (min) 133 (major) and 146 (minor)

Scheme 315 Derivatisations performed to establish the enantiomeric excess of allylic alkylation product 33 Reagents and conditions i) 1 O3 DCMMeOH -78degC 2 NaBH4 (5 equiv) rt 77 ii) BnOC(NH)CCl3 TfOH cyclohexane CCl4 rt 25 iii) TBAF THF rt

(minus)-(S)-3-(tert-Butyl-diphenyl-silanyloxy)-2-methylpropan-1-ol (51)49

The title compound was prepared in an analogous way to 42 from 33 (029 mmol 931 mg) Purification by flash column chromatography (SiO2 1585 Et2Opentane Rf = 020) afforded 51

NH

O

O

O

O

SiO OH


95


(730 mg) as a colorless oil [77 yield 94 ee [α]D = minus 60 (c 15 CHCl3) lit49 [α]D = minus 53 (c 33 CHCl3)] 1H-NMR δ 771 (dd J = 16 and 78Hz 4H) 749-739 (m 6H) 377-359 (m 4H) 268 (bs 1H) 207-196 (m 1H) 109 (s 9H) 086 (d J = 69Hz 3H) 13C-NMR δ 1355 1355 1331 1331 1297 1277 686 675 373 268 191 131 MS (EI) mz 272 (7) 271 ([M-tBu]+ 30) 229 (8) 201 (5) 200 (19) 199 (100) 197 (7) 193 (18) 181 (9) 139 (20) 77 (7) MS (CI) mz 348 (8) 347 (28) 346 ([M+NH4]+ 100) 330 (13) 329 ([M+H]+ 47) 69 (14) HRMS Calcd for [M-tBu]+ C16H19O2Si 2711154 found 2711149 Enantiomeric excess determined on derivatized product 42

(S)-1-Benzyloxy-3-(t-butyl-diphenyl-silanyloxy)-2-methylpropane (52)

To a solution of 51 (015 mmol 498 mg) benzyltrichloroacetimidate (03 mmol 56 μL) and cyclohexane (03 mmol 33 μL) in CCl4 (1 mL) a catalytic amount of TfOH (2 μL) was added The mixture was stirred at rt for 25 h and quenched with 1 mL sat

aq NaHCO3 after which 10 mL Et2O was added and the resulting solution washed with 10 mL H2O and 10 mL sat aq NaCl The organic layer was dried with MgSO4 and concentrated in vacuo Purification by flash column chromatography (SiO2 199 Et2Opentane Rf = 020) afforded an inseparable mixture of 52 and the byproduct dibenzylether50 (324 mg) as a colorless oil [52Bn2O = 43 25 calc yield of 52 94 ee] 1H-NMR δ 769-764 (m 4H) 745-726 (m 11H + Bn2O 10H) 458 (Bn2O s 4H) 450 (s 2H) 368-361 (m 2H) 356 (dd J = 64 and 90 Hz 1H) 340 (dd J = 61 and 90 Hz 1H) 209-197 (m 1H) 106 (s 9H) 099 (d J = 69 Hz 3H)13C-NMR δ 1388 1383 (Bn2O) 1356 1339 1295 1284 (Bn2O) 1283 1278 (Bn2O) 1276 (Bn2O) 1276 1275 1273 730 725 721 (Bn2O) 657 363 269 193 141 MS (EI) mz 199 (8) 195 (7) 194 (18) 193 ([M - Ph tBu Bn]+ 100) 181 (6) 91 (50) MS (CI) mz 438 (13) 437 (35) 436 ([M+NH4]+ 100) 419 ([M+H]+ 14) HRMS Calcd for [M - Ph tBu Bn]+ C10H13O2Si 1930685 found 1930676 Enantiomeric excess determined for derivatized product 42 To the mixture of 52 and dibenzylether (approx 37 μmol 52 21 mg) 4 equivalents of TBAF (015 mmol 10M in THF 015 mL) were added at room temperature After stirring for 25 h the reaction mixture was diluted with Et2Opentane (11

SiO O

Chapter 3

96


1mL) and the resulting mixture was flushed over a MgSO4 and SiO2 plug The solution was concentrated providing the mixture of 42 and Bn2O as an oil The enantiomeric excess of 42 was determined to be 94 by chiral HPLC analysis Chiralcel AS (985 n-heptanei-PrOH) 40ordmC retention times (min) 47 (Bn2O) 118 (major) and 141 (minor)


97


References 1 a) Warren S Organic Synthesis The Disconnection Approach Wiley Chichester 1982 b) Hanessian S Total Synthesis of Natural Products The lsquoChironrsquo Approach Organic Chemistry Series Vol 3 Baldwin J E Ed Pergamon Oxford 1983 c) Corey E J Cheng X-M The Logic of Chemical Synthesis Wiley New York 1989 d) Nicolaou K C Sorensen E J Classics in Total Synthesis Targets Strategies Methods VCH Weinheim 1996 e) Nicolaou K C Snyder S A Classics in Total Synthesis II More Targets Strategies Methods Wiley-VCH Weinheim 2003 2 a) Sheldon R A Chirotechnology Dekker New York 1993 b) Chirality in Industry Collins A N Sheldrake G N Crosby J Eds Wiley Chichester 1992 c) Asymmetric Catalysis on Industrial Scale Blaser H U Schmidt E Eds Wiley-VCH Weinheim 2004 3 a) Murphy K E Hoveyda A H Org Lett 2005 7 1255-1258 b) Murphy K E Hoveyda A H J Am Chem Soc 2003 125 4690-4691 4 Similar substrates were also used by Hoveyda and coworkers in a Cu-free allylic alkylation Lee Y Hoveyda A H J Am Chem Soc 2006 128 15604-15605 5 a) Goldsmith P J Teat S J Woodward S Angew Chem Int Ed 2005 44 2235-2237 b) Boumlrner C Gimeno J Gladiali S Goldsmith P J Ramazzotti D Woodward S Chem Commun 2000 2433-2434 6 a) Okamoto S Tominaga S Saino N Kase K Shimoda K J Organomet Chem 2005 690 6001-6007 b) Tominaga S Oi Y Kato T An D K Okamoto S Tetrahedron Lett 2004 45 5585-5588 7 Falciola C A Alexakis A Angew Chem Int Ed 2007 46 2619-2622 8 a) Piarulli U Daubos P Claverie C Monti C Gennari C Eur J Org Chem 2005 895-906 b) Piarulli U Claverie C Daubos P Gennari C Minnaard A J Feringa B L Org Lett 2003 5 4493-4496 c) Piarulli U Daubos P Claverie C Roux M Gennari C Angew Chem Int Ed 2003 42 234-236 9 Geurts K Fletcher S P Feringa B L J Am Chem Soc 2006 128 15572-15573 10 Si a) Kacprzynski M A May T L Kazane S A Hoveyda A H Angew Chem Int Ed 2007 46 4554-4558 B b) Carosi L Hall D G Angew Chem Int Ed 2007 46 5913-5915 11 Luchaco-Cullis C A Mizutani H Murphy K E Hoveyda A H Angew Chem Int Ed 2001 40 1456-1460 12 Tissot-Croset K Alexakis A Tetrahedron Lett 2004 45 7375-7378

Chapter 3

98


13 Although Beilstein and SciFinder will not provide this result the reaction can be found as a table footnote in Hiyama T Wakasa N Tetrahedron Lett 1985 26 3259-3262 14 Gillingham D G Hoveyda A H Angew Chem Int Ed 2007 46 3860-3864 15 Kottirsch G Koch G Feifel R Neumann U J Med Chem 2002 45 2289-2293 16 a) Cerezo S Cortegraves J Galvan D Lago E Marchi C Molins E Moreno-Mantildeas M Pleixats R Torrejoacuten J Vallribera A Eur J Org Chem 2001 329-337 b) Neustadt B R Tetrahedron Lett 1994 35 379-380 17 a) Lemieux R M Devine P N Mechelke M F Meyers A I J Org Chem 1999 64 3585-3591 b) Thurner A Faigl F Tőke L Mordini A Valacchi M Reginato G Czira G Tetrahedon 2001 57 8173-8180 c) McDonald W S Verbicky C A Zercher C K J Org Chem 1997 62 1215-1222 18 Derivatization of the products was necessary because separation of the enantiomers was not found on chiral GC or HPLC see Experimental Part 19 Munakata R Ueki T Katakai H Takao K-I Tadano K-I Org Lett 2001 3 3029-3032 20 For a review on hydroboration see Smith K Pelter A in Comprehensive Organic Synthesis Trost B M Fleming I Eds Pergamon Oxford 1991 Vol 8 Chapter 310 21 Schmid R Antoulas S Ruumlttimann A Schmid M Vecchi M Weiser H Helv Chim Acta 1990 73 1276-1299 22 Fuganti C Grasselli P J Chem Soc Chem Commun 1979 995-997 23 a) Smith A B III Kozmin S A Paone D V J Am Chem Soc 1999 121 7423-7424 b) Smith A B III Adams C M Kozmin S A Paone D V J Am Chem Soc 2001 123 5925-5937 24 For reviews on the Wacker oxidation see a) Hintermann L in Transition Metals for Organic Synthesis 2nd Ed Beller M Bolm C Eds Wiley-VCH Weinheim 2004 Vol 2 Chapter 28 b) Takacs J M Jiang X-T Curr Org Chem 2003 7 369-396 25 Paterson I Anderson E A Dalby S M Loiseleur O Org Lett 2005 7 4125-4128 26 OrsquoSullivan P T Buhr W Fuhry M A M Harrison J R Davies J E Feeder N Marshall D R Burton J W Holmes A B J Am Chem Soc 2004 126 2194-2207 27 Evans D A Ripin D H B Halstead D P Campos K R J Am Chem Soc 1999 121 6816-6826 28 White J D Reddy G N Spessard G O J Am Chem Soc 1988 110 1624-1626 29 a) McGuirk P R Collum D B J Am Chem Soc 1982 104 4496-4497 b) McGuirk P R Collum D B J Org Chem 1984 49 843-852


99


30 For a review on application of ozonolysis in synthesis see Van Ornum S G Champeau R M Pariza R Chem Rev 2006 106 2990-3001 31 For examples see a) Ghosh A K Wang Y Kim J T J Org Chem 2001 66 8973-8982 b) Statsuk A V Liu D Kozmin S A J Am Chem Soc 2004 126 9546-9547 c) Deng L-S Huang X-P Zhao G J Org Chem 2006 71 4625-4635 32 For example see Ley S V Brown D S Clase J A Fairbanks A J Lennon I C Osborn H M I Stokes E S E Wadsworth D J J Chem Soc Perkin Trans 1 1998 2259-2276 33 For example see Ponpipom M M Hagmann W K Tetrahedron 1999 55 6749-6758 34 Huffman J W Liddle J Duncan S G Jr Yu S Martin B R Wiley J L Bioorg Med Chem 1998 6 2383-2396 35 Soucy F Grenier L Behnke M L Destree A T McCormack T A Adams J Plamondon L J Am Chem Soc 1999 121 9967-9976 36 Carlsen P H J Katsuki T Martin V S Sharpless K B J Org Chem 1981 46 3936-3938 37 Nyasse B Grehn L Ragnarsson U Chem Commun 1997 1017-1018 38 For a review on N-Boc reactivity see a) Agami C Couty F Tetrahedron 2002 58 2701-2724 For examples of Boc-protecting group migration see b) Kise N Ozaki H Terui H Ohya K Ueda N Tetrahedron Lett 2001 42 7637-7639 c) Bunch L Norrby P-O Frydenvang K Krogsgaard-Larsen P Madsen U Org Lett 2001 3 433-435 d) Skwarczynski M Sohma Y Kimura M Hayashi Y Kimura T Kiso Y Bioorg Med Chem Lett 2003 13 4441-4444 e) Mohal N Vasella A Helv Chim Acta 2005 88 100-119 39 a) Smith M B Methods of Non-α-Amino Acid Synthesis Dekker New York 1995 b) Lelais G Seebach D Biopolymers (Peptide Sci) 2004 76 206-243 c) Enantioselective Synthesis of β-Amino Acids 2nd ed Juaristi E Soloshonok V A Eds Wiley Hoboken 2005 See also d) Duursma A Minnaard A J Feringa B L J Am Chem Soc 2003 125 3700-3701 e) Huang H Liu X Deng J Qiu M Zheng Z Org Lett 2006 8 3359-3362 40 a) Salamonczyk G M Han K Guo Z-W Sih C J J Org Chem 1996 61 6893-6900 b) Ghosh A K Bischoff A Eur J Org Chem 2004 2131-2141 41 a) Lebel H Paquet V J Am Chem Soc 2004 126 320-328 b) Grandguillot J-C

Rouessac F Tetrahedron 1991 47 5133-5148 42 Yadav J S Reddy P S Synth Commun 1986 16 1119-1131 43 Larpent C Chasseray X Tetrahedron 1992 48 3903-3914 44 Garcia-Ruiz V Woodward S Tetrahedron Asymm 2002 13 2177-2180

Chapter 3

100


45 Schmid R Hansen H-J Helv Chim Acta 1990 73 1258-1275 46 The optical rotation in CHCl3 is reported only once but appears to be reported with the wrong sign See reference 21 47 Myers A G Yang B H Chen H McKinstry L Kopecky D J Gleason J L J Am Chem Soc 1997 119 6496-6511 48 Paquette L A Guevel R Sakamoto S Kim I H Crawford J J Org Chem 2003 68 6096-6107 49 Blakemore P R Browder C C Hong J Lincoln C M Nagornyy P A Robarge L A Wardrop D J White J D J Org Chem 2005 70 5449-5460 50 The identity of the byproduct was established through comparison of 1H-NMR and 13C-NMR spectroscopy and GCMS-data with a commercial sample 52 was characterised as a mixture of compounds


In this chapter a new protocol for the synthesis of chiral vicinal dialkyl arrays is described Using consecutive copper catalyzed enantioselective allylic alkylation ruthenium catalyzed metathesis and asymmetric copper catalyzed conjugate addition reactions it is possible to synthesize compounds containing a vicinal dialkyl motif In this fashion almost complete catalyst stereocontrol which overrules the inherent substrate control is achieved This allows the synthesis of either stereoisomer with excellent stereoselectivity The versatility of this protocol in natural product synthesis is demonstrated in the preparation of the ant pheromones lasiol and faranal

This chapter has been published in part van Zijl A W Szymanski W Loacutepez F Minnaard A J Feringa B L J Org Chem 2008 73 6994-7002

Chapter 4

102


41 Introduction In the synthesis of chiral natural products with multiple stereogenic

centers it is imperative that the stereochemistry of each of these centers can be controlled Therefore methods that allow for the introduction of each stereochemical element independently (reagent or catalyst control) as opposed to being dependent on chirality introduced previously (substrate control) are an invaluable addition to the synthetic chemistrsquos tool-box1 The Cu-catalyzed asymmetric allylic alkylation (AAA)2 and conjugate addition (CA)3 are two powerful C-C bond forming reactions enabling the formation of stereogenic centers with alkyl substituents As discussed in chapter 2 we have recently reported catalysts based on copper and diphosphine ligands (Figure 41) that can perform both the enantioselective Cu-catalyzed allylic alkylation4 and conjugate addition56 using Grignard reagents These reactions provide the chiral products in high yields and with excellent regioselectivity and enantiomeric excess7

Figure 41 Diphosphine ligands for asymmetric Cu-catalyzed conjugate addition and allylic alkylation with Grignard reagents

Iterative protocols based on the enantioselective Cu-catalyzed conjugate addition for the synthesis of compounds with two or more stereocentres in a 13-relation8 or 15-relation9 to each other have been developed in our group recently (see section 413) The utility of these protocols has been demonstrated in the total synthesis of several natural products10 However these approaches do not provide for the stereoselective synthesis of vicinal (12-relation) dialkyl arrays

Catalytic enantioselective synthesis of vicinal dialkyl arrays

103


This chapter will discuss the development of a versatile protocol for the synthesis of such vicinal 12-dialkyl arrays based on three successive modern catalytic transformations (Scheme 41) The strategy consists of initial Cu-catalyzed asymmetric allylic alkylation (AAA) to build the first stereogenic center a subsequent cross-metathesis (CM) reaction11 which transforms the terminal alkene moiety generated into an αβ-unsaturated system and finally a Cu-catalyzed enantioselective conjugate addition (CA) of a Grignard reagent which delivers the desired 12-dialkyl motif In this manner adjacent stereocentres with simple alkyl substituents are introduced with independent control of the stereochemistry ie both diastereomers syn and anti can be prepared selectively Furthermore this protocol was applied in the synthesis of the two ant pheromones lasiol and faranal

Scheme 41 Synthetic protocol providing vicinal dialkyl compounds (LG = leaving group)

411 The presence of vicinal dialkyl arrays in natural products The vicinal dialkyl motif is not as frequently encountered as for

instance the ubiquitous 13-dimethyl deoxypropionate unit in polyketide derived natural products Nevertheless dialkyl arrays and in particular the 12-dimethyl motif can be found in a wide variety of compounds from many different natural product classes (Figure 42 and Schemes 42-44)

The motif is common in lignans neolignans and other related compounds (eg compounds 2 and 4 Figure 42)12 These natural products which can be isolated from vascular plants are phenylpropanoid dimers ie they are biosynthesized from two cinnamic acid residues Many plant extracts used in traditional medicine contain mixtures of several lignans and these compounds have a number of medically important biological functions and effects This makes them important lead structures for drug development13

Chapter 4

104


12-Dimethyl arrays are present in the side chains of several steroid compounds They are particularly common in withanolides which contain dimethyl substituted lactones in the side chain14 The biologically active withanolides can be isolated from several plant species from the Solanaceae family also known as the nightshade or the potato family Many steroid compounds isolated from marine organisms including starfish metabolite 1 (Figure 42) feature the 12-dimethyl motif in their side chains also15

Figure 42 Examples of natural products containing both syn and anti vicinal dimethyl motifs certonardosterol J (1) dihydroguiaretic acid (2) faranal (3) eupomatilone 7 (4) kalkitoxin (5)

The marine neurotoxin kalkitoxin (5) (Figure 42)16 a secondary metabolite from the cyanobacterium Lyngbya majuscula bears the vicinal dimethyl array The dinoflagellate Gambierdiscus toxicus implicated in ciguatera food poisoning produces several polycyclic ether neurotoxins both ciguatoxin (Scheme 42)17 and maitotoxin18 contain a dimethyl motif either as part of one of the cyclic ethers (ciguatoxin) or in a side chain of the final ring (maitotoxin)


105


Finally some insects produce pheromones containing the motif eg faranal (3) and lasiol (vide infra) The stereochemical nature and purity of pheromones can be highly relevant to their bioactivity19 As is obvious from the examples given a synthetic method allowing for the preparation of either enantiomer of both the syn and the anti-motif (both present in these compounds see Figure 42) of vicinal dialkyl and in particular dimethyl arrays would be invaluable

412 Methods previously reported for the asymmetric synthesis of vicinal dialkyl arrays

4121 Stoichiometric methods Most of the existing methods for the asymmetric synthesis of vicinal

dialkyl arrays are based on chiral pool or chiral auxiliaries and reagents For instance a substrate controlled stereospecific Ireland-Claisen rearrangement was applied to construct the vicinal dimethyl containing L ring of ciguatoxin (6) (Scheme 42)20

Scheme 42 Ireland-Claisen rearrangement applied in the total synthesis of ciguatoxin (6) i) LDA TMSCl HMPA THF minus78 degC rarr rt 82 dr = 3 1 dr = diastereomeric ratio TIPDS = -Si(i-Pr)2OSi(i-Pr)2-

Chiral auxiliary based conjugate additions with MeMgBr and CuBrmiddotSMe2 were used in the introduction of the second methyl group of the side chain of maitotoxin21 and in the total synthesis of kalkitoxin16 In both cases the other methyl group had been introduced earlier in the synthesis Both methyl groups can be introduced through a 14-addition and subsequent α-alkylation also Hanessian and coworkers used this approach in the synthesis of manassantins (a class of dineolignans) Their approach relied upon diastereoselective substrate control induced by the stereogenic

Chapter 4

106


center at the γ-position (Scheme 43)22 The groups of Badiacutea and White performed these reactions in one pot ie 14-addition enolate trapping using chiral auxiliaries23

Scheme 43 Substrate control in 14-addition and subsequent α-alkylation in the synthesis of manassantin B (7) i) Me2CuLi TMSCl THF 87 dr = 12 1 ii) KHMDS MeI THF 85 dr = 12 1

Scheme 44 Reagent controlled tiglylation followed by diastereoselective hydroboration in the synthesis of interiotherin A (8) i) CH2Cl2 minus50 degC rarr 0 degC 78 dr = 100 0 96 ee ii) TBSCl 26-lutidine iii) 9-BBN THF 0 degC iv) ArBr Pd(PPh3)4 Ph3P NaOH THF 70 degC 77

Reagent controlled introduction of the first methyl group by asymmetric tiglylation was applied in the syntheses of several dibenzocyclooctadiene lignan natural products24 Tiglylating reagents based on several metals (eg B Cr Sn In and Si) were explored Reaction with a chiral tiglylsilicon


107


reagent proved to be the most selective (Scheme 44) Subsequent hydroboration of the gem-disubstituted double bond of the product yielded the vicinal dimethyl motif

Michael reactions with the appropriate enolate nucleophile can provide vicinal dialkyl arrays also This has been applied in the syntheses of 34-dimethylglutamine (chiral auxiliary) and roccellic acid (chiral sulfoxide electrophile)25

4122 Catalytic methods As discussed in chapter 1 the replacement of stoichiometric methods for

the synthesis of chiral compounds with catalytic protocols is highly desirable The copper catalyzed Mukaiyama-Michael reaction developed by the group of Evans allows for the catalytic enantioselective synthesis of an anti vicinal dimethyl array in high enantioselectivity and diastereoselectivity (88 99 1 dr 98 ee)26 Using their chiral oxazaborolidinone catalyst Harada and coworkers reported the formation of a syn-diastereomer through use of an enolsilane with opposite double bond geometry albeit with lower selectivity (54 88 1 dr 75 ee)27

Catalytic desymmetrization of vicinal dimethyl containing meso-compounds is another efficient method to obtain these target structures For instance the desymmetrization of cyclic anhydrides provides for anti-dialkyl bearing compounds with differentiated carbonyl functionalities eg hemiesters28 or keto acids29 The Rh-catalyzed coupling to diarylzinc reagents was used in the total synthesis of three different eupomatilones29a

Scheme 45 Base catalyzed desymmetrization of a cyclic epoxide i) 5 mol catalyst LDA DBU THF 0 degC 95 9 1 dr 94 ee (major)

Another elegant example is the base catalyzed desymmetrization of cyclic epoxides to allylic alcohols (Scheme 45)30 A major disadvantage is

Chapter 4

108


that the diastereomers of the substrate could not be separated from each other inherently providing the product in the same ratio of diastereomers In all of the desymmetrization reactions on cyclic compounds only the anti-dialkyl diastereomer can be obtained


The existing methods described in section 412 are all either non-catalyzed or the two chiral centers cannot be controlled independently (vide supra) Independent control of the stereochemistry of each stereochemical element enables one to prepare all possible diastereomers of a compound This can be an advantage if for instance the complete stereochemical configuration of a natural product is not yet known Some examples of this approach have been reported in the literature for 13- and 15-dimethyl motifs

Scheme 46 Enantioselective copper catalyzed conjugate addition of zinc reagents to cyclooctadienone to obtain the different diastereomers of 15-dimethyl building blocks β-mannosyl phosphomycoketide (9) i) 5 mol Cu(OTf)2 10 mol L Me2Zn PhMe minus25 degC 85 gt99 ee ii) 25 mol Cu(OTf)2 5 mol L Me2Zn CH2Cl2 minus25 degC then Et3N TMEDA TMSOTf Et2Zn rt gt98 de iii) 25 mol Cu(OTf)2 5 mol ent-L Me2Zn CH2Cl2 minus25 degC then Et3N HMPA TMSCl Et2Zn rt gt98 de iv) 1 O3 MeOH CH2Cl2 minus78 degC then NaBH4 rt 2 MeOH TMSCl reflux 45 in two steps


109


The consecutive conjugate addition of dimethyl zinc to cyclooctadienone can be used to obtain any of the four possible stereoisomers of an acyclic chiral isoprenoid building block (15-dimethyl) depending on the ligand used in the reactions (Scheme 46) This reaction has been applied in the synthesis of two apple leafminer pheromones9 and β-mannosyl phosphomycoketide (9)10d a mycobacterial antigen isolated from Mycobacterium tuberculosis In principle this protocol allows for the synthesis of all possible stereoisomers of the alkyl chain

Deoxypropionate units (13-dimethyl) are a common motif in natural products also Several ways exist to prepare the different diastereomers with high stereoselectivity through substrate or reagent control31 Efficient catalytic methods that allow independent stereocontrol over each stereogenic center have only recently begun to appear For instance the copper catalyzed conjugate addition of Me2Zn to unsaturated malonate esters could be performed with high enantioselectivity8b The product could be extended in four steps to provide a new unsaturated malonate substrate for the conjugate addition Both diastereomers of the product of the second 14-addition could be obtained in high diastereomeric ratio depending on the enantiomer of the ligand used

Recently Negishi and coworkers developed a Zr-catalyzed asymmetric carboalumination of alkenes the ZACA-reaction (Scheme 47)32 The stereoselectivity of the reaction (in general ca 80-90 ee) is not as high as in other state-of-the-art enantioselective transition metal catalyzed reactions However the amplification of the enantiomeric excess through multiple enantioselective reactions is elegantly utilised by separating the diastereomers of the product at a later stage

In other cases an enzymatic resolution of the enantiomerically enriched compounds provides optically pure products The combination of the enantioselective reaction and the resolution is far more effective than either method on its own This protocol has been applied in several natural product syntheses32a33 including both syn and the less common anti arrays eg compound 10 (Scheme 47) which was isolated from the cuticle of the cane beetle Antitrogus parvulus33a

In principle the iterative sequence needs a single step to introduce one methyl substituent providing an extended terminal olefin in each reaction

Chapter 4

110


(for example Scheme 47 reaction iii) However an alcohol functionality is needed to separate the diastereomers or perform the enzymatic resolution This prevents the continuous one-step introduction of the methyl substituents

Scheme 47 Zr-catalyzed asymmetric carboalumination of alkenes (ZACA-reaction) applied in the synthesis of hydrocarbon 10 i) 1 Me3Al 4 mol cat CH2Cl2 rt then O2 (81 6 1 dr before enzymatic purification) 2 Amano PS lipase vinyl acetate CH2Cl2 60 gt95 5 dr ii) 1 I2 PPh3 2) t-BuLi Et2O minus78 degC then ZnBr2 then vinyl bromide Pd(PPh3)4 iii) 1 Me3Al 3 mol ent-cat CH2Cl2 2 evaporation of Me3Al and CH2Cl2 then Zn(OTf)2 DMF 70 degC 3 Pd(DPEphos)Cl2 DIBAL-H vinyl bromide 70 iv) Me3Al 4 mol cat CH2Cl2 rt then O2 (80 4 1 dr before chromatographic purification) 45 gt98 2 dr

The enantioselective copper catalyzed conjugate addition of Grignard reagents to αβ-unsaturated thioesters5a8a discussed in chapter 2 allows for the iterative synthesis of deoxypropionate units also The reaction proceeds in excellent enantioselectivity and the resulting saturated thioester can be transformed readily in two steps to an extended αβ-unsaturated substrate for a consecutive 14-addition (Scheme 48) Both diastereomers of the product can be obtained in high diastereoselectivity depending on the enantiomer of the ligand used


111


Several natural product syntheses of compounds containing multiple syn deoxypropionate units have been performed using this protocol8a10a-c Although more steps are needed per iterative methyl introduction than with the ZACA-reaction the much higher stereoselectivity and yields provide for a higher overall yield For instance the pheromone lardolure (11) was obtained in 26 overall yield after 12 steps and the heptamethyl-branched phthioceranic acid (12) was prepared in 24 steps with a 4 overall yield

Scheme 48 Synthesis of deoxypropionate units via conjugate addition to thioesters lardolure (11) phthioceranic acid (12) i) MeMgBr 1 mol CuBrmiddotSMe2 L1 t-BuOMe minus75 degC 93 95 ee ii) PdC Et3SiH CH2Cl2 rt 92 iii) Ph3PCHCOSEt CH2Cl2 reflux 88 iv) MeMgBr 1 mol CuBrmiddotSMe2 L1 t-BuOMe minus75 degC 90 96 4 dr v) MeMgBr 1 mol CuBrmiddotSMe2 ent-L1 t-BuOMe minus75 degC 91 95 5 dr

A similar approach which makes use of 14-addition to oxoesters was reported recently34 The use of oxoesters allows the two steps needed to transform the conjugate addition product into an extended substrate to be performed in one pot

Chapter 4

112


414 Application of cross-metathesis to allylic alkylation products The approaches to the preparation of 15- and 13-dimethyl arrays

discussed in section 413 allow independent stereocontrol of the created stereocenters The intended catalytic protocol discussed at the beginning of section 41 (Scheme 41) should enable the asymmetric synthesis of vicinal dialkyl arrays with similar independent stereocontrol of the adjacent stereogenic centers The catalytic sequence will utilize a cross-metathesis reaction to transform the product of an enantioselective copper catalyzed allylic alkylation into a substrate for enantioselective 14-addition

There are precedents for the use of cross-metathesis to further functionalize the products of Cu-catalyzed asymmetric allylic alkylation For example cross-metathesis reactions with methyl vinyl ketone or acrylates providing γ-chiral αβ-unsaturated carbonyl compounds have been reported35

Scheme 49 Total synthesis of elenic acid through copper catalyzed asymmetric allylic alkylation and cross-metathesis i) 35 mol HG-2 THF 40 degC 40 3 1 EZ ii) BBr3 CH2Cl2 minus78 degC rarr rt 85

Hoveyda and coworkers applied cross-metathesis to the total synthesis of elenic acid36 The natural product was obtained in only two steps after the allylic alkylation (Scheme 49) however the cross-metathesis partner had to be synthesized in six steps As a significant decrease in the enantiomeric


113


excess was not observed the utility of the combination of these two reaction in total synthesis was demonstrated clearly although the catalyst loading (35 mol) and EZ ratio (31) leave room for improvement

The transformation via cross-metathesis of a product of asymmetric allylic alkylation to another substrate for allylic alkylation was reported by the group of Hoveyda also (Scheme 410)37 The product could be converted to a new substrate in three steps Asymmetric allylic alkylation of this substrate with dimethylzinc provided the anti-product containing a vicinal dialkyl motif efficiently However the substrate was almost unreactive to allylic alkylation with the enantiomer of the ligand Although this implies that the racemic substrate might be eligible for kinetic resolution using this reaction ideally it would be possible to prepare both diastereomers in high selectivity The proposed protocol of enantioselective copper catalyzed allylic alkylation cross-metathesis and asymmetric copper catalyzed 14-addition (Scheme 41 vide supra) should provide access to all stereoisomers of these relevant vicinal dialkyl synthons

Scheme 410 Allylic alkylation of a chiral substrate obtained through Cu-AAA and cross-metathesis i) 1 cis-14-diacetoxybut-2-ene 10 mol HG-2 CH2Cl2 rt 2 K2CO3 MeOH 3 ClPO(OEt)2 DMAP Et3N 44 in three steps ii) 5 mol (CuOTf)2middotC6H6 10 mol L Me2Zn THF minus15 degC 91 gt98 de iii) 5 mol (CuOTf)2middotC6H6 10 mol ent-L Me2Zn THF minus15 degC 10-15 conv lt5 de

Chapter 4

114



421 Synthesis of chiral substrates for conjugate addition through allylic alkylation and metathesis

The Cu-catalyzed allylic alkylations were performed as discussed in chapter 2 with cinnamyl bromide 13 as a model substrate and MeMgBr or EtMgBr as Grignard reagents The reactions were performed in CH2Cl2 at minus75 degC in the presence of a copper catalyst which was preformed in situ from CuBrmiddotSMe2 and ligand L2 Taniaphos (Figure 41 vide supra)4c The enantioselective allylic alkylation is high yielding and gives the chiral product with excellent enantioselectivity (Table 41) In the AAA with methylmagnesium bromide the regioselectivity is high (gt97 3) However the AAA with ethyl magnesium bromide provided a mixture of SN2rsquo and SN2 products 14 and 15 in a ratio of 80 20 Since 14 and 15 were inseparable by standard column chromatography the cross-metathesis reactions were performed on the mixture Consequently for R = Et the cross-metathesis reaction leads to both products 17 and 18 from 14 and 15 respectively (Scheme 411)

Scheme 411 Formation of distinct products in copper catalyzed asymmetric allylic alkylation (AAA) and subsequent cross-metathesis (CM)


115


Our previous reports on the enantioselective Cu-catalyzed conjugate addition have focused on three types of acyclic substrates αβ-unsaturated esters ketones and thioesters Therefore three different electron deficient olefins 16 (Scheme 411) were used in the cross-metathesis reactions methyl acrylate 16a methyl vinyl ketone 16b and S-ethyl thioacrylate 16c The results of the two-step syntheses of 17a-e are summarized in Table 41

Table 41 Synthesis of 17a-e through allylic alkylation followed by cross-metathesisa

entry

R

16

Ru-cat(Figure 43)

17

yieldb

(eec)

17 18d

1 Me 16a (Y = OMe) HG-2 17a 66 nd gt97 3

2 Me 16b (Y = Me) HG-2 17b 80 (99) gt97 3

3e Me 16c (Y = SEt) HG-2 17c 74 (97) gt97 3

4 Et 16a (Y = OMe) HG-2 17d 67g (98) 80 20

5f Et 16a (Y = OMe) G-2 17d 49g (98) 90 10

6e Et 16c (Y = SEt) HG-2 17e 67g (97) 80 20 a Reaction conditions 1 13 (10 equiv) CuBrmiddotSMe2 (10 mol) (+)-(RRFc)-L2 (12 mol) RMgBr (12 equiv) CH2Cl2 minus75 degC 2 14 + 15 (10 equiv) 16 (5 equiv) Ru-cat (2 mol) CH2Cl2 rt b Isolated yield of 17 after two steps c Determined by chiral HPLC d Determined by 1H-NMR spectroscopy e 2 equiv of 16 used 10 mol catalyst added in two portions of 50 mol f 15 mol catalyst used g Calculated yield of 17 from 13 after two steps based on overall yield and ratio of 17 and 18

Compounds 17a and 17b an αβ-unsaturated ester and ketone respectively with R = Me could be obtained readily (Table 41 entries 1

Chapter 4

116


and 2) The reactions were performed in CH2Cl2 at room temperature using five equivalents of olefin 16 and 2 mol of the Hoveyda-Grubbs 2nd generation catalyst (HG-2 Figure 43) Compound 17c was obtained by a similar route using two equivalents of 16c38 and two portions of 5 mol catalyst (Table 41 entry 3)

Figure 43 Ruthenium based metathesis catalysts Grubbs 2nd generation (G-2) and Hoveyda-Grubbs 2nd generation (HG-2)

Despite the different reactivities of terminal and internal olefins under the aforementioned conditions the SN2-product 15 was transformed into the cinnamic acid derivative 18 quantitatively This gave in the case of 17d and 17e where R = Et a mixture of 17 and 18 (80 20) which was not separable (Table 41 entries 4 and 6)39 The reaction with the Grubbs 2nd generation catalyst (G-2 Figure 43) was more selective (90 10) however this decreased the total yield of 17 (Table 41 entry 5)

422 Asymmetric conjugate addition reactions with Grignard reagents on the chiral metathesis products

4221 Conjugate addition to chiral αβ-unsaturated esters The results of the subsequent asymmetric 14-addition reactions with

EtMgBr on the αβ-unsaturated esters 17a and 17d are summarized in Table 42 Stereoselective synthesis of a 12-methylethyl motif was accomplished readily Thus depending on the enantiomer of ligand L3 used either anti-19a or syn-19a was obtained in good yield and diastereoselectivity from substrate 17a (Table 42 entries 1 and 2) The synthesis of anti-19b which has a diethyl motif proceeded in good yield and diastereoselectivity from


117


17d (Table 42 entry 3)39 The reaction using the ligand (SR)-L3 was slower however providing syn-19b in 30 yield albeit with excellent diastereoselectivity (Table 42 entry 4) Introduction of a methyl substituent at the β-position with methyl Grignard reagent was not possible with this catalyst system due to the insufficient reactivity of oxo esters40

Table 42 Asymmetric conjugate additions with Grignard reagents to αβ-unsaturated esters 17a and 17da

entry R 17 ligand yieldb anti sync eec

1 Me 17a (RS)-L3 anti-19a 81 99 1 gt995

2 Me 17a (SR)-L3 syn-19a 84 4 96 gt995

3 Et 17d (RS)-L3 anti-19b 77 91 9 gt995

4 Et 17d (SR)-L3 syn-19b 30d 4 96 99 a Reaction conditions 17 (10 equiv) CuBrmiddotSMe2 (50 mol) L3 (60 mol) EtMgBr (50 equiv) CH2Cl2 minus78 degC 18 h b Isolated yield of the mixture of diastereomers c Determined by chiral GC or HPLC d Conv = 5041

4222 Conjugate addition to chiral αβ-unsaturated ketones The results of the asymmetric 14-addition to the αβ-unsaturated ketone

17b are summarized in Table 43 Enones are more active Michael acceptors than esters which allows for the introduction of a second methyl group through 14-addition with this catalyst system Thus stereoselective synthesis of a 12-dimethyl motif was accomplished through 14-addition with MeMgBr (Table 43 entries 1 and 2) The product anti-20a could be obtained in high yield and excellent diastereoselectivity and enantiomeric excess in contrast to the syn-product 20a which was obtained in lower

Chapter 4

118


yield and with reduced diastereoselectivity Interestingly the enantiomeric excess of the syn-product 20a was found to be 66 which implies that racemization of the substrate occurs under the reaction conditions When the reaction was performed with EtMgBr the same trend was observed (Table 43 entries 3 and 4) although substantial racemization was not observed42

Table 43 Asymmetric conjugate additions with Grignard reagents to αβ-unsaturated ketones 17ba

entry RrsquoMgBr ligand yieldb anti sync eec

1 MeMgBr (RS)-L1 anti-20a 73 98 2 gt 995

2 MeMgBr (SR)-L1 syn-20a 46 14 86 66

3 EtMgBr (RS)-L1 anti-20b 89 92 8 gt 995

4 EtMgBr (SR)-L1 syn-20b 64 40 60 97 a Reaction conditions 17b (10 equiv) CuBrmiddotL1 (70 mol) RrsquoMgBr (13 equiv) t-BuOMe minus78 degC 18 h b Isolated yield of the mixture of diastereomers c Determined by chiral GC or HPLC

4223 Conjugate addition to chiral αβ-unsaturated thioesters Compounds containing an αβ-unsaturated thioester are more reactive

electrophiles than their corresponding oxo esters Nevertheless their synthetic versatility is similar In our group two catalysts that perform the 14-addition on thioesters effectively and selectively Cu JosiPhos L1 and Cu Tol-BINAP L4 were reported previously The results of the 14-additions are summarized in Table 44 Conjugate addition with methyl Grignard to the methyl containing substrate 17c gave product 21a with a 12-dimethyl motif The performance of Tol-BINAP L4 was better in all


119


aspects using MeMgBr (Table 44 entries 1-4) Although the use of L1 provided anti-21a in good yield and excellent stereoselectivity L4 provided the compound in higher yield and equally excellent selectivity The other diastereomer syn-21a could be obtained in good yield and excellent stereoselectivity with ligand L4 whereas a catalyst system with ligand L1 was significantly less active and selective (Table 44 entry 4 vs entry 2)

Table 44 Asymmetric conjugate additions with Grignard reagents to αβ-unsaturated thioesters 17c and 17ea

entry R RrsquoMgBr ligand yieldb (anti syn)c eec

1 Me 17c MeMgBr (RS)-L1 anti-21a 59 99 1 99

2d Me 17c MeMgBr (SR)-L1 syn-21a 17 61 39 nd

3 Me 17c MeMgBr (R)-L4 anti-21a 96 995 05 99

4 Me 17c MeMgBr (S)-L4 syn-21a 82 5 95 gt995

5 Me 17c EtMgBr (R)-L4 anti-21b 91 98 2 94

6 Me 17c EtMgBr (S)-L4 syn-21b 58 64 36 gt995

7d Et 17e MeMgBr (RS)-L1 anti-21c 67 98 2 gt995

8d Et 17e MeMgBr (SR)-L1 syn-21c 6c 45 55 nd

9 Et 17e MeMgBr (R)-L4 anti-21c lt5c nd nd

10 Et 17e MeMgBr (S)-L4 syn-21c 71 12 88 gt995 a Reaction conditions 17 (10 equiv) CuBrmiddotL1 (60 mol) or CuI (30 mol) and L4 (33 mol) RrsquoMgBr (30-40 equiv) t-BuOMe minus75 degC 18 h b Isolated yield of the mixture of diastereomers c Determined by chiral GC or HPLC d Reaction time 40 h

Chapter 4

120


The anti-diastereomer of product 21b could be obtained with excellent selectivity using ligand L4 and EtMgBr However product syn-21b could not be obtained selectively by this route (Table 44 entries 5 and 6) Curiously stereoselective synthesis of anti-21c which contains a 12-ethylmethyl motif could be accomplished with ligand L1 while the use of L4 was necessary to obtain the other diastereomer syn-21c39 Hence the two ligand systems are complementary in this case (Table 44 entries 7-10)

423 Total synthesis of the ant pheromones (minus)-lasiol and (+)-faranal As discussed in section 411 in natural products the 12-dimethyl motif

is the most common of the vicinal dialkyl arrays It is present for example in the two ant pheromones lasiol (22) and faranal (3) (Scheme 412) Lasiol is a volatile compound which was isolated from the mandibular glands of male Lasius meridionalis ants43 Shortly after its discovery and racemic synthesis by Lloyd et al43 both enantiomers of the pheromone lasiol were synthesized by Kuwahara et al from the chiral pool44 and by Mori and co-workers using a non-catalytic desymmetrization similar to that in Scheme 45 mediated by a chiral base45 Since then several total syntheses and formal syntheses have followed46

Scheme 412 Retrosynthetic analysis of the ant pheromones lasiol (22) and faranal (3) to a common intermediate 23

Faranal is the trail pheromone of Monomorium pharaonis the pharaohrsquos ant a common pest in households food storage facilities and hospitals47 The absolute configuration of natural faranal was established through biological tests with diastereomeric mixtures of faranal where one of the


121


stereogenic centers was set using an enzymatic condensation47a Some stereoselective but racemic syntheses have been published48 The first truly asymmetric total synthesis of natural (+)-faranal (3) involved the resolution of a racemate49 and was followed by other routes that made use of the chiral pool50 chiral bases51 or enzymatic desymmetrization52

Importantly in both natural products the vicinal 12-dimethyl motif has an anti configuration Retrosynthetic analysis (Scheme 412) shows that they can be derived from a common intermediate 23 which can be obtained in turn through the allylic alkylation cross-metathesis conjugate addition protocol

Scheme 413 Synthesis of common intermediate 23 via Cu-catalyzed enantioselective allylic alkylation cross-metathesis and asymmetric conjugate addition

Allylic alkylation of compound 2653 with MeMgBr using the preformed complex CuBrmiddot(RRFc)-L2 as the catalyst gave product 27 in excellent yield regioselectivity and enantioselectivity (Scheme 413) Cross-metathesis with thioacrylate 16c gave αβ-unsaturated thioester 28 in good yield together

Chapter 4

122


with a small percentage of the dimer 29 (ratio = 94 6)54 Conjugate addition to 28 with MeMgBr and (R)-L4 as the ligand gave anti-23 in good yield and excellent diastereoselectivity The other diastereomer syn-23 could be obtained in high diastereoselectivity by using ligand (S)-L4 instead In both cases the opposite enantiomer of the major diastereomer could not be detected which highlights the potential of this protocol in synthesis

(minus)-Lasiol (22) which has the (2S3S) absolute configuration55 was synthesized from the common intermediate anti-23 The thioester was first reduced to aldehyde 30 using DIBAL-H (Scheme 414) A Wittig reaction with isopropyltriphenylphosphonium iodide was performed to obtain benzyl ether 31 followed by quantitative deprotection of the alcohol using a dissolving metal reduction Thus (minus)-lasiol (22) was synthesized in six steps from 26 in an overall yield of 60

Scheme 414 Synthesis of (minus)-lasiol (22) from common intermediate compound anti-23 through reduction Wittig reaction and deprotection of the benzyl ether

The synthesis of (+)-faranal (3) from compound anti-23 started with its reduction to aldehyde 30 (Scheme 414 vide supra) The aldehyde was subsequently protected as its acetal with ethylene glycol to give dioxolane 32 (Scheme 415) The benzyl ether was cleaved through hydrogenolysis with Pd(OH)2 to furnish alcohol 3356 which was converted to the alkyl iodide 25 using iodine triphenylphosphine and imidazole Compound 25 was converted in situ to the corresponding alkyl zinc bromide with tBuLi and ZnBr2 and used in a Negishi-coupling reaction57 with alkenyl iodide 24 a known compound which was synthesized according to the methods of Baker et al48b and Mori et al51b and catalytic [Pd(dppf)Cl2] to obtain


123


faranal precursor 34 Hydrolysis of the acetal in THF and water under dilute conditions completed the synthesis of (+)-faranal (3) in nine steps and an overall yield of 25 from the achiral precursor 26

Scheme 415 Synthesis of (+)-faranal (3) from precursor 30 via protection of the aldehyde hydrogenolysis iodination and a Negishi coupling to 24 followed by deprotection

Chapter 4

124


43 Conclusions In summary a new protocol for the stereoselective synthesis of vicinal

dialkyl arrays is reported The protocol which combines enantioselective allylic alkylation cross-metathesis and enantioselective 14-addition allows for the preparation of both of the diastereomers in enantiopure form with judicious choice of the ligands in the copper catalyzed reactions The anti-diastereomer of the products was formed more easily than the syn-product in most cases but on many occasions it was possible to form either diastereomer in high diastereoselectivity and excellent enantioselectivity This demonstrates the high catalyst control versus substrate control in the conjugate addition to these γ-chiral αβ-unsaturated carbonyl compounds

The protocols utility was demonstrated through the total syntheses of the ant pheromones (minus)-lasiol and (+)-faranal in six and nine steps respectively from an achiral precursor The products were obtained with excellent diastereomeric and enantiomeric purity and high overall yields These approaches comprise the shortest highest yielding and most selective catalytic asymmetric total syntheses of these pheromones reported to date and are very competitive with existing methods that employ the chiral pool chiral auxiliaries or other methods based on stoichiometric chiral reagents


125


44 Experimental Part General Remarks For general remarks see the experimental part of previous chapters In addition the following remarks should be taken into account

Ligand L4 and metathesis catalysts G-2 and HG-2 were purchased from Aldrich and used as received Methyl acrylate 16a and methyl vinyl ketone 16b were purchased from Aldrich and distilled under reduced pressure prior to their use Compounds 16c38 and 2448b51b were prepared according to literature procedures Et2O and THF were distilled from Nabenzophenone and CH2Cl2 t-BuOMe and DMF (under reduced pressure) were distilled from CaH2 Other solvents and reagents were used as received Allylic alkylations metathesis reactions and conjugate additions were conducted under a nitrogen atmosphere using standard Schlenk techniques

Diastereomeric mixtures of racemic products for GC and HPLC reference were obtained by conjugate addition on the racemic metathesis products with the corresponding Grignard reagent (13 equiv) at 0 degC in Et2O in the presence of CuI (13 equiv) The products 17b 22 3 28 and 35 have been described previously (see appropriate references in the following pages) For experimental procedures of copper catalyzed allylic alkylations see preceding chapters 14a (R = Me) 14b (R = Et) in chapter 2 and 27 in chapter 3

(minus)-(SE)-methyl 4-phenylpent-2-enoate (17a)

In a Schlenk tube equipped with septum and stirring bar CuBrmiddotSMe2 (150 μmol 308 mg) and ligand L2 (180 μmol 124 mg) were dissolved in CH2Cl2 (30 mL) and stirred under argon at room

temperature for 10 min The mixture was cooled to ndash75 oC and MeMgBr (30 M solution in Et2O 173 mmol 0575 ml) was added dropwise Following this cinnamyl bromide (296 mg 150 mmol) was added dropwise over 15 min via a syringe pump Once the addition was complete the resulting mixture was stirred at ndash75 oC for 4 h The reaction was quenched by addition of MeOH (05 mL) and the mixture was allowed to reach rt Aqueous NH4Cl solution (1M 2 mL) was added to the mixture

OMe

O

Chapter 4

126


The organic layer was separated and the resulting aqueous layer was extracted with Et2O (05 mL 3x) The combined organic layers were dried and concentrated to a yellow oil which was dissolved in CH2Cl2 (3 mL) in a dry Schlenk tube under argon Methyl acrylate (645 mg 75 mmol) and Hoveyda-Grubbs 2nd generation catalyst (18 mg 003 mmol) were added sequentially producing a light green solution which was stirred for 36 h at rt The mixture was then concentrated in vacuo to a dark brown oil Purification of this residue by silica gel chromatography (SiO2 2 98 to 5 95 Et2On-pentane) afforded 17a as a colorless oil [66 yield [α]D = minus20 (c 03 CHCl3)] 1H-NMR δ 729-725 (m 2H) 721-714 (m 3H) 707 (dd J = 157 and 67 Hz 1H) 577 (dd J = 157 and 15 Hz 1H) 367 (s 3H) 361-354 (m 1H) 138 (d J = 71 Hz 3H) 13C-NMR δ 1671 1529 1432 1286 1273 1267 1196 514 420 201 MS (EI) mz 190 (M+ 40) 159 (18) 131 (100) 91 (22) 51 (13) HRMS Calcd for C12H14O2 1900994 found 1900995

(minus)-(SE)-5-phenyl-hex-3-en-2-one (17b)58

A solution of terminal olefin 14a (050 mmol) in dry CH2Cl2 (20 ml) was stirred under a N2-atmosphere at room temperature Methylvinylketone 16b (25 mmol) was added via syringe in one portion followed by

Hoveyda-Grubbs 2nd generation catalyst (63 mg 2 mol) The mixture was stirred overnight After completion of the reaction the solvent was evaporated and the crude mixture was subjected to flash chromatography (silica gel n-pentane ndash n-pentaneethyl acetate 99505 vv) affording product 17b Reaction time 20 h [90 yield gt995 ee [α]D = minus206 (c 10 CHCl3)] Rf = 050 (n-pentaneEtOAc 91 vv) 1H NMR (400 MHz CDCl3) δ 143 (d J = 68 Hz 3H) 224 (s 3H) 362-365 (m 1H) 607 (dd J = 160 and 12 Hz 1H) 692 (dd J = 160 and 68 Hz 1H) 717-735 (m 5H) 13C NMR (50 MHz CDCl3) δ 204 272 425 1271 1276 1290 1299 1435 1519 1992 MS (EI) mz 174 (M+ 56) 131 (100) 91 (30) HRMS Calcd for C12H14O 1741045 found 1741043 Enantiomeric excess was determined by chiral HPLC analysis (Chiralcel OB-H n-heptanei-PrOH 982 vv) retention times (min) 368 (R) and 409 (S)

O


127


(minus)-Methyl (SE)-4-phenyl-hex-2-enoate (17d)

The same procedure as 17b although with olefins 14b and 16a instead Reaction time 17 h Reaction afforded a 8020 mixture of 17d and 18 [95 yield 98 ee [α]D = minus48 (c 027 CHCl3)] Rf =

067 (n-pentaneEtOAc 91 vv) 1H NMR (400 MHz CDCl3) δ 088 (t J = 72 Hz 3H) 176-185 (m 2H) 326-332 (m 1H) 371 (s 3H) 579 (dd J = 160 and 12 Hz 1H) 708 (dd J = 160 and 80 Hz 1H) 707-732 (m 5H) 13C NMR (50 MHz CDCl3) δ 120 279 502 514 1204 1267 1277 1286 1421 1520 1670 MS (EI) mz 204 (M+ 8) 145 (37) 115 (100) HRMS Calcd for C13H16O2 2041150 found 2041162 Enantiomeric excess was determined by chiral HPLC analysis (Whelk n-heptanei-PrOH 99505 vv) retention times (min) 201 (S) and 216 (R)

(minus)-S-Ethyl (SE)-4-phenyl-pent-2-enethioate (17c)

A solution of terminal olefin 14a (050 mmol) in dry CH2Cl2 (20 ml) was stirred under a N2-atmosphere at room temperature Ethyl thioacrylate (16c) (10 mmol 116 μl) was added via syringe in one portion

followed by Hoveyda-Grubbs 2nd generation catalyst (5 mol 160 mg) After 8 h another portion of Hoveyda-Grubbs 2nd generation catalyst (5 mol 160 mg) was added Upon complete conversion of 14a (40 h) the solvent was evaporated and the crude mixture was subjected to flash chromatography (silica gel n-pentane ndash n-pentaneethyl acetate 99505 vv) affording the product 17c [83 yield 97 ee [α]D = minus70 (c 10 CHCl3)] Rf = 048 (n-pentaneEt2O 955 vv) 1H NMR (400 MHz CDCl3) δ 127 (t J = 72 Hz 3H) 143 (d J = 76 Hz 3H) 293 (q J = 72 Hz 2H) 356-362 (m 1H) 607 (dd J = 156 and 16 Hz 1H) 703 (dd J = 156 and 68 Hz 1H) 720-733 (m 5H) 13C NMR (50 MHz CDCl3) δ 148 202 231 420 1268 1274 1287 1431 1484 1902 MS (EI) mz 220 (M+ 24) 159 (100) 115 (37) HRMS Calcd for C13H16OS 2200922 found 2200921 Enantiomeric excess was determined by chiral HPLC analysis (Chiracel OD-H n-heptanei-PrOH 99505 vv) retention times (min) 185 (S) and 212 (R)

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SEt

O

Chapter 4

128


(minus)-S-Ethyl (S)-4-phenyl-hex-2-enethioate (17e)

As for 17c although with olefin 14b instead of 14a Reaction time 23 h Reaction afforded a 8020 mixture of 17e and 18 [95 yield 97 ee [α]D = minus216 (c 10 CHCl3)] Rf = 073 (n-pentaneEtOAc 91 vv) 1H NMR (300 MHz CDCl3) δ 088 (t J =

75 Hz 3H) 126 (t J = 72 Hz 3H) 175-185 (m 2H) 292 (q J = 72 Hz 2H) 322-330 (m 1H) 605 (d J = 153 Hz 1H) 698 (dd J = 153 and 81 Hz 1H) 714-740 (m 5H) 13C NMR (50 MHz CDCl3) δ 121 148 231 280 502 1268 1278 1280 1287 1419 1475 1902 MS (EI) mz 234 (M+ 25) 173 (100) 145 (46) 115 (32) HRMS Calcd for C14H18OS 2341078 found 2341087 Enantiomeric excess was determined by chiral HPLC analysis (Chiracel OJ-H n-heptanei-PrOH 955 vv) retention times (min) 105 (S) and 124 (R)

(+)-(3S4S)-methyl 3-ethyl-4-phenylpentanoate (anti-19a)

In a Schlenk tube CuBrmiddotSMe2 (80 μmol 162 mg) and ligand (RS)-L3 (94 μmol 560 mg) were dissolved in CH2Cl2 (15 mL) and stirred under argon at room temperature for 10 min The mixture

was cooled to -75 ordmC and EtMgBr (30 M in Et2O 078 mmol) was added dropwise After stirring for 5 min at that temperature a solution of 17a (30 mg 016 mmol) in CH2Cl2 (025 mL) was added dropwise over 10 min After stirring at ndash75 oC for 22 h MeOH (025 mL) and aq NH4Cl (1M 2 mL) were added sequentially and the mixture was warmed to rt After extraction with Et2O (05 mL 3x) the combined organic layers were dried and concentrated to a yellow oil which was purified by flash chromatography (SiO2 2 99 Et2On-pentane) to yield anti-19a as a colourless oil [81 yield 98 de gt995 ee (major diastereomer) [α]D = +25 (c 02 CHCl3)] 1H-NMR δ 726-712 (m 5H) 357 (s 3H) 282-273 (m 1H) 230-215 (m 2H) 208-197 (m 1H) 138-127 (m 1H) 117 (d J = 71 Hz 3H) 114-106 (m 1H) 081 (t J = 74 Hz 3H) 13C-NMR δ 1741 1456 1282 1277 1260 514 428 414 353 244 171 111 MS (EI) mz 220 (M+ 20) 189 (11) 146 (43) 105 (100) 57 (21) HRMS Calcd for C14H20O2 2201463 found 2201457 Diastereoselectivity was determined using a Chiraldex G-TA column (30 m x 025 mm) 100 ordmC

SEt

O

OMe

O


129


isothermic retention times (min) 596 (minor 3R4S and 3S4R) and 624 (major 3S4S) Alternatively the diastereoselectivity was determined by 1H-NMR spectroscopy by integration of the signals at 35 ppm corresponding to the methyl ester group Enantiomeric excess was determined using a Chiraldex B-PM column (30m x 025mm) 85 degC isothermic retention times (min) 2405 (3S4S) 2455 (3R4R)

(+)-(3R4S)-methyl 3-ethyl-4-phenylpentanoate (syn-19a) As for anti-19a however using (SR)-L3 instead of (RS)-L3 [84 yield 92 de gt995 ee (major diastereomer) [α]D = +6 (c 06 CHCl3)] 1H-NMR δ 724-720 (m 2H) 714-711 (m 3H) 353 (s

3H) 271-267 (m 1H) 216-201 (m 3H) 144-129 (m 2H) 119 (d J = 72 Hz 3H) 083 (t J = 74 Hz 3H) 13C-NMR δ 1740 1456 1282 1278 1261 513 425 418 363 231 182 104 MS (EI) mz 220 (M+ 18) 189 (12) 146 (58) 105 (100) HRMS Calcd for C14H20O2 2201463 found 2201462 Diastereoselectivity was determined using a Chiraldex G-TA column (30 m x 025 mm) 100 ordmC retention times (min) 596 (major 3R4S) 624 (minor 3S4S) and 633 (minor 3R4R) Alternatively the de was determined by 1H-NMR spectroscopy by integration of the signals at 357 and 353 ppm corresponding to the methyl ester groups Enantiomeric excess was determined using a CP Chiralsil Dex CB column (25m x 025mm) initial T = 70 degC gradient 3 degC min to 110 degC 110 degC isothermic retention times (min) 785 (3S4R) 803 (3R4S)

(+)-Methyl (3S4S)-3-ethyl-4-phenylhexanoate (anti-19b)

The same procedure as for anti-19a however using 17d (contaminated with 18) instead of 17a afforded a mixture of syn-19b and anti-19b and the product of 18 which could be separated by column chromatography [77 yield 82 de gt995 ee

(major diastereomer) [α]D = +94 (c 10 CHCl3)] Rf = 049 (n-pentaneEt2O 955 vv) 1H NMR (400 MHz CDCl3) δ 073 (t J = 72 Hz 3H) 084 (t J = 72 Hz 3H) 098-108 (m 1H) 135-145 (m 1H) 159-176 (m 2H) 206-210 (m 1H) 228-231 (m 2H) 247-253 (m 1H) 367 (s 3H) 712-730 (m 5H) 13C NMR (50 MHz CDCl3) δ 111 125 238 248 359 419 502 515 1260 1280 1287 1431 1742 MS (EI) mz

OMe

O

OMe

O

Chapter 4

130


234 (M+ 34) 160 (78) 119 (100) 91 (98) HRMS Calcd for C15H22O2 2341620 found 2341628 Diastereomeric ratio was determined by chiral GC analysis CP Chiralsil Dex CB (25 m x 025 mm) initial temp 75 ordmC gradient 3 ordmCmin retention times (min) 298 (syn) and 300 (anti) Alternatively the dr was determined by 1H NMR spectroscopy by comparison of the OCH3 signals (366 ppm for anti 358 ppm for syn) Enantiomeric excess was determined by chiral HPLC analysis (Chiralcel OJ-H n-heptanei-PrOH 991 vv 40 degC) retention times (min) 111 (3S4S) and 117 (3R4R)

(+)-Methyl (3R4S)-3-ethyl-4-phenylhexanoate (syn-19b)

The same procedure as for anti-19a however using 17d (contaminated with 18) instead of 17a and (SR)-L3 instead of (RS)-L3 afforded a mixture of syn-19b and anti-19b and the product of 18 which could be separated by column chromatography

[30 yield 92 de 99 ee (major diastereomer) [α]D = +72 (c 05 CHCl3)] Rf = 049 (n-pentaneEt2O 955 vv) 1H NMR (400 MHz CDCl3) δ 072 (t J = 72 Hz 3H) 090 (t J = 72 Hz 3H) 138-145 (m 2H) 153-162 (m 1H) 176-182 (m 1H) 201 (dd J = 148 and 84 Hz 1H) 208-218 (m 1H) 221 (dd 1H J = 148 and 48 Hz) 245-253 (m 1H) 358 (s 3H) 711-731 (m 5H) 13C NMR (50 MHz CDCl3) δ 104 124 238 253 362 413 497 513 1261 1281 1287 1431 1742 MS (EI) mz 234 (M+ 34) 160 (63) 119 (90) 91 (100) HRMS Calcd for C15H22O2 2341620 found 2341628 Diastereoisomeric ratio was determined by chiral GC analysis CP Chiralsil Dex CB (25 m x 025 mm) initial temp 75 ordmC gradient 3 ordmCmin retention times (min) 298 (syn) and 300 (anti) Alternatively the dr was determined by 1H NMR spectroscopy by comparison of the OCH3 signals (366 ppm for anti 358 ppm for syn) Enantiomeric excess was determined by chiral HPLC analysis (Chiralcel OJ-H n-heptanei-PrOH 991 vv 40 degC) retention times (min) 117 (3R4S) and 126 (3S4R)

(+)-(4S5S)-4-methyl-5-phenylhexan-2-one (anti-20a)

In a Schlenk tube (RS)-L1 (75 μmol 554 mg) was dissolved in t-BuOMe (10 mL) and stirred under a N2-atmosphere at room temperature for 10 min The

OMe

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O


131


mixture was cooled to minus75 ordmC and MeMgBr (015 mmol 30 M solution in Et2O) was added dropwise After stirring for 5 min at that temperature a solution of 17b (011 mmol 20 mg) in dry t-BuOMe (05 ml) was added dropwise over 10 min After 16 h methanol (05 ml) was added and the mixture was allowed to reach rt Aqueous NH4Cl (2 ml) was added and the biphasic system was stirred for 10 min The organic layer was separated and the aqueous layer was extracted with Et2O (2 x 3 ml) The combined organic layers were dried (MgSO4) and the solvent was evaporated Flash chromatography (silica gel n-pentane minus n-pentaneEt2O 99505 vv) afforded a mixure of syn-20a and anti-20a [73 yield 96 de gt995 ee (major diastereomer) [α]D = +125 (c 10 CHCl3)] Rf = 052 (n-pentaneEtOAc 91 vv) 1H NMR (300 MHz CDCl3) δ 079 (d J = 63 Hz 3H) 127 (d J = 69 Hz 3H) 213 (s 3H) 209-234 (m 2H) 247-253 (m 1H) 260-270 (m 1H) 715-732 (m 5H) 13C NMR (50 MHz CDCl3) δ 176 181 305 352 445 482 1260 1279 1281 1451 2089 MS (EI) mz 190 (M+ 8) 132 (100) 105 (86) HRMS Calcd for C13H18O 1901358 found 1901352 Diastereoisomeric ratio and enantiomeric excess were determined by chiral GC analysis CP Chiralsil Dex CB (25 m x 025 mm) initial temp 75 ordmC gradient 3 ordmCmin retention times (min) 264 (syn) and 258 (4S5S) 261 (4R5R) Alternatively the dr was determined by 1H NMR spectroscopy by comparison of the COCH3 signals (213 ppm for anti 200 ppm for syn)

(+)-(4R5S)-4-methyl-5-phenylhexan-2-one (syn-20a)

The same procedure as for anti-20a however using (SR)-L1 instead of (RS)-L1 Reaction time 18 h The reaction afforded a mixture of syn and anti isomers [46 yield 72 de 66 ee (major diastereomer) [α]D

= +47 (c 03 CHCl3 84 ee 92 de)59] Rf = 058 (n-pentaneEtOAc 91 vv) 1H NMR (300 MHz CDCl3) δ 094 (d J = 63 Hz 3H) 125 (d J = 69 Hz 3H) 200 (s 3H) 209-234 (m 3H) 245-258 (m 1H) 715-732 (m 5H) 13C NMR (50 MHz CDCl3) δ 174 185 304 355 451 494 1261 1276 1283 1462 2090 MS (EI) mz 190 (M+ 8) 149 (35) 132 (100) 105 (75) HRMS Calcd for C13H18O 1901358 found 1901349 Diastereoisomeric ratio was determined by chiral GC analysis CP Chiralsil Dex CB (25 m x 025 mm) initial temp 75 ordmC gradient 3 ordmCmin retention times (min) 264 (syn) and 258 (4S5S) 261 (4R5R) Alternatively the dr

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was determined by 1H NMR spectroscopy by comparison of the COCH3 signals (213 ppm for anti 200 ppm for syn) Enantiomeric excess was determined by chiral HPLC analysis (Chiralcel OJ-H n-heptanei-PrOH 991 vv 40 degC) retention times (min) 208 (4S5R) and 224 (4R5S)

(+)-(4S5S)-4-ethyl-5-phenylhexan-2-one (anti-20b)

The same procedure as for anti-20a however using EtMgBr instead of MeMgBr Reaction time 16 h The reaction afforded a mixture of syn and anti isomers [89 yield 84 de gt995 ee (major diastereomer)

[α]D = +84 (c 09 CHCl3)] Rf = 063 (n-pentaneEtOAc 91 vv) 1H NMR (400 MHz CDCl3) δ 085 (t J = 72 Hz 3H) 118 (d J = 72 Hz 3H) 110-140 (m 2H) 206 (s 3H) 213-218 (m 1H) 226-239 (m 2H) 282-286 (m 1H) 717-731 (m 5H) 13C NMR (50 MHz CDCl3) δ 113 167 246 302 412 415 449 1260 1278 1281 1457 2090 MS (EI) mz 204 (M+ 8) 146 (100) 131 (40) 105 (88) HRMS Calcd for C14H20O 2041514 found 2041519 Diastereoisomeric ratio was determined by chiral GC analysis CP Chiralsil Dex CB (25 m x 025 mm) initial temp 75 ordmC gradient 3 ordmCmin retention times (min) 244 (syn) and 253 (anti) Alternatively the dr was determined by 1H NMR spectroscopy by comparison of the COCH3 signals (206 ppm for anti 196 ppm for syn) Enantiomeric excess was determined by chiral HPLC analysis (Chiralcel OD-H n-heptanei-PrOH 99505 vv 40degC) retention times (min) 153 (4S5S) and 144 (4R5R)

(+)-(4R5S)-4-ethyl-5-phenylhexan-2-one (syn-20b)

The same procedure as for anti-20a however using EtMgBr instead of MeMgBr and using (SR)-L1 instead of (RS)-L1 Reaction time 16 h The reaction afforded a mixture of syn and anti isomers [64 yield

20 de 97 ee (major diastereomer) [α]D = +52 (c 10 CHCl3)] Rf = 059 (n-pentaneEtOAc 91 vv) 1H NMR (400 MHz CDCl3) δ 086 (t J = 72 Hz 3H) 123 (d J = 72 Hz 3H) 110-140 (m 2H) 196 (s 3H) 216-220 (m 1H) 220-239 (m 2H) 264-288 (m 1H) 717-731 (m 5H) 13C NMR (50 MHz CDCl3) d 104 186 234 303 413 420 457 1261 1277 1283 1460 2090 MS (EI) mz 204 (M+ 8) 146 (100) 131 (42) 105 (75) HRMS Calcd for C14H20O 2041514 found 2041513

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Diastereoisomeric ratio was determined by chiral GC analysis CP Chiralsil Dex CB (25 m x 025 mm) initial temp 75 ordmC gradient 3 ordmCmin retention times (min) 244 (syn) and 253 (anti) Alternatively the dr was determined by 1H NMR spectroscopy by comparison of the COCH3 signals (206 ppm for anti 196 ppm for syn) Enantiomeric excess was determined on a derivative of syn-20b the tertiary alcohol (4R5S)-4-ethyl-2-methyl-5-phenylhexan-2-ol To a cooled (0 degC) solution of a sample of syn-20b in Et2O was added MeMgBr (ca 5 equiv) the reaction mixture was stirred at rt for 2 h quenched with sat aqueous NH4Cl and extracted with Et2O GC analysis was performed on a crude sample of the tertiary alcohol Chiraldex B-PM column (30m x 025mm) 85 degC isothermic retention times (min) 3304 (4S5R) 3363 (4S5S) 3437 (4R5R) 3540 (3R4S)

(+)-S-Ethyl (3S4S)-3-methyl-4-phenylpentanethioate (anti-21a)

In a Schlenk tube CuI (33 μmol 063 mg) and (R)-L4 (36 μmol 246 mg) were dissolved in CH2Cl2

(05 mL) and stirred under a N2-atmosphere at room temperature for 50 min The solvent was evaporated

and the residue was dissolved in t-BuOMe (12 ml) The mixture was cooled to minus75 ordmC and MeMgBr (30 M in Et2O 044 mmol) was added dropwise After stirring for 5 min at that temperature a solution of 17c (011 mmol) in CH2Cl2 (04 mL) was added dropwise over 10 min After stirring at ndash75 degC for 18 h MeOH (025 mL) and aq NH4Cl (1M 2 mL) were added sequentially and the mixture was warmed to rt After extraction with Et2O (05 mL 3x) the combined organic layers were dried and concentrated to a yellow oil which was subjected to flash chromatography (silica gel n-pentaneEt2O 9975025 vv) to afford syn-21a and anti-21a [96 yield 99 de 99 ee (major diastereomer) [α]D = +314 (c 035 CHCl3)] Rf = 050 (pentaneEt2O 955 vv) 1H NMR (400 MHz CDCl3) δ 080 (d J = 68 Hz 3H) 124 (t J = 72 Hz 3H) 127 (d J = 64 Hz 3H) 224-236 (m 2H) 262-268 (m 2H) 287 (q J = 76 Hz 2H) 715-731 (m 5H) 13C NMR (50 MHz CDCl3) δ 148 172 185 233 370 445 488 1261 1278 1281 1448 1993 MS (EI) mz 236 (M+ 12) 175 (100) 132 (35) 105 (66) 91 (30) HRMS Calcd for C14H20OS 2361235 found 2361244 Diastereoisomeric ratio was determined by chiral GC analysis Chiralsil G-TA (25 m x 025 mm) initial temp 75 ordmC gradient 3 ordmCmin retention times (min) 300 (syn) and 306 (anti) Alternatively the dr was determined

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by 1H NMR spectroscopy by comparison of the PhCHCH3 signals (doublet 080 ppm for anti 095 ppm for syn) Enantiomeric excess was determined by chiral HPLC analysis (Chiralcel OD-H n-heptanei-PrOH 991 vv 40degC) retention times (min) 123 (3S4S) and 135 (3R4R)

(+)-S-Ethyl (3R4S)-3-methyl-4-phenylpentanethioate (syn-21a)

The same procedure as for anti-21a however using (S)-L4 instead of (R)-L4 The reaction afforded a mixture of syn and anti isomers [82 yield 90 de gt995 ee (major diastereomer) [α]D = +230 (c

10 CHCl3)] Rf = 050 (n-pentaneEt2O 955 vv) 1H NMR (400 MHz CDCl3) δ 095 (d J = 68 Hz 3H) 121 (t J = 72 Hz 3H) 125 (d J = 64 Hz 3H) 216-233 (m 2H) 244-262 (m 2H) 283 (q J = 76 Hz 2H) 716-733 (m 5H) 13C NMR (50 MHz CDCl3) δ 148 166 180 232 373 447 496 1262 1276 1283 1457 1994 MS (EI) mz 236 (M+ 12) 175 (100) 132 (43) 105 (64) 91 (34) HRMS Calcd for C14H20OS 2361235 found 2361247 Diastereoisomeric ratio was determined by chiral GC analysis Chiralsil G-TA (25 m x 025 mm) initial temp 75 ordmC gradient 3 ordmCmin retention times (min) 300 (syn) and 306 (anti) Alternatively the dr was determined by 1H NMR spectroscopy by comparison of the PhCHCH3 signals (doublet 080 ppm for anti 095 ppm for syn) Enantiomeric excess was determined on a derivative of syn-21a the tertiary alcohol (4R5S)-24-dimethyl-5-phenylhexan-2-ol To a cooled (0degC) solution of a sample of syn-21a in Et2O was added MeMgBr (ca 5 equiv) the reaction mixture was heated at reflux for 2 h quenched with sat aqueous NH4Cl and extracted with Et2O GC analysis was performed on a crude sample of the tertiary alcohol CP Chiralsil Dex CB column (25m x 025mm) initial T = 70 degC gradient 3 degC min to 150 degC 150 degC isothermic retention times (min) 301 (4S5R) 304 (4R5S)

(+)-S-Ethyl (3S4S)-3-ethyl-4-phenylpentanethioate (anti-21b)

The same procedure as for anti-21a however using EtMgBr instead of MeMgBr The reaction afforded a mixture of syn and anti isomers [91 yield 96 de 94 ee (major diastereomer) [α]D = +130 (c 10

CHCl3)] Rf = 060 (n-pentaneEt2O 955 vv) 1H NMR (400 MHz CDCl3) δ 086 (t J = 72 Hz 3H) 112-120 (m 1H) 122 (d J = 76 Hz 3H) 123

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(t J = 72 Hz 3H) 134-142 (m 1H) 213-221 (m 1H) 244-256 (m 2H) 280-288 (m 1H) 285 (q J = 76 Hz 2H) 718-730 (m 5H) 13C NMR (50 MHz CDCl3) δ 112 147 174 233 240 413 433 453 1260 1278 1282 1454 1996 MS (EI) mz 250 (M+ 16) 189 (100) 146 (36) 105 (78) HRMS Calcd for C15H22OS 2501391 found 2501404 Diastereoisomeric ratio was determined by chiral GC analysis Chiralsil G-TA (25 m x 025 mm) initial temp 75 ordmC gradient 3 ordmCmin retention times (min) 320 (syn) and 326 (anti) Enantiomeric excess was determined by chiral HPLC analysis (Chiralcel OD-H n-heptanei-PrOH 991 vv 40 degC) retention times (min) 925 (3S4S) and 1076 (3R4R)

(+)-S-Ethyl (3R4S)-3-ethyl-4-phenylpentanethioate (syn-21b)

The same procedure as for anti-21a however using EtMgBr instead of MeMgBr and using (S)-L4 instead of (R)-L4 The reaction afforded a mixture of syn and anti isomers [58 yield 28 de gt995 ee

(major diastereomer) [α]D = +122 (c 10 CHCl3)] Rf = 057 (n-pentaneEt2O 955 vv) 1H NMR (400 MHz CDCl3) δ 088 (t J = 72 Hz 3H) 121 (t J = 76 Hz 3H) 125 (d J = 72 Hz 3H) 134-146 (m 2H) 215-220 (m 1H) 233-254 (m 2H) 274-283 (m 1H) 283 (q J = 72 Hz 2H) 717-730 (m 5H) 13C NMR (50 MHz CDCl3) δ 104 148 178 226 233 415 431 460 1261 1278 1283 1455 1996 MS (EI) mz 250 (M+ 18) 189 (100) 146 (47) 105 (78) 91 (24) HRMS Calcd for C15H22OS 2501391 found 2501396 Diastereoisomeric ratio was determined by chiral GC analysis Chiralsil G-TA (25 m x 025 mm) initial temp 75 ordmC gradient 3 ordmCmin retention times (min) 320 (syn) and 326 (anti) Enantiomeric excess was determined on a derivative of syn-21b the methyl oxoester syn-19b A solution of a sample of syn-21b in MeOH was stirred with K2CO3 (ca 10 equiv) at rt for 3 h The mixture was concentrated in vacuo and the residu taken up in H2O which was extracted with Et2O GC analysis was performed on a crude sample of the methyl oxoester CP Chiralsil Dex CB column (25m x 025mm) initial T = 70 degC gradient 3 degC min to 110 degC 110 degC isothermic retention times (min) 785 (3S4R) 803 (3R4S)

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(+)-S-Ethyl (3R4S)-3-methyl-4-phenyl-thiohexanoate (syn-21c)

The same procedure as for anti-21a however using 17e (contaminated with 18) instead of 17c and using (S)-L4 instead of (R)-L4 The reaction afforded a mixture of syn and anti isomers and the product of

18 which could be separated by column chromatography [71 yield 76 de gt995 ee (major diastereomer) [α]D = +50 (c 04 CHCl3)] Rf = 063 (n-pentaneEt2O 955 vv) 1H NMR (400 MHz CDCl3) δ 071 (t J = 72 Hz 3H) 099 (d J = 60 Hz 3H) 121 (t J = 72 Hz 3H) 152-162 (m 1H) 178-187 (m 1H) 213 (dd J = 144 and 96 Hz 1H) 227-232 (m 2H) 244 (dd J = 144 and 32 Hz 1H) 283 (q J = 72 Hz 2H) 711-730 (m 5H) 13C NMR (50 MHz CDCl3) δ 122 148 176 232 251 362 494 531 1262 1282 1285 1433 1995 MS (EI) mz 250 (M+ 10) 189 (100) 146 (30) 105 (43) 91 (41) HRMS Calcd for C15H22OS 2501391 found 2501401 Diastereoisomeric ratio was determined by chiral GC analysis Chiralsil G-TA (25 m x 025 mm) initial temp 75 ordmC gradient 3 ordmCmin retention times (min) 316 (syn) and 3210 (anti) Alternatively the dr was determined by 1H NMR spectroscopy by comparison of the CHCH3 signals (078 ppm for anti 099 ppm for syn) Enantiomeric excess was determined on a derivative of syn-21c the methyl oxoester (3R4S)-methyl 3-methyl-4-phenylhexanoate A solution of a sample of syn-21c in MeOH was stirred with K2CO3 (ca 10 equiv) at rt for 3 h The mixture was concentrated in vacuo and the residu taken up in H2O which was extracted with Et2O GC analysis was performed on a crude sample of the methyl oxoester CP Chiralsil Dex CB column (25m x 025mm) initial T = 70 degC gradient 3 degC min to 110 degC 110 degC isothermic retention times (min) 709 (3R4S) 730 (3S4R)

(+)-S-Ethyl (3S4S)-3-methyl-4-phenyl-thiohexanoate (anti-21c)

In a Schlenk tube CuBrmiddot(RS)-L1 (90 μmol 660 mg) was dissolved in t-BuOMe (10 mL) and stirred under a N2-atmosphere at room temperature for 10 min The mixture was cooled to ndash75 ordmC and MeMgBr (30 M in Et2O 045 mmol) was added

dropwise After stirring for 5 min at that temperature a solution of 17e (330 mg 015 mmol) in t-BuOMe (10 mL) was added dropwise over 10 min After stirring for 40 h at ndash75 degC MeOH (025 mL) and aq NH4Cl (1M 2

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mL) were added sequentially and the mixture was warmed to rt After extraction with Et2O (05 mL 3x) the combined organic layers were dried and concentrated to a yellow oil which was subjected to flash chromatography (silica gel n-pentaneEt2O 9975025 vv) to afford a mixture of syn-21c and anti-21c [67 yield 96 de gt995 ee (major diastereomer) [α]D = +191 (c 08 CHCl3)] Rf = 065 (pentaneEt2O 955 vv) 1H NMR (400 MHz CDCl3) δ 074 (t J = 72 Hz 3H) 078 (d J = 64 Hz 3H) 125 (t J = 72 Hz 3H) 165-175 (m 2H) 224 (dd J = 144 and 88 Hz 1H) 230-240 (m 2H) 265 (dd J = 144 and 48 Hz 1H) 288 (q J = 72 Hz 2H) 710-730 (m 5H) 13C NMR (50 MHz CDCl3) δ 124 148 166 233 257 356 496 524 1262 1280 1289 1423 1994 MS (EI) mz 250 (M+ 10) 189 (100) 146 (30) 105 (40) 91 (43) HRMS Calcd for C15H22OS 2501391 found 2501403 Diastereoisomeric ratio was determined by chiral GC analysis Chiralsil G-TA (25 m x 025 mm) initial temp 75 ordmC gradient 3 ordmCmin retention times (min) 316 (syn) and 321 (anti) Alternatively the dr was determined by 1H NMR spectroscopy by comparison of the CHCH3 signals (078 ppm for anti 099 ppm for syn) Enantiomeric excess was determined on a derivative of anti-21c the methyl oxoester (3S4S)-methyl 3-methyl-4-phenylhexanoate A solution of a sample of anti-21c in MeOH was stirred with K2CO3 (ca 10 equiv) at rt for 3 h The mixture was concentrated in vacuo and the residue taken up in H2O which was extracted with Et2O GC analysis was performed on a crude sample of the methyl oxoester Chiraldex G-TA column (30m x 025mm) initial T = 70 degC gradient 2 degC min to 90 degC 90 degC isothermic retention times (min) 1332 (3R4R) 1371 (3S4S)

(minus)-Methyl (E4S)-5-(benzyloxy)-4-methyl-2-pentenoate (35)60

In a dried Schlenk tube under a N2-atmosphere Hoveyda-Grubbs 2nd generation catalyst (50 μmol 315 mg) was added to a solution of methyl acrylate 16a (125 mmol

11 mL) and 27 (25 mmol 440 mg) in CH2Cl2 (5 mL) The resulting green solution was stirred for 20 h at rt The mixture was then concentrated in vacuo and the residue purified by flash chromatography (SiO2 2 98 to 5 95 Et2O n-pentane gradient Rf (595) = 02) which afforded 35 (479 mg) as a colorless oil [82 yield 94 ee [α]D = minus164 (c 19 CHCl3) lit60 [α]D = +150 (c 302 CHCl3 (R)-35)] 1H-NMR δ 737-726 (m 5H) 696

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(dd J = 158 and 71 Hz 1H) 587 (dd J = 158 and 14 Hz 1H) 451 (s 2H) 373 (s 3H) 344-336 (m 2H) 272-261 (m 1H) 109 (d J = 68 Hz 3H) 13C-NMR δ 1671 1515 1381 1283 1276 1276 1205 739 731 514 368 160 MS (EI) mz 234 (M+ 06) 113 (9) 92 (9) 91 (100) 65 (6) HRMS Calcd for C14H18O3 2341256 found 2341267 Enantiomeric excess was determined by chiral HPLC analysis Chiralcel OD (98 n-heptanei-PrOH) 40ordmC retention times (min) 69 (S-enantiomer) and 92 (R-enantiomer)

(minus)-S-Ethyl (E4S)-(2)-5-(benzyloxy)-4-methyl-2-pentenethioate (28)61 Route A from the methyl ester 35 To a solution of 35 (307 mmol 720 mg) in THF (10 mL) in a dry Schlenk tube under a N2-atmosphere AlCl3 (36 mmol 480 mg) and

EtSSiMe3 (60 mmol 970 μL) were added sequentially The resulting solution was heated at reflux temperature for 16 h after which the reaction was quenched with an aq phosphate buffer solution (pH = 7 125 mL) The mixture was extracted with Et2O (15 mL 3x) and the combined organic layers were dried (MgSO4) and concentrated in vacuo The residue was purified by flash chromatography (SiO2 5 95 tBuOMe pentane Rf = 05) which afforded 28 as a colorless oil (695 mg 86 yield) Route B from the terminal olefin 27 In a dry Schlenk tube under a N2-atmosphere Hoveyda-Grubbs 2nd generation catalyst (50 μmol 313 mg) was added to a solution of S-ethyl thioacrylate 16c (20 mmol 229 μL) and 27 (10 mmol 176 mg) in CH2Cl2 (25 mL) The resulting green solution was heated for 6 h at reflux temperature The mixture was allowed to cool a second portion of the catalyst was added (50 μmol 313 mg) and the mixture was heated for another 18 h at reflux temperature The mixture was then concentrated in vacuo and purified by flash chromatography (SiO2 5 95 Et2O n-pentane Rf = 05) which afforded an inseparable mixture of 28 and the side product 29 (236 mg ratio 2829 = 201 83 corrected yield 28) as a colorless oil [94 ee [α]D = minus176 (c 19 CHCl3)] 1H-NMR δ 737-726 (m 5H) 688 (dd J = 157 and 70 Hz 1H) 614 (dd J = 157 and 14 Hz 1H) 452 (s 2H) 344-337 (m 2H) 295 (q J = 74 Hz 2H) 269-261 (m 1H) 128 (t J = 74 Hz 3H) 110 (d J = 68 Hz 3H) 13C-NMR δ 1901 1469 1381 1283 1282 1276 1275 737 731 367 231 160 148 MS (EI) mz 264 (M+ 02) 235 (2) 203 (4) 174 (11) 145 (9) 117 (12) 92 (8) 91 (100)

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83 (6) 82 (14) 65 (6) HRMS Calcd for C15H20SO2 2641187 found 2641184 Enantiomeric excess was determined by chiral HPLC analysis Chiralcel OB-H (98 n-heptanei-PrOH) 40ordmC retention times (min) 207 (S-enantiomer) and 263 (R-enantiomer)

(2S5SE)-16-dibenzyloxy-25-dimethylhex-3-ene (29)

In a dry Schlenk tube under a N2-atmosphere Hoveyda-Grubbs 2nd generation catalyst (50 μmol 313 mg) was added to a solution of 27 (05 mmol 88 mg) in CH2Cl2 (05 mL) The

resulting green solution was stirred for 20 h at rt The mixture was then concentrated in vacuo and purified by flash chromatography (SiO2 0 100 to 5 95 Et2O n-pentane gradient Rf (595) = 05) which afforded 29 (64 mg 80 yield) as a colorless oil 1H-NMR δ 736-725 (m 10H) 543 (dd J = 40 and 18 Hz 2H) 451 (s 4H) 337 (dd J = 91 and 63 Hz 2H) 326 (dd J = 91 and 73 Hz 2H) 252-243 (m 2H) 103 (d J = 68 Hz 6H) 13C-NMR δ 1386 1324 1282 1274 1273 754 728 368 172 MS (EI) mz 324 (M+ 005) 234 (5) 233 (31) 97 (8) 96 (6) 92 (9) 91 (100) 65 (5) HRMS Calcd for C22H28O2 3242089 found 324 2084

(+)-S-Ethyl (3S4S)-5-(benzyloxy)-34-dimethyl-pentanethioate (anti-23) A dry Schlenk tube equipped with septum and stirring bar was charged with CuI (42 μmol 80 mg) (R)-Tol-BINAP (46 μmol 312 mg) and t-BuOMe (110 mL) and stirred

under a N2-atmosphere at room temperature until a yellow colour appeared The mixture was cooled to ndash70 oC methyl Grignard reagent (56 mmol 3M solution in Et2O 185 mL) was added dropwise and the mixture was stirred for 10 min Unsaturated thioester 28 (contaminated with 29) (139 mmol 94 wt 391 mg) was added dropwise as a solution in 35 mL CH2Cl2 at that temperature The resulting mixture was stirred at ndash70 oC for 16 h The reaction was quenched by addition of MeOH (2 mL) and sat aqueous NH4Cl solution (10 mL) the mixture was removed from the cooling bath and allowed to reach rt Subsequently enough H2O to dissolve all salts and 15 mL Et2O were added the organic layer was separated and the resulting aqueous layer was extracted with Et2O (2x 10 mL) The combined organic layers were dried (MgSO4) filtered and concentrated in vacuo to yield a

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yellow oil which was purified by flash chromatography (SiO2 5 95 Et2O n-pentane Rf = 035) affording anti-23 as a colorless oil (352 mg) [91 yield 98 2 dr gt995 ee (major diastereomer) [α]D = +51 (c 24 CHCl3)] 1H-NMR δ 735-726 (m 5H) 450 (s 2H) 339 (dd J = 93 and 65 Hz 1H) 329 (dd J = 93 and 64 Hz 1H) 288 (q J = 74 Hz 2H) 262 (dd J = 144 and 43 Hz 1H) 235 (dd J = 144 and 97 Hz 1H) 228-218 (m 1H) 187-176 (m 1H) 125 (t J = 74 Hz 3H) 093 (d J = 68 Hz 3H) 090 (d J = 70 Hz 3H) 13C-NMR δ 1996 1386 1283 1275 1274 732 730 478 378 329 233 168 148 139 MS (EI) mz 280 (M+ 03) 219 (14) 92 (9) 91 (100) HRMS Calcd for C16H24SO2 2801497 found 2801498 Enantiomeric excess and diastereomeric ratio were determined by chiral HPLC analysis Chiralcel OB-H (997 n-heptanei-PrOH) 40ordmC retention times (min) 254 (3R4S) 290 (3S4S [major]) 335 (3R4R) and 381 (3S4R) (+)-S-Ethyl (3R4S)-5-(benzyloxy)-34-dimethylpentanethioate (syn-23)

The same procedure as for anti-23 however using (S)-L4 instead of (R)-L4 and the reaction was performed at 025 mmol scale Purification by flash chromatography (SiO2 5 95 Et2O n-pentane Rf = 035) afforded

syn-23 as a colorless oil (595 mg) [85 yield 96 4 dr gt995 ee (major diastereomer) [α]D = +58 (c 37 CHCl3)] 1H-NMR δ 737-725 (m 5H) 452-445 (m 2H) 337 (dd J = 93 and 67 Hz 1H) 328 (dd J = 93 and 66 Hz 1H) 287 (q J = 74 Hz 2H) 258 (dd J = 144 and 56 Hz 1H) 240 (dd J = 144 and 88 Hz 1H) 235-224 (m 1H) 189-180 (m 1H) 124 (t J = 74 Hz 3H) 086 (d J = 54 Hz 3H) 084 (d J = 53 Hz 3H) 13C-NMR δ 1992 1385 1283 1275 1274 737 729 493 368 320 232 148 146 122 MS (EI) mz 219 (12) 113 (5) 92 (11) 91 (100) HRMS Calcd for C14H19O2 [MminusSEt]+ 2191385 found 2191387 Enantiomeric excess and diastereomeric ratio were determined by chiral HPLC analysis Chiralcel OB-H (997 n-heptanei-PrOH) 40ordmC retention times (min) 254 (3R4S [major]) 290 (3S4S) 335 (3R4R) and 381 (3S4R)

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(+)-(3S4S)-5-(Benzyloxy)-34-dimethylpentanal (30)

Thioester anti-23 (036 mmol 101 mg) was dissolved in CH2Cl2 (35 mL) under a N2-atmosphere in a dry Schlenk tube equipped with stirring bar and septum The solution was

cooled down to ndash55 oC and a solution of diisobutylaluminumhydride (055 mmol 10 M in CH2Cl2 055 mL) was added dropwise After stirring at ndash55 oC for 2 h a sat aqueous solution of Rochelle salt (5 mL) was added and the resulting mixture was stirred vigorously at rt for 1 h The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2x 5 mL) The combined organic layers were washed with brine (1 mL) dried (MgSO4) and concentrated in vacuo The residue was purified by flash chromatography (SiO2 10 90 Et2O n-pentane Rf = 035) which afforded 30 as a colorless oil (76 mg) [96 yield [α]D = +147 (c 14 CHCl3)] 1H-NMR δ 972 (dd J = 29 and 16 Hz 1H) 737-726 (m 5H) 450 (d J = 120 Hz 1H) 446 (d J = 120 Hz 1H) 336 (dd J = 93 and 70 Hz 1H) 332 (dd J = 94 and 60 Hz 1H) 246 (ddd J = 159 43 and 14 Hz 1H) 235-225 (m 1H) 217 (ddd J = 158 92 and 29 Hz 1H) 189-178 (m 1H) 095 (d J = 69 Hz 3H) 089 (d J = 70 Hz 3H) 13C-NMR δ 2030 1384 1283 1275 1275 731 730 473 378 295 176 135 MS (EI) mz 220 (M+ 5) 177 (6) 129 (7) 113 (22) 111 (6) 108 (27) 107 (32) 96 (7) 95 (6) 92 (35) 91 (100) 83 (12) 81 (11) 79 (6) 77 (7) 71 (20) 70 (8) 69 (15) 65 (13) HRMS Calcd for C14H20O2 2201463 found 2201455

(+)-Benzyl (2S3S)-236-trimethyl-5-heptenyl ether (31)

In a dry Schlenk tube equipped with septum and stirring bar isopropyltriphenyl-phosphonium iodide (133 mmol 577 mg) was suspended in THF (85 mL) under a N2-

atmosphere and cooled to 0 degC A solution of n-BuLi (133 mmol 16 M in hexanes 083 mL) was added dropwise and the mixture was stirred at 0 degC for 15 min The resulting red mixture was cooled down to ndash78 oC and stirred 15 min at this temperature after which a solution of aldehyde 30 (043 mmol 949 mg) in THF (45 mL) was added dropwise The reaction mixture was stirred at ndash78 oC for 60 min then at 0 degC for 15 h and then a sat aqueous solution of NH4Cl (1 mL) was added The mixture was diluted with EtOAc (20 mL) and washed with a sat aqueous solution of NH4Cl (2x 5

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Chapter 4

142


mL) The organic layer was dried (MgSO4) filtered and concentrated in vacuo The residue was purified by flash chromatography (SiO2 1 99 Et2O n-pentane Rf = 055) which afforded 31 as a colorless oil (95 mg) [90 yield [α]D = +84 (c 21 CHCl3)] 1H-NMR δ 736-725 (m 5H) 512 (t J = 72 Hz 1H) 450 (s 2H) 346 (dd J = 91 and 57 Hz 1H) 329 (dd J = 91 and 73 Hz 1H) 206-199 (m 1H) 186-174 (m 2H) 170 (s 3H) 159 (s 3H) 163-154 (m 1H) 094 (d J = 69 Hz 3H) 086 (d J = 69 Hz 3H) 13C-NMR δ 1388 1318 1283 1275 1274 1238 738 730 378 358 315 258 178 169 144 MS (EI) mz 247 (7) 246 (M+ 38) 175 (14) 155 (9) 138 (8) 137 (42) 97 (23) 96 (11) 95 (20) 92 (12) 91 (100) 83 (10) 81 (17) 71 (6) 70 (6) 69 (53) 65 (7) 57 (10) 55 (16) HRMS Calcd for C17H26O 2461984 found 2461979

(2S3S)-236-trimethyl-5-hepten-1-ol [(minus)-Lasiol] (22)43-4546b

Liquid NH3 was condensed in a dry Schlenk flask under a N2-atmosphere at minus78 degC A second dry Schlenk flask under N2 was equipped with septum and stirbar charged with pieces of Li (58 mmol 40

mg) and THF (30 mL) and also cooled to minus78 degC The flasks were connected via cannula and the flask with NH3 was removed from the cooling bath allowing the NH3 (ca 10 mL) to distill into the second flask After stirring at minus78 degC for 30 min a solution of 31 (034 mmol 843 mg) in THF (20 mL) was added dropwise to the dark blue solution After 20 min solid NH4Cl (15 g) was added carefully and the NH3 was allowed to evaporate using a waterbath at rt A sat aqueous solution of NaCl (10 mL) was added and just enough H2O to dissolve all the salts The organic layer was separated and the resulting water layer was extracted with Et2O (3x 15 mL) The combined organic layers were dried (MgSO4) filtered and concentrated in vacuo The residue was purified by flash chromatography (SiO2 20 80 Et2O n-pentane Rf = 04) affording (minus)-lasiol 22 as a colorless liquid (52 mg) [99 yield [α]D = minus102 (c 19 n-hexane) lit46b [α]D = minus121 (c 0995 n-hexane)] 1H-NMR δ 512 (br t J = 72 Hz 1H) 365 (dd J = 106 and 54 Hz 1H) 346 (dd J = 106 and 71 Hz 1H) 200-207 (m 1H) 184-151 (m 10H containing two singlets of each 3H 170 and 160 ppm) 093 (d J = 68 Hz 3H) 087 (d J = 68 Hz 1H) 13C-NMR δ 1320 1235 660 402 354 313 258 177 169 137 MS (EI) mz 156 (M+ 38) 139 (7) 138 (10) 137 (9) 125 (6) 123 (33) 109 (19) 97

HO


143


(21) 96 (34) 95 (25) 86 (6) 85 (32) 83 (13) 82 (24) 81 (21) 71 (16) 70 (55) 69 (100) 68 (12) 67 (16) 59 (10) 58 (7) 57 (19) 56 (17) 55 (46) 53 (11) HRMS Calcd for C10H20O 1561514 found 1561519

(+)-2-((2S3S)-4-(Benzyloxy)-23-dimethylbutyl)-13-dioxolane (32)

A catalytic amount of p-TsOHmiddotH2O (026 mmol 50 mg) was added to a stirred suspension of aldehyde 30 (47 mmol 104 g) ethylene glycol (30 mmol 1 5 mL) and

50 g MgSO4 in 60 mL benzene The mixture was heated at reflux temperature for 14 h after which it was diluted with 50 mL Et2O and filtered The filtrate was washed with sat aq NaHCO3 (40 mL) and brine (20 mL) dried with MgSO4 filtered and concentrated in vacuo The residue was purified by flash chromatography (SiO2 10 90 Et2O n-pentane Rf = 025) affording 32 as a colorless oil (119 g) [95 yield [α]D = +30 (c 52 CHCl3)] 1H-NMR δ 736-725 (m 5H) 489 (dd J = 59 and 44 Hz 1H) 449 (s 2H) 399-391 (m 2H) 389-880 (m 2H) 342 (dd J = 92 and 60 Hz 1H) 327 (dd J = 92 and 70 Hz 1H) 190-176 (m 2H) 169 (ddd J = 138 59 and 38 Hz 1H) 147 (ddd J = 140 98 and 44 Hz 1H) 096 (d J = 68 Hz 3H) 090 (d J = 68 Hz 3H) 13C-NMR δ 1387 1282 1274 1273 1041 734 729 647 645 383 369 310 171 136 MS (EI) mz 264 (M+ 08) 173 (6) 157 (10) 115 (11) 113 (14) 107 (7) 97 (6) 96 (6) 92 (7) 91 (54) 73 (100) 65 (6) HRMS Calcd for C16H24O3 2641726 found 2641735

(minus)-(2S3S)-4-(13-Dioxolan-2-yl)-23-dimethylbutan-1-ol (33)

A suspension of benzyl ether 32 (03 mmol 79 mg) and Pd(OH)2C (15 μmol 60 wt (moist) dry 20 wt Pd(OH)2 26 mg) in EtOAc (30 mL) was stirred vigorously at rt under a H2-atmosphere for 30 min

Celite was added and the suspension was filtered over Celite The filtercake was washed with EtOAc and the combined filtrates were concentrated The residue was purified by flash chromatography (SiO2 20 80 to 100 0 Et2O n-pentane gradient Rf (7030) = 035) affording 33 as a colorless oil (52 mg) [99 yield [α]D = minus203 (c 24 CHCl3)] 1H-NMR δ 486 (dd J = 62 and 36 Hz 1H) 397-388 (m 2H) 386-378 (m 2H) 349 (dd J = 110 and 74 Hz 1H) 339 (dd J = 110 and 65 Hz 1H) 238 (br s 1H) 189-

O O

O

HO O

O

Chapter 4

144


179 (m 1H) 169-159 (m 2H) 145-138 (m 1H) 094 (d J = 69 Hz 3H) 079 (d J = 69 Hz 3H) 13C-NMR δ 1039 651 645 644 402 357 295 177 122 MS (EI) mz 173 ([MminusH]+ 4) 115 (8) 113 (7) 102 (10) 88 (13) 85 (5) 74 (12) 73 (100) 71 (8) 69 (7) 55 (8) MS (CI) mz 193 (11) 192 ([M+NH4]+ 100) 175 ([M+H]+ 6) 147 (12) 131 (6) 130 (62) 113 (16) HRMS Calcd for [MminusH]+ C9H17O3 1731178 found 1731185

(+)-2-((2S3S)-4-Iodo-23-dimethylbutyl)-13-dioxolane (25)

To a stirred solution of alcohol 33 (027 mmol 46 mg) PPh3 (04 mmol 105 mg) and imidazole (05 mmol 34 mg) in benzene (20 mL) and DMF (01 mL) I2 (045 mmol 114 mg) was added in one portion The resulting

mixture was stirred at rt for 45 min after which it was poured into 5 mL sat aq Na2S2O3 solution and extracted with Et2O (5 mL 2x) The combined organic layers were dried (MgSO4) filtered and concentrated The residue was purified by flash chromatography (SiO2 5 95 Et2O n-pentane Rf = 025) affording 25 as a colorless oil (69 mg) [91 yield [α]D = +13 (c 32 CHCl3)] 1H-NMR δ 489 (dd J = 58 and 43 Hz 1H) 400-392 (m 2H) 389-381 (m 2H) 327 (dd J = 97 and 47 Hz 1H) 310 (dd J = 97 and 79 Hz 1H) 185-176 (m 1H) 168 (ddd J = 137 57 and 38 Hz 1H) 164-156 (m 1H) 148 (ddd J = 139 96 and 43 Hz 1H) 100 (d J = 67 Hz 3H) 096 (d J = 69 Hz 3H) 13C-NMR δ 1036 647 645 405 365 335 171 171 142 MS (EI) mz 283 (7) 157 (8) 95 (7) 73 (100) MS (CI) mz 302 ([M+NH4]+ 17) 69 (100) HRMS Calcd for [MminusH]+ C9H16O2I 2830195 found 2830248

(minus)-2-((2S3R5E9Z)-23610-Tetramethyl-dodeca-59-dienyl)-13- dioxolane (34)

A dry Schlenk tube equipped with septum and stirring bar was charged with alkyl iodide 25 (232 μmol 66 mg)

and Et2O (12 mL) under a N2-atmosphere and cooled to minus78 degC Via syringe t-BuLi (051 mmol 19 M soln in pentane 027 mL) was added dropwise and the solution was stirred at minus78 degC for 20 min A solution of dried ZnBr2 (029 mmol 65 mg) in THF (07 mL) was added dropwise via syringe and the resulting mixture was allowed to warm to 0 degC in 1 h At 0

I O

O

O

O


145


degC a solution of (1E5Z)-1-iodo-26-dimethylocta-15-diene 24 (035 mmol 92 mg) and [Pd(dppf)Cl2]middotCH2Cl2 (116 μmol 95 mg) in a mixture of THF DMF (08 mL 1 1) was added via syringe and the resulting green suspension was stirred at rt for 16 h H2O (5 mL) was added to the mixture which was extracted with Et2O (3 x 5 mL) The combined organic layers were dried (MgSO4) filtered and concentrated in vacuo The residue was purified by flash chromatography (SiO2 1 99 to 2 98 Et2O n-pentane gradient Rf (1 99) = 01) affording 34 as a colorless oil (48 mg) [71 yield [α]D = minus38 (c 09 CHCl3)] 1H-NMR δ 512 (br t J = 67 Hz 1H) 506 (br t J = 65 Hz 1H) 488 (dd J = 58 and 44 Hz 1H) 400-391 (m 2H) 389-380 (m 2H) 210-195 (m 7H) 183-175 (m 1H) 174-167 (m 2H) 166 (dd J = 24 and 12 Hz 3H) 158 (s 3H) 140-142 (m 2H) 096 (t J = 72 Hz 3H) 093 (d J = 61 Hz 3H) 082 (d J = 68 Hz 3H) 13C-NMR δ 1369 1353 1239 1237 1043 647 645 401 388 371 335 313 262 247 228 168 160 159 128 MS (EI) mz 294 (M+ 4) 149 (6) 123 (7) 121 (5) 115 (7) 114 (6) 113 (100) 107 (16) 95 (15) 93 (6) 83 (21) 81 (16) 73 (66) 69 (10) 67 (10) 55 (44) HRMS Calcd for C19H34O2 2942559 found 2942550

(3S4R6E10Z)-34711-tetramethyl-trideca-610-dienal [(+)-Faranal] (3)48-52

In a Schlenk flask under a N2-atmosphere dioxolane 34 (63 μmol 185 mg) was dissolved in a mixture of THF and water

(24 mL 5 1) p-TsOHmiddotH2O (126 mmol 240 mg) was added and the solution was heated at reflux temperature for 1 h The mixture was poured into sat aqueous NaHCO3 (20 mL) and extracted with 40 mL Et2O The organic layer was subsequently washed with sat aqueous NaHCO3 (10 mL) and brine (10 mL) dried (MgSO4) filtered and concentrated in vacuo The residue was purified by flash chromatography (SiO2 2 98 Et2O n-pentane Rf = 02) affording 3 as a colorless oil (97 mg) [62 yield [α]D = +192 (c 10 CHCl3) lit52 [α]D = +174 (c 412 CHCl3) lit51b [α]D = +175 (c 052 n-hexane)] 1H-NMR δ 974 (dd J = 17 and 26 Hz 1H) 511 (br t J = 67 Hz 1H) 505 (br t J = 66 Hz 1H) 247-241 (m 1H) 221-195 (m 9H) 187-178 (m 1H) 166 (s 3H) 158 (s 3H) 152-142 (m 1H) 096 (t J = 76 Hz 3H) 094 (d J = 66 Hz 3H) 084 (d J = 68 Hz 3H) 13C-NMR δ 2033 1371 1359 1238 1230 474 401 384

H

O

Chapter 4

146


320 318 262 247 228 175 161 159 128 MS (EI) mz 250 (M+ 6) 203 (5) 194 (7) 193 (44) 177 (5) 175 (12) 149 (9) 138 (6) 137 (23) 136 (6) 124 (5) 123 (29) 122 (7) 121 (9) 111 (8) 109 (13) 107 (17) 99 (6) 97 (9) 96 (7) 95 (20) 93 (9) 84 (8) 83 (100) 82 (23) 81 (27) 79 (6) 69 (20) 68 (7) 67 (17) 57 (5) 55 (87) 53 (7) HRMS Calcd for C17H30O 2502297 found 2502307


147


References 1 Taylor M S Jacobsen E N Proc Nat Acad Sci USA 2004 101 5368-5373 2 a) Geurts K Fletcher S P van Zijl A W Minnaard A J Feringa B L Pure Appl Chem 2008 80 1025-1037 b) Falciola C A Alexakis A Eur J Org Chem 2008 3765-3780 c) Yorimitsu H Oshima K Angew Chem Int Ed 2005 44 4435-4439 d) Alexakis A Malan C Lea L Tissot-Croset K Polet D Falciola C Chimia 2006 60 124-130 3 a) Christoffers J Koripelly G Rosiak A Roumlssle M Synthesis 2007 1279-1300 b) Feringa B L Naasz R Imbos R Arnold L A Copper-catalyzed Enantioselective Conjugate Addition Reactions of Organozinc Reagents in Modern Organocopper Chemistry Krause N (Ed) Wiley-VCH Weinheim 2002 Chapter 7 c) Alexakis A Benhaim C Eur J Org Chem 2002 3221-3236 d) Feringa B L Acc Chem Res 2000 33 346-353 4 a) van Zijl A W Loacutepez F Minnaard A J Feringa B L J Org Chem 2007 72 2558-2563 b) Geurts K Fletcher S P Feringa B L J Am Chem Soc 2006 128 15572-15573 c) Loacutepez F van Zijl A W Minnaard A J Feringa B L Chem Commun 2006 409-411 5 a) Maciaacute Ruiz B Geurts K Fernaacutendez-Ibaacutentildeez M A ter Horst B Minnaard A J Feringa B L Org Lett 2007 9 5123-5126 b) Harutyunyan S R Loacutepez F Browne W R Correa A Pentildea D Badorrey R Meetsma A Minnaard A J Feringa B L J Am Chem Soc 2006 128 9103-9118 and references therein 6 L4rsquos performance in conjugate addition was first reported by Loh and coworkers Wang S-Y Ji S-J Loh T-P J Am Chem Soc 2007 129 276-277 7 For reviews on the use of Grignard reagents in asymmetric allylic alkylation and conjugate addition see a) Loacutepez F Minnaard A J Feringa B L in The Chemistry of Organomagnesium Compounds Eds Rappoport Z Marek I 2008 Wiley Chichester Part 2 Chapter 17 b) Harutyunyan S R den Hartog T Geurts K Minnaard A J Feringa B L Chem Rev 2008 108 in press c) Loacutepez F Minnaard A J Feringa B L Acc Chem Res 2007 40 179-188 8 a) Des Mazery R Pullez M Loacutepez F Harutyunyan S R Minnaard A J Feringa B L J Am Chem Soc 2005 127 9966-9967 b) Schuppan J Minnaard A J Feringa B L Chem Commun 2004 792-793 9 van Summeren R P Reijmer S J W Feringa B L Minnaard A J Chem Commun 2005 1387-1389 10 a) Casas-Arce E ter Horst B Feringa B L Minnaard A J Chem Eur J 2008 14 4157-4159 b) ter Horst B Feringa B L Minnaard A J Org Lett 2007 9 3013-3015

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c) ter Horst B Feringa B L Minnaard A J Chem Commun 2007 489-491 d) van Summeren R P Moody D B Feringa B L Minnaard A J J Am Chem Soc 2006 128 4546-4547 11 a) Chatterjee A K Choi T-L Sanders D P Grubbs R H J Am Chem Soc 2003 125 11360-11370 b) Connon S J Blechert S Angew Chem Int Ed 2003 42 1900-1923 12 a) Umezawa T Phytochem Rev 2003 2 371-390 b) Ward R S Nat Prod Rep 1999 16 75-96 c) Ward R S Nat Prod Rep 1997 14 43-74 13 Apers S Vlietinck A Pieters L Phytochem Rev 2003 2 201-217 14 Su B-N Gu J-Q Kang Y-H Park E-J Pezzuto J M Kinghorn A D Mini Rev Org Chem 2004 1 115-123 15 See for example a) Chao C-H Huang L-F Wu S-L Su J-H Huang H-C Sheu J-H J Nat Prod 2005 68 1366-1370 b) Wang W Li F Park Y Hong J Lee C-O Kong J Y Shin S Im K S Jung J H J Nat Prod 2003 66 384-391 16 Wu M Okino T Nogle L M Marquez B L Williamson R T Sitachitta N Berman F W Murray T F McGough K Jacobs R Colsen K Asano T Yokokawa F Shioiri T Gerwick W H J Am Chem Soc 2000 122 12041-12042 17 Inoue M Miyazaki K Ishihara Y Tatami A Ohnuma Y Kawada Y Komano K Yamashita S Lee N Hirama M J Am Chem Soc 2006 128 9352-9354 18 a) Satake M Ishida S Yasumoto T Murata M Utsumi H Hinomoto T J Am Chem Soc 1995 117 7019-7020 b) Yokoyama A Murata M Oshima Y Iwashita T Yasumoto T J Biochem 1988 104 184-187 19 Mori K Bioorg Med Chem 2007 15 7505-7523 20 Oishi T Shoji M Kumahara N Hirama M Chem Lett 1997 845-846 21 Morita M Ishiyama S Koshino H Nakata T Org Lett 2008 10 1675-1678 22 Hanessian S Reddy G J Chahal N Org Lett 2006 8 5477-5480 23 a) Reyes E Vicario J L Carrillo L Badiacutea D Uria U Iza A J Org Chem 2006 71 7763-7772 b) White J D Lee C-S Xu Q Chem Commun 2003 2012-2013 24 Coleman R S Gurrala S R Mitra S Raao A J Org Chem 2005 70 8932-8941 25 a) Liang B Carroll P J Joullieacute M M Org Lett 2000 2 4157-4160 b) Brebion F Delouvrieacute B Naacutejera F Fensterbank L Malacria M Vaissermann J Angew Chem Int Ed 2003 42 5342-5345 See also Feringa B L Jansen J F G A in Houben-Weyl Methods of Organic Chemistry 4th Ed Vol E21b Eds Helmchen G Hoffmann R W Mulzer J Schaumann E Thieme Stuttgart 1995 Chap 1524 2104-2155


149


26 Evans D A Scheidt K A Johnston J N Willis M C J Am Chem Soc 2001 123 4480-4491 27 Harada T Yamauchi T Adachi S Synlett 2005 2151-2154 28 Chen Y Tian S-K Deng L J Am Chem Soc 2000 122 9542-9543 29 a) Johnson J B Bercot E A Williams C M Rovis T Angew Chem Int Ed 2007 46 4514-4518 b) Bercot E A Rovis T J Am Chem Soc 2004 126 10248-10249 30 Soumldergren M J Bertilsson S K Andersson P G J Am Chem Soc 2000 122 6610-6618 31 Hanessian S Giroux S Mascitti V Synthesis 2006 1057-1076 32 a) Negishi E Bull Chem Soc Jpn 2007 80 233-257 b) Negishi E Tan Z Liang B Novak T Proc Nat Acad Sci USA 2004 101 5782-5787 33 a) Zhu G Liang B Negishi E Org Lett 2008 10 1099-1101 b) Zhu G Negishi E Org Lett 2007 9 2771-2774 34 Lum T-K Wang S-Y Loh T-P Org Lett 2008 10 761-764 35 a) Kacprzynski M A May T L Kazane S A Hoveyda A H Angew Chem Int Ed 2007 46 4554-4558 b) Tissot-Croset K Polet D Alexakis A Angew Chem Int Ed 2004 43 2426-2428 c) Alexakis A Croset K Org Lett 2002 4 4147-4149 36 Murphy K E Hoveyda A H J Am Chem Soc 2003 125 4690-4691 37 Kacprzynski M A Hoveyda A H J Am Chem Soc 2004 126 10676-10681 38 van Zijl A W Minnaard A J Feringa B L J Org Chem 2008 73 5651-5653 see also chapter 5 39 All conjugate additions with substrates 17d and 17e were performed on their mixtures with 18 The conjugate addition products of 18 were separated by column chromatography from the products of 17 40 Recently Loh and coworkers reported that the use of MeMgBr was possible under certain reaction conditions with their catalyst system Wang S-Y Lum T-K Ji S-J Loh T-P Adv Synth Catal 2008 350 673-677 see also reference 34 41 Extended reaction times to allow completion of the reaction did not improve the yield but did lead to a reduction in diastereoselectivity and enantiomeric excess 42 We cannot explain the different extents of racemization using MeMgBr and using EtMgBr A difference in basicity has never been reported However it is known that the reagents have different Schlenk equilibria in some solvents See The Chemistry of Organomagnesium Compounds Eds Rappoport Z Marek I 2008 Wiley Chichester 43 Lloyd H A Jones T H Hefetz A Tengouml J Tetrahedron Lett 1990 31 5559-5562

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44 Kuwahara S Shibata Y Hiramatsu A Liebigs Ann Chem 1992 993-995 45 Kasai T Watanabe H Mori K Bioorg Med Chem 1993 1 67-70 46 Catalytic asymmetric desymmetrizations a) Vasilrsquoev A A Vielhauer O Engman L Pietzsch M Serebryakov E P Russ Chem Bull Int Ed 2002 51 481-487 see also reference 30 Chiral auxiliary-based methods b) Asano S Tamai T Totani K Takao K Tadano K Synlett 2003 2252-2254 c) Schneider C Eur J Org Chem 1998 1661-1663 47 a) Kobayashi M Koyama T Ogura K Seto S Ritter F J Bruumlggemann-Rotgans I E M J Am Chem Soc 1980 102 6602-6604 b) Ritter F J Bruumlggemann-Rotgans I E M Verwiel P E J Persoons C J Talman E Tetrahedron Lett 1977 18 2617-2618 48 a) Vasilrsquoev A A Engman L Serebryakov E P J Chem Soc Perkin Trans 1 2000 2211-2216 b) Baker R Billington D C Ekanayake N J Chem Soc Perkin Trans 1 1983 1387-1393 c) Knight D W Ojhara B J Chem Soc Perkin Trans 1 1983 955-960 49 Mori K Ueda H Tetrahedron 1982 38 1227-1233 50 Wei S-Y Tomooka K Nakai T J Org Chem 1991 56 5973-5974 51 a) Yasuda K Shindo M Koga K Tetrahedron Lett 1997 38 3531-3534 b) Mori K Murata N Liebigs Ann 1995 2089-2092 52 Poppe L Novaacutek L Kolonits P Bata Aacute Szaacutentay C Tetrahedron 1988 44 1477-1487 53 Kottirsch G Koch G Feifel R Neumann U J Med Chem 2002 45 2289-2293 54 The dimer 29 could not be separated from 28 It could be separated from the product of the following conjugate addition however Pure 28 could be obtained via cross-metathesis with methyl acrylate (product 35) followed by transesterification For this route and the separate synthesis and characterization of 29 see Experimental Part 55 Despite selective syntheses of both enantiomers of lasiol the absolute configuration of the natural compound has not been established 56 Certain reaction conditions such as extended reaction times or the use of PdC as the catalyst led to the formation of a complex mixture of products probably due to partial trans-acetalization For precedents see a) Andrey O Vidonne A Alexakis A Tetrahedron Lett 2003 44 7901-7904 b) Boumlrjesson L Csoumlregh I Welch C J J Org Chem 1995 60 2989-2999 57 a) Negishi E Liou S-Y Xu C Huo S Org Lett 2002 4 261-264 b) Negishi E Valente L F Kobayashi M J Am Chem Soc 1980 102 3298-3299 58 a) Concelloacuten J M Rodriacuteguez-Solla H Concelloacuten C Diacuteaz P Synlett 2006 837-840 b) Ibarra C A Arias S Fernaacutendez M J Sinisterra J V J Chem Soc Perkin Trans 2


151


1989 503-508 c) Heathcock C H Kiyooka S Blumenkopf T A J Org Chem 1984 49 4214-4223 59 Optical rotation measured of the product of a reaction with reaction time 3 h which had lower conversion and yield 60 Nagaoka H Kishi Y Tetrahedron 1981 37 3873-3888 61 Keck G E Boden E P Mabury S A J Org Chem 1985 50 709-710


In this chapter the cross-metathesis reaction of S-ethyl thioacrylate with a range of olefins is described as well as a new procedure for the preparation of S-ethyl thioacrylate via a Wittig reaction The metathesis reaction is catalyzed effectively using a commercially available ruthenium benzylidene olefin metathesis catalyst This new preparative method provides a convenient and versatile route to substituted αβ-unsaturated thioesters key building blocks in organic synthesis

This chapter has been published in part van Zijl A W Minnaard A J Feringa B L J Org Chem 2008 73 5651-5653

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51 Introduction Thioesters are becoming increasingly important compounds due to their

distinctive chemical properties the reduced electron delocalization provides for enhanced reactivity compared to oxoesters1 The importance of thioesters in the cell is well established biological systems use their relative reactivity in many enzymatic reactions by employing for example acetyl coenzyme A cysteine proteases or polyketide and fatty acid synthases2 Their enhanced reactivity compared to oxoesters has been employed successfully in a wide range of synthetic organic transformations some inspired directly by related biosynthetic pathways Stereoselective aldol reactions often depend on the distinctive reactivity of thioesters3 and their synthetic versatility is further illustrated by other well-known transformations including α-alkylations4 selective reductions45 and Pd-catalyzed coupling reactions6 amongst others7 αβ-Unsaturated thioesters show important differences in their reactivity as Michael acceptors compared to oxoesters3d8 They have been found to be excellent substrates in the enantioselective Cu-catalyzed conjugate additions of Grignard reagents9 and their reactivity has proven exceptionally versatile in the synthesis of several natural products9b10

Although a highly useful intermediate occasionally difficulties are encountered in the synthesis of αβ-unsaturated thioesters through classic methods11 such as DCCDMAP-coupling of acids with thiols and trans-esterification with trimethylsilyl thioethers due to 14-addition of thiolate to the product

Scheme 51 Formation of a by-product in trans-esterification through conjugate addition of thiolate to the thioester product

For example a thioester intermediate in the total synthesis of lasiol and faranal was obtained via the trans-esterification of the corresponding oxo methyl ester (Scheme 51)12 Up to 10 of the thiolate adduct was obtained

Straightforward synthesis of αβ-unsaturated thioesters via olefin cross-metathesis with thioacrylate

155


which was difficult to separate from the main product As routine application of αβ-unsaturated thioesters relies on methods that give ready access to these compounds we were interested in examining whether it was possible to synthesize these compounds via cross-metathesis with a thioacrylate This is a particularly attractive route also because it would be directly applicable to the products of copper catalyzed allylic alkylation which contain a terminal olefin as was demonstrated in chapter 4

511 Cross-metathesis with sulfur containing compounds Ruthenium-catalyzed olefin metathesis has emerged as one of the most

versatile of synthetic methods over the past decade13 It is frequently the method of choice for the construction of carbon-carbon double bonds In particular cross-metathesis allows for the formation of highly complex products from much simpler precursors14 The increased functional group tolerance as a result of the development of new catalysts (Figure 51) their commercial availability and the Grubbs model to predict the selectivity15 have enhanced greatly the utility of cross-metathesis reactions

Figure 51 Ruthenium based metathesis catalysts Grubbs 1st generation (G-1) Hoveyda-Grubbs 1st generation (HG-1) Grubbs 2nd generation (G-2) Hoveyda-Grubbs 2nd generation (HG-2) Grelarsquos catalyst (Gre-2)

The use of electron deficient terminal olefins as cross-metathesis partners such as acrylates and vinyl ketones which are type II or type III olefins according to the Grubbs model is now relatively widespread The application of sulfur containing alkenes has been described previously also The earliest reports of metathesis reactions with thioethers and disulfides featured molybdenum and tungsten catalysts16 In 2002 the ruthenium based

Chapter 5

156


Grubbs second generation catalyst (G-2) was found to catalyze metathesis reactions with thioethers and disulfide compounds for which the Grubbs first generation catalyst was not applicable17 The first report of the use of a thioester compound in metathesis ie propargylic thiol benzoates and acetates for ethylene alkyne metathesis (Scheme 52) was disclosed in the same year18

Scheme 52 Ethylene metathesis with propargylic thioesters i) 5 mol G-2 ethylene (60-80 psi) CH2Cl2 97 (PG = Ac) 99 (PG = Bz)

Reports of the application of vinyl sulfides19 dithianes20 and also non-conjugated unsaturated thioesters21 have followed However to the best of our knowledge the use of thioacrylate compounds has so far not been described


157


52 Results and Discussion Thioacrylates are not commercially available and the current preparative

methods are either unsafe or expensive22 Standard procedures for the preparation of thioesters were explored to obtain S-ethyl thioacrylate However the reactions of acryloyl chloride with ethane thiol DCCDMAP-coupling of acrylic acid and transesterification of methyl acrylate did not give satisfactory results The reactions led to the formation of the 14-adduct of EtSH to thioacrylate as the major product or to complex mixtures probably due to polymerisation of the product

However it was found that compound 2 (Scheme 53) could be prepared from Wittig reagent 1 which is readily available from bromoacetic acid through DCCDMAP-coupling with ethanethiol followed by reaction with PPh323 Thioacrylate 2 could be obtained in 73 yield after refluxing 1 in CH2Cl2 with 5 equiv of paraformaldehyde The reaction could be performed on a synthetically useful scale yielding up to 25 mL of pure thioacrylate This new method provides an excellent protocol to prepare thioacrylates on a multigram scale

Scheme 53 Preparation of S-ethyl thioacrylate 2 through a Wittig reaction with reagent 1 and paraformaldehyde

521 Optimization of metathesis reaction conditions With a new route to thioacrylate 2 in hand the compound was studied in

a cross-metathesis reaction with a type I cross-metathesis partner 1-octene and five well-known catalysts (Figure 51) The results are summarized in Table 51 entries 1-5 As expected according to the Grubbs model15 both the Grubbs and the Hoveyda-Grubbs 1st generation catalyst (G-1 and HG-1)

Chapter 5

158


were found to be unsuitable for the reaction since only dimerisation of the 1-octene was observed

When using 2 mol of the Grubbs 2nd generation catalyst (G-2) and 25 equivalents of 1-octene full conversion of the thioacrylate was observed after 20 h at room temperature and product (E)-3 could be isolated in 76 yield However the Hoveyda-Grubbs 2nd generation catalyst (HG-2)24 gave a cleaner reaction and under the same conditions (E)-3 was obtained in 93 The Gre-2 catalyst reported by Grela and co-workers25 was tested also due to its known potential in metathesis reactions with electron deficient olefins This catalyst did not provide full conversion however and (E)-3 was obtained in only 72 yield In all cases only traces of the Z-isomer of 3 were detected which were removed readily by column chromatography

Table 51 Cross-metathesis reactions with S-ethyl thioacrylate and 1-octenea

entry cat T time yield

1 G-1 (2 mol ) rt 20 h ndb

2 HG-1 (2 mol ) rt 20 h ndb

3 G-2 (2 mol ) rt 20 h 76

4 HG-2 (2 mol ) rt 20 h 93

5 Gre-2 (2 mol ) rt 20 h 72

6 HG-2 (2 mol ) reflux 60 min 94


8 HG-2 (05 mol ) reflux 24 h 42 a Reaction conditions 2 (10 mmol) 1-octene (25 equiv) catalyst (05-20 mol) CH2Cl2 (c = 04 M) b Only formation of tetradec-7-ene was observed


159


With the best catalyst HG-2 the reaction temperature and catalyst loading were varied (entries 6-8) The reaction can be accelerated substantially by elevating the reaction temperature heating the mixture in CH2Cl2 at reflux for 60 min yielded 94 of compound 3 With only 1 mol catalyst the same excellent yield was obtained in 120 min but the use of 05 mol of HG-2 led to incomplete conversion after 1 d and only 42 yield of 3

These optimised conditions for the cross-metathesis reaction can be applied to a wide range of substrates to provide various αβ-unsaturated thioesters (Table 52) The reactions were performed in CH2Cl2 heated to reflux with 2 mol HG-2 Most cross-metathesis partners which contain a terminal olefin and are not branched at the allylic position led to fast reactions which provided the products in excellent yields (Table 52 entries 1-4) Thioesters with a phenyl ring or trimethylsilyl group at the γ-position (products 4 and 5) or a more remote oxoester group (products 6 and 7) were thus obtained

Table 52 Cross-metathesis reactions with S-ethyl thioacrylate and a range of olefinsa

entry CM-partner product time yield

1 Ph SEt

OPh

4 1 h 95

2 Me3Si SEt

OMe3Si

5 2 h 92

3 AcO SEt

OAcO

6 4 h 86

4 MeO2C SEt

O

MeO2C 7 4 h 91

5 Ph Ph SEt

O

8 18 h 72

Chapter 5

160


6b HO2C SEt

O

HO2C 9 24 h 83

7b HO ( )3 SEt

O

HO ( )3 10 24 h 93

8b O SEt

OO

11 24 h 75

9b Br ( )3 SEt

O

Br ( )3 12 24 h 75

10b OH SEt

O

OH 13 24 h 66

11b OH

SEt

O

OH 14 24 h 71

12b TsHN SEt

OTsHN

15 24 h 59

13bc AcO OAc SEt

OAcO

16 24 h 65

14bc BrBr SEt

OBr

17 24 h 64

a Reaction conditions 2 (10 mmol) CM-partner (25 equiv) HG-2 (20 mol) CH2Cl2 (c = 04 M) reflux b HG-2 (40 mol) added in 2 portions c CM-partner (15 equiv)

Reaction with styrene featuring a conjugated double bond required an extended reaction time (Table 52 entry 5) providing the cinnamic acid thioester 8 in 72 yield after 18 h In the case of linear terminal olefins with a carboxylic acid an unprotected alcohol an aldehyde or a bromide functionality a second portion of catalyst was needed to bring the reaction to completion (entries 6-9) the same held for secondary and tertiary unprotected allylic alcohols and allyl tosylamide (entries 10-12) The products 9-15 were all obtained in good yield after 24 h

Reactions with olefins containing an internal double bond such as 14-diacetoxy-cis-but-2-ene or 14-dibromo-trans-but-2-ene were performed


161


with only 15 equivalents of the cross-metathesis partner and again two portions of the catalyst were needed (Table 52 entries 13 and 14) Crotonic acid thioesters with an acetoxy or bromo substituent at the γ-position (products 16 and 17 respectively) were obtained in good yield after 24 h Cross-metathesis with 33-dimethyl-1-butene was attempted but product formation was not observed The reaction was performed under the standard conditions employed in this chapter (as specified in Table 52) although with 33-dimethyl-1-butene as cosolvent

Chapter 5

162


53 Conclusions In summary a mild and scalable new route to S-ethyl thioacrylate is

presented The feasibility of the use of this olefin in cross-metathesis reactions with the Hoveyda-Grubbs second generation catalyst is demonstrated The high functional group tolerance of the reaction allows the preparation of a broad range of versatile functionalized αβ-unsaturated thioesters The relevance of this new approach to obtain these compounds has been demonstrated in its application in the protocol to obtain vicinal dimethyl arrays described in chapter 4


163



Catalyst Gre-225 and Wittig reagent 123 were synthesized according to literature procedures Paraformaldehyde and all cross-metathesis partners were purchased from chemical suppliers and used without further purification with the exception of methyl 4-pentenoate which was synthesized from 4-pentenoic acid and trimethylsilyldiazomethane and allyl tosylamide which was synthesized from allylamine and tosyl chloride

S-Ethyl thioacrylate (2)

A flame dried Schlenk-flask under N2-atmosphere was charged with Wittig reagent 1 (298 g 82 mmol) paraformaldehyde (123 g 410 mmol) and CH2Cl2 (200

mL) The resulting suspension was stirred for 30 min at reflux temperature The mixture was concentrated in vacuo and the residue was suspended in n-pentane (100 mL) and filtered over silica The filtercake was washed (1090 Et2On-pentane 250 mL) and the filtrates combined Hydroquinone (ca 30 mg) was added to the solution to prevent polymerisation and the solvents were removed by distillation at atmospheric pressure using an efficient fractionating column The crude thioacrylate was further purified by distillation at reduced pressure (50 mbar 56-58degC) which afforded 2 (693 g 73 yield) as a colorless oil The compound was stored without stabilizer and used as such in the metathesis reactions to prevent decomposition it was shielded from light and stored at 5-8 degC 1H-NMR δ 637 (dd J = 172 97 Hz 1H) 628 (dd J = 172 16 Hz 1H) 566 (dd J = 97 16 Hz 1H) 296 (q J = 74 Hz 2H) 129 (t J = 74 Hz 3H) 13C-NMR (400 MHz CDCl3) δ 1900 1349 1257 229 144 MS (EI) mz 116 (M+ 37) 91 (6) 89 (6) 86 (17) 84 (25) 62 (10) 61 (16) 55 (100) HRMS Calcd for C5H8OS 1160296 found 1160299

S

O

Chapter 5

164


(E)-S-ethyl non-2-enethioate (3)

A flame dried Schlenk-flask under N2-atmosphere was charged with S-ethyl thioacrylate 2 (10 mmol 116 mg) 1-octene (25 mmol 395 μl) and CH2Cl2 (25

mL) Hoveyda-Grubbs 2nd generation catalyst (2 mol 20 μmol 125 mg) was added and the resulting solution was stirred for 60 min at reflux temperature The mixture was then concentrated in vacuo and the residue purified by flash column chromatography (SiO2 05 995 to 5 95 Et2O n-pentane gradient Rf (2 98) = 045) which afforded 3 (188 mg 94 yield) as a colorless oil 1H-NMR δ 689 (dt J = 155 70 Hz 1H) 610 (dt J = 155 16 Hz 1H) 294 (q J = 74 Hz 2H) 222-214 (m 2H) 150-138 (m 2H) 135-124 (m 9H) 088 (t J = 69 Hz 1H) 13C-NMR δ 1900 1453 1285 321 315 287 278 229 224 147 139 MS (EI) mz 200 (M+ 11) 140 (10) 139 (100) 81 (6) 69 (36) 68 (11) 67 (7) 55 (66) 53 (9) HRMS Calcd for C11H20OS 2001235 found 2001236

(E)-S-ethyl 4-phenylbut-2-enethioate (4)

The title compound was prepared from S-ethyl thioacrylate 2 (10 mmol 116 mg) and allylbenzene (25 mmol 330 μl) following the procedure

described for 3 (reaction time 60 min) Purification by flash column chromatography (SiO2 1 99 to 5 95 Et2O n-pentane gradient Rf (1 99) = 015) afforded 4 (195 mg 95 yield) as a colorless oil 1H-NMR δ 747-711 (m 5H) 703 (dt J = 154 68 Hz 1H) 610 (dt J = 154 16 Hz 1H) 352 (d J = 68 Hz 2H) 294 (q J = 74 Hz 2H) 127 (t J = 74 Hz 3H) 13C-NMR δ 1899 1431 1373 1294 1287 1286 1266 383 230 147 MS (EI) mz 206 (M+ 19) 146 (11) 145 (100) 127 (28) 117 (22) 116 (6) 115 (31) 91 (10) HRMS Calcd for C12H14OS 2060765 found 2060756

(E)-S-Ethyl 4-(trimethylsilyl)but-2-enethioate (5)

The title compound was prepared from S-ethyl thioacrylate 2 (10 mmol 116 mg) and allyltrimethylsilane (25 mmol 397 μl) following

the procedure described for 3 (reaction time 2 h) Purification by flash column chromatography (SiO2 05 995 to 2 98 Et2O n-pentane gradient Rf (2 98) = 04) afforded 5 (187 mg 92 yield) as a colorless oil

S

O

5

S

OPh

S

OMe3Si


165


1H-NMR δ 699 (dt J = 153 89 Hz 1H) 597 (dt J = 152 13 Hz 1H) 293 (q J = 74 Hz 2H) 172 (dd J = 89 13 Hz 2H) 127 (t J = 74 Hz 3H) 006 (s 9H) 13C-NMR δ 1894 1442 1267 249 228 148 -18 MS (EI) mz 205 (8) 173 ([MminusC2H5]+ 48) 141 (60) 119 (21) 91 (5) 84 (5) 75 (7) 74 (9) 73 (100) HRMS Calcd for C7H13OSiS = [MminusC2H5]+

1730456 found 1730449

(E)-6-(Ethylthio)-6-oxohex-4-enyl acetate (6)

The title compound was prepared from S-ethyl thioacrylate 2 (10 mmol 116 mg) and 4-pentenyl acetate (25 mmol 353 μl) following

the procedure described for 3 (reaction time 4 h) Purification by flash column chromatography (SiO2 5 95 to 10 90 Et2O n-pentane gradient Rf (10 90) = 025) afforded 6 (186 mg 86 yield) as a colorless oil 1H-NMR δ 686 (dt J = 155 69 Hz 1H) 611 (dt J = 155 16 Hz 1H) 407 (t J = 64 Hz 2H) 293 (q J = 74 Hz 2H) 233-222 (m 2H) 204 (s 3H) 186-174 (m 2H) 126 (t J = 74 Hz 3H) 13C-NMR δ 1899 1709 1434 1292 634 286 269 230 208 147 MS (EI) mz 216 (M+ 2) 155 (19) 114 (6) 113 (100) 95 (31) 71 (6) 68 (6) 67 (45) 55 (6) HRMS Calcd for C10H16O3S 2160820 found 2160816

(E)-Methyl 6-(ethylthio)-6-oxohex-4-enoate (7)

The title compound was prepared from S-ethyl thioacrylate 2 (10 mmol 116 mg) and methyl 4-pentenoate (25 mmol 285 mg) following

the procedure described for 3 (reaction time 4 h) Purification by flash column chromatography (SiO2 5 95 to 10 90 Et2O n-pentane gradient Rf (10 90) = 025) afforded 7 (184 mg 91 yield) as a colorless oil 1H-NMR δ 685 (dt J = 156 65 Hz 1H) 612 (dt J = 156 15 Hz 1H) 368 (s 3H) 293 (q J = 74 Hz 2H) 260-241 (m 4H) 127 (t J = 74 Hz 3H) 13C-NMR δ 1898 1725 1422 1293 517 321 270 230 146 MS (EI) mz 202 (M+ 4) 142 (8) 141 (100) 113 (21) 109 (29) 81 (13) 71 (45) 59 (10) 53 (8) HRMS Calcd for C9H14O3S 2020664 found 2020673

S

OAcO

S

O

MeO2C

Chapter 5

166


(E)-S-ethyl 3-phenylprop-2-enethioate (8)

The title compound was prepared from S-ethyl thioacrylate 2 (10 mmol 116 mg) and styrene (25 mmol 287 μl) following the procedure described for 3 (reaction time 18 h) Purification by flash column

chromatography (SiO2 05 995 to 1 99 Et2O n-pentane gradient Rf (1 99) = 010) afforded 8 (139 mg 72 yield) as a colorless oil 1H-NMR δ 761 (d J = 158 Hz 1H) 757-751 (m 2H) 742-736 (m 3H) 671 (d J = 158 Hz 1H) 302 (q J = 74 Hz 2H) 132 (t J = 74 Hz 3H) 13C-NMR δ 1899 1401 1341 1304 1289 1283 1250 233 148 MS (EI) mz 192 (M+ 12) 132 (10) 131 (100) 103 (27) 77 (13) HRMS Calcd for C11H12OS 1920609 found 1920599

(E)-6-(ethylthio)-6-oxohex-4-enoic acid (9)

The title compound was prepared from S-ethyl thioacrylate 2 (10 mmol 116 mg) and 4-pentenoic acid (25 mmol 258 μl) following the procedure described for 3 (second portion of 2

mol catalyst added after 16 h total reaction time 24 h) Purification by flash column chromatography (SiO2 05 5 95 to 2 20 80 AcOH EtOAc n-pentane gradient Rf (1 10 90) = 02) afforded 9 (156 mg 83 yield) as an off-white solid Traces of AcOH could be removed by trituration from CHCl3 with n-pentane mp = 695-698 degC 1H-NMR δ 1020 (br s 1H) 684 (dt J = 154 67 Hz 1H) 615 (dt J = 155 15 Hz 1H) 295 (q J = 74 Hz 2H) 259-249 (m 4H) 128 (t J = 74 Hz 1H) 13C-NMR δ 1900 1782 1419 1293 320 266 230 146 MS (EI) mz 188 (M+ 12) 128 (7) 127 (100) 109 (14) 99 (52) 81 (14) 71 (7) 57 (39) 55 (9) 53 (22) HRMS Calcd for C8H12O3S 1880507 found 1880516

(E)-S-Ethyl 7-hydroxyhept-2-enethioate (10)

The title compound was prepared from S-ethyl thioacrylate 2 (10 mmol 116 mg) and 5-hexen-1-ol (25 mmol 300 μl) following

the procedure described for 3 (second portion of 2 mol catalyst added after 16 h total reaction time 24 h) Purification by flash column chromatography (SiO2 40 60 to 70 30 Et2O n-pentane gradient Rf (50 50) = 025) afforded 10 (175 mg 93 yield) as a colorless oil 1H-NMR

S

O

HO S

O

HOS

O

O


167


δ 688 (dt J = 155 69 Hz 1H) 611 (dt J = 155 15 Hz 1H) 365 (t J = 52 Hz 2H) 293 (q J = 74 Hz 2H) 228-219 (m 2H) 166-150 (m 4H) 136 (br s 1H) 127 (t J = 74 Hz 3H) 13C-NMR δ 1902 1447 1286 620 318 316 240 228 146 MS (EI) mz 188 (M+ 7) 127 (31) 99 (5) 82 (7) 81 (100) 79 (8) 68 (9) 57 (6) 55 (16) 53 (10) HRMS Calcd for C9H16O2S 1880871 found 1880876

(E)-S-Ethyl 6-oxohex-2-enethioate (11)

The title compound was prepared from S-ethyl thioacrylate 2 (10 mmol 116 mg) and 1-pentenal (25 mmol 247 μl) following the procedure described for 3 (second portion of 2 mol

catalyst added after 16 h total reaction time 24 h) Purification by flash column chromatography (SiO2 10 90 to 20 80 Et2O n-pentane gradient Rf (10 90) = 02) afforded 11 (129 mg 75 yield) as a colorless oil 1H-NMR δ 979 (t J = 11 Hz 1H) 684 (dt J = 154 67 Hz 1H) 612 (dt J = 155 15 Hz 1H) 293 (q J = 74 Hz 2H) 267-261 (m 2H) 255-247 (m 2H) 126 (t J = 74 Hz 3H) 13C-NMR δ 2000 1895 1420 1292 415 241 229 145 MS (EI) mz 172 (M+ 29) 112 (8) 111 (100) 83 (49) 55 (46) 53 (7) HRMS Calcd for C8H12O2S 1720558 found 1720557

(E)-S-Ethyl 7-bromohept-2-enethioate (12)

The title compound was prepared from S-ethyl thioacrylate 2 (10 mmol 116 mg) and 6-bromohex-1-ene (25 mmol 337 μl)

following the procedure described for 3 (second portion of 2 mol catalyst added after 16 h total reaction time 24 h) Purification by flash column chromatography (SiO2 05 995 to 2 98 Et2O n-pentane gradient Rf (1 99) = 010) afforded 12 (180 mg 72 yield) as a colorless oil 1H-NMR δ 686 (dt J = 155 69 Hz 1H) 612 (dt J = 155 15 Hz 1H) 341 (t J = 66 Hz 2H) 294 (q J = 74 Hz 2H) 228-218 (m 2H) 195-183 (m 2H) 171-158 (m 2H) 128 (t J = 74 Hz 3H) 13C-NMR δ 1899 1439 1290 331 319 311 264 230 147 MS (EI) mz 252 (M+ 11) 250 (M+ 11) 192 (7) 191 (98) 190 (8) 189 (100) 177 (9) 175 (9) 81 (13) 55 (58) HRMS Calcd for C9H15OSBr 2500027 found 2500034

S

O

Br

S

OO

H

Chapter 5

168


(E)-S-Ethyl 4-hydroxypent-2-enethioate (13)

The title compound was prepared from S-ethyl thioacrylate 2 (10 mmol 116 mg) and 3-buten-2-ol (25 mmol 217 μl) following the procedure described for 3 (second portion of 2 mol catalyst added after 16

h total reaction time 24 h) Purification by flash column chromatography (SiO2 10 90 to 50 50 Et2O n-pentane gradient Rf (30 70) = 025) afforded 13 (106 mg 66 yield) as a yellowish oil 1H-NMR δ 679 (dd J = 155 45 Hz 1H) 622 (dd J = 155 17 Hz 1H) 439 (qdd J = 66 46 16 Hz 1H) 327 (br s 1H) 287 (q J = 74 Hz 2H) 125 (d J = 67 Hz 3H) 120 (t J = 74 Hz 3H) 13C-NMR δ 1906 1468 1260 666 231 223 144 MS (EI) mz 160 (M+ 5) 115 (7) 100 (5) 99 (100) 71 (20) 55 (9) HRMS Calcd for C7H12O2S 1600558 found 1600550

(E)-S-Ethyl 4-hydroxy-4-methylpent-2-enethioate (14)

The title compound was prepared from S-ethyl thioacrylate 2 (10 mmol 116 mg) and 2-methyl-3-buten-2-ol (25 mmol 261 μl) following the procedure described for 3 (second portion of 2 mol catalyst

added after 16 h total reaction time 24 h) Purification by flash column chromatography (SiO2 20 80 to 40 60 Et2O n-pentane gradient Rf (30 70) = 03) afforded 14 (124 mg 71 yield) as a yellowish oil 1H-NMR δ 686 (d J = 155 Hz 1H) 626 (d J = 155 Hz 1H) 290 (q J = 74 Hz 2H) 235 (br s 1H) 133 (s 6H) 123 (t J = 74 Hz 3H) 13C-NMR δ 1906 1502 1247 706 291 231 146 MS (EI) mz 174 (M+ 6) 131 (12) 116 (16) 114 (7) 113 (100) 95 (15) 85 (16) 69 (8) 67 (9) 59 (7) 57 (7) 55 (8) HRMS Calcd for C8H14O2S 1740715 found 1740721

(E)-S-Ethyl 4-(4-methylphenylsulfonamido)but-2-enethioate (15)

The title compound was prepared from S-ethyl thioacrylate 2 (10 mmol 116 mg) and N-allyl-4-methylbenzenesulfonamide (25 mmol 528 mg) following the procedure described for 3 (second portion

of 2 mol catalyst added after 16 h total reaction time 24 h) Purification by flash column chromatography (SiO2 20 80 to 60 40 Et2O n-pentane gradient Rf (40 60) = 02) afforded 15 (176 mg 71 yield) as a white

S

O

OH

S

O

OH

HN

S

O

SO O


169


solid mp = 685-694 degC 1H-NMR δ 773 (d J = 83 Hz 2H) 730 (d J = 83 Hz 2H) 663 (dt J = 155 51 Hz 1H) 614 (dt J = 155 17 Hz 1H) 520 (t J = 63 Hz 1H) 377-369 (m 2H) 289 (q J = 74 Hz 2H) 241 (s 3H) 123 (t J = 74 Hz 3H) 13C-NMR δ 1894 1437 1379 1365 1298 1292 1270 436 232 214 145 MS (EI) mz 299 (M+ 07) 239 (6) 238 (40) 156 (7) 155 (89) 144 (23) 92 (9) 91 (100) 82 (10) 65 (13) 55 (7) HRMS Calcd for C13H17NS2O3 2990650 found 2990666

(E)-4-(Ethylthio)-4-oxobut-2-enyl acetate (16)

The title compound was prepared from S-ethyl thioacrylate 2 (10 mmol 116 mg) and cis-14-diacetoxy 2-butene (15 mmol 239 μl) following

the procedure described for 3 (second portion of 2 mol catalyst added after 16 h total reaction time 24 h) Purification by flash column chromatography (SiO2 5 95 to 10 90 Et2O n-pentane gradient Rf (10 90) = 030) afforded 16 (123 mg 65 yield) as a colorless oil 1H-NMR δ 682 (dt J = 156 46 Hz 1H) 627 (dt J = 156 19 Hz 1H) 472 (dd J = 46 19 Hz 2H) 295 (q J = 74 Hz 2H) 211 (s 3H) 126 (t J = 74 Hz 3H) 13C-NMR δ 1893 1701 1366 1287 623 232 206 146 MS (EI) mz 234 (6) 188 (M+ 10) 159 (23) 132 (10) 131 (15) 127 (34) 111 (17) 85 (100) 71 (10) 57 (5) HRMS Calcd for C8H12O3S 1880507 found 1880514

(E)-S-ethyl 4-bromobut-2-enethioate (17)

The title compound was prepared from S-ethyl thioacrylate 2 (10 mmol 116 mg) and trans-14-dibromo 2-butene (15 mmol 321 mg) following the

procedure described for 3 (second portion of 2 mol catalyst added after 16 h total reaction time 24 h) Purification by flash column chromatography (SiO2 05 995 to 2 98 Et2O n-pentane gradient Rf (2 98) = 025) afforded 17 (134 mg 64 yield) as a yellowish oil 1H-NMR δ 691 (dt J = 152 73 Hz 1H) 627 (dt J = 152 12 Hz 1H) 400 (dd J = 73 12 Hz 2H) 297 (q J = 74 Hz 2H) 129 (t J = 74 Hz 3H) 13C-NMR δ 1890 1371 1308 291 232 145 MS (EI) mz 250 (7) 210 (M+ 6) 208 (M+ 7) 189 (22) 149 (55) 147 (100) 129 (12) 121 (5) 119 (6) 113 (9) 103 (9) 91 (7) 85 (6) 83 (8) 69 (6) 68 (22) 57 (7) 55 (5) HRMS Calcd for C6H9OSBr79 2079557 found 2079563

S

OAcO

S

OBr

Chapter 5

170


References 1 a) Yang W Drueckhammer D G J Am Chem Soc 2001 123 11004-11009 b) Wiberg K B J Chem Educ 1996 73 1089-1095 c) Cronyn M W Chang M P Wall R A J Am Chem Soc 1955 77 3031-3034 2 a) Staunton J Weissman K J Nat Prod Rep 2001 18 380-416 b) Stryer L Biochemistry 4th ed Freeman New York 1995 c) Bruice T C Benkovic S J Bioorganic Mechanisms W A Benjamin New York 1966 Vol 1 3 a) Johnson J S Evans D A Acc Chem Res 2000 33 325-335 b) Fortner K C Shair M D J Am Chem Soc 2007 129 1032-1033 c) Gennari C Vulpetti A Pain G Tetrahedron 1997 53 5909-5924 d) Kobayashi S Uchiro H Fujishita Y Shiina I Mukaiyama T J Am Chem Soc 1991 113 4247-4252 e) Gennari C Beretta M G Bernardi A Moro G Scolastico C Todeschini R Tetrahedron 1986 42 893-909 f) Evans D A Nelson J V Vogel E Taber T R J Am Chem Soc 1981 103 3099-3111 4 McGarvey G J Williams J M Hiner R N Matsubara Y Oh T J Am Chem Soc 1986 108 4943-4952 5 Fukuyama T Lin S-C Li L J Am Chem Soc 1990 112 7050-7051 6 a) Wittenberg R Srogl J Egi M Liebeskind L S Org Lett 2003 5 3033-3035 b) Liebeskind L S Srogl J J Am Chem Soc 2000 122 11260-11261 7 For a review on thioester chemistry developed in the last ten years see Fujiwara S-I Kambe N Top Curr Chem 2005 251 87-140 8 a) Agapiou K Krische M J Org lett 2003 5 1737-1740 b) Bandini M Melloni A Tommasi S Umani-Ronchi A Helv Chim Acta 2003 86 3753-3763 c) Emori E Arai T Sasai H Shibasaki M J Am Chem Soc 1998 120 4043-4044 d) Kobayashi S Tamura M Mukaiyama T Chem Lett 1988 91-94 9 a) Maciaacute Ruiz B Geurts K Fernaacutendez-Ibaacutentildeez M A ter Horst B Minnaard A J Feringa B L Org Lett 2007 9 5123-5126 b) Des Mazery R Pullez M Loacutepez F Harutyunyan S R Minnaard A J Feringa B L J Am Chem Soc 2005 127 9966-9967 10 a) ter Horst B Feringa B L Minnaard A J Org Lett 2007 9 3013-3015 b) ter Horst B Feringa B L Minnaard A J Chem Commun 2007 489-491 c) van Summeren R P Moody D B Feringa B L Minnaard A J J Am Chem Soc 2006 128 4546-4547 d) Howell G P Fletcher S P Geurts K ter Horst B Feringa B L J Am Chem Soc 2006 128 14977-14985 11 The classical synthetic methods are described in the Supporting Information of ref 9b


171


12 See chapter 4 Experimental Part 13 a) Hoveyda A H Zhugralin A R Nature 2007 450 243-251 b) Nicolaou K C Bulger P G Sarlah D Angew Chem Int Ed 2005 44 4490-4527 c) Grubbs R H Tetrahedron 2004 60 7117-7140 d) Fuumlrstner A Alkene Metathesis in Organic Synthesis Springer Berlin 1998 14 Connon S J Blechert S Angew Chem Int Ed 2003 42 1900-1923 15 Chatterjee A K Choi T-L Sanders D P Grubbs R H J Am Chem Soc 2003 125 11360-11370 16 a) Shon Y-S Lee T R Tetrahedron Lett 1997 38 1283-1286 b) Armstrong S K Christie B A Tetrahedron Lett 1996 37 9373-9376 c )Lefebvre F Leconte M Pagano S Mutch A Basset J-M Polyhedron 1995 14 3209-3226 d) OrsquoGara J E Portmess J D Wagener K B Macromolecules 1993 26 2837-2841 17 a) Spagnol G Heck M-P Nolan S P Mioskowski C Org Lett 2002 4 1767-1770 b) Toste F D Chatterjee A K Grubbs R H Pure Appl Chem 2002 74 7-10 18 Smulik J A Giessert A J Diver S T Tetrahedron Lett 2002 43 209-211 19 See for example a) Sashuk V Samojłowicz C Szadkowska A Grela K Chem Commun 2008 2468-2470 b) Katayama H Nagao M Ozawa F Organometallics 2003 22 586-593 20 See for example Nicolaou K C Koftis T V Vyskocil S Petrovic G Ling T Yamada Y M A Tang W Frederick M O Angew Chem Int Ed 2004 43 4318-4324 see also reference 17a 21 a) Bieniek M Michrowska A Usanov D L Grela K Chem Eur J 2008 14 806-818 b) Shi Z Harrison B A Verdine G L Org Lett 2003 5 633-636 22 a) Schaumann E Mergardt B J Chem Soc Perkin Trans 1 1989 1361-1363 b) Braude G J Org Chem 1957 22 1675-1678 c) Marvel C S Jacobs S L Taft W K Labbe B G J Polymer Sci 1956 19 59-72 23 Keck G E Boden E P Mabury S A J Org Chem 1985 50 709-710 24 Kingsbury J S Harrity J P A Bonitatebus P J Jr Hoveyda A H J Am Chem Soc 1999 121 791-799 25 Grela K Harutyunyan S Michrowska A Angew Chem Int Ed 2002 41 4038-4040


In this chapter the application of copper catalyzed asymmetric allylic alkylation in the preparation of chiral heterocyclic compounds is described The products of Cu-AAA are subjected to ring-closing metathesis Heck reactions and iodo-cyclization reactions thus allowing for the relevant chiral heterocyclic building blocks to be obtained in high optical purity

Chapter 6

174


61 Introduction Heterocycles form a common structural element in natural products and

pharmaceutical compounds Many of the most famous natural or unnatural drugs consist of at least one heterocycle (Figure 61)1 In addition these heterocycles are frequently substituted in a chiral fashion ie the ring contains stereogenic centers The diversity in structure of these heterocyclic motifs is enormous since variation in ring size number and nature of the heteroatoms and substitution pattern on the ring is effectively unlimited

Figure 61 A selection of pharmaceutical compounds containing a chiral heterocyclic motif efavirenz (1) an HIV-1 non-nucleoside reverse transcriptase inhibitor vinblastine (2) an anti-cancer chemotherapeutic agent fenoldopam mesylate (3) a dopamine D1-like receptor agonist artemisinin (4) an anti-malarial agent penicillin G (5) an antibiotic morphine (6) an analgesic

Catalytic enantioselective methods that allow for the preparation of single enantiomers of heterocyclic compounds are relevant and widely recognized objectives for synthetic chemists The development of new routes to these compounds which are faster more economical or allow for more facile structural variation is important in general and particularly for the pharmaceutical industry

Preparation of chiral heterocyclic compounds via enantioselective Cu-catalyzed allylic alkylation

175


611 Application of Cu-AAA products in cyclization reactions Copper catalyzed asymmetric allylic alkylation (Cu-AAA) furnishes

products which have a terminal double bond adjacent to the stereogenic center being formed This double bond can be an ideal handle in cyclization reactions It allows for ring-closing metathesis Heck reactions radical cyclization iodo-lactonization etc The only prerequisite is the presence of functionality elsewhere in the molecule that enables the intended reaction

Scheme 61 Cyclization of allylic alkylation products a) introduction of the necessary reactive functional group during Cu-AAA b) presence of the necessary reactive functional group before Cu-AAA FG = functional group LG = leaving group

The required functional group can (a) be introduced as part of the nucleophile or (b) be present in the substrate before the allylic alkylation (Scheme 61) The reactive functionality should be compatible with the conditions of the allylic alkylation A few examples of the application of cyclization reactions to the products of copper catalyzed asymmetric allylic alkylation have been reported elsewhere For instance in the formal total synthesis of ethosuximide discussed earlier in section 313 (Scheme 39) hydroboration of the double bond leads to lactone formation2

Alexakis and coworkers applied ring-closing metathesis (RCM) to products obtained through allylic alkylation with unsaturated alkyl Grignard reagents (Scheme 62)3 The reaction provided five- and six-membered carbocycles containing a di- or tri-substituted alkene double bond without a decrease in the excellent enantiomeric excess compared to the uncyclized products The reaction could be performed in one-pot with the copper

Chapter 6

176


catalyzed allylic alkylation demonstrating the compatibility of the metathesis catalyst with excess Grignard reagent magnesium salts and the copper catalyst

Scheme 62 Ring-closing metathesis reaction performed on the products of an enantioselective copper catalyzed allylic alkylation TC = 2-thiophenecarboxylate G-1 = Grubbs first generation catalyst

A similar procedure was applied by Geurts et al to two chiral allylic esters which were obtained through copper catalyzed allylic alkylation of 3-bromoprop-1-enyl esters with Grignard reagents and the ligand Taniaphos L1 (Scheme 63)4 Both approaches (a) and (b) shown in Scheme 61 were employed In one case a similar approach that Alexakis and co-workers used was followed ie the introduction of an additional olefin through the use of an unsaturated Grignard reagent Ring-closing metathesis yielded the carbocycle cyclopent-2-enyl benzoate in good yield and excellent enantiomeric excess (85 97 ee)

Scheme 63 Ring-closing metathesis applied to chiral allylic esters obtained through copper catalyzed allylic alkylation using the ligand Taniaphos L1 G-2 = Grubbs second generation catalyst HG-2 = Hoveyda-Grubbs second generation catalyst Bz = benzoyl Cin = cinnamoyl


177


Ring-closing metathesis (RCM) of a chiral cinnamate ester where the second double bond was present in the substrate before allylic alkylation provided a naturally occurring butyrolactone with excellent enantioselectivity (78 98 ee)5 This compound has been applied several times in natural product synthesis also This new route represents one of the most direct and fastest routes to obtaining this intermediate in an asymmetric fashion6

As discussed previously the possiblility of subsequent cyclization reactions depends on the compatibility of the reactive functionality with the conditions of the allylic alkylations The high functional group tolerance of the copper catalyzed allylic alkylation with Grignard reagents using the ligand Taniaphos (see chapters 2 and 3) was an incentive to explore the possibilities of this reaction in the preparation of heterocyclic compounds further In this chapter copper catalyzed allylic alkylation will be applied in the synthesis of several chiral nitrogen and oxygen containing heterocycles

Chapter 6

178



621 Application of Cu-AAA and ring-closing metathesis Ring-closing metathesis7 is an elegant and efficient method to obtain

cyclic chiral compounds from the products of Cu-AAA8 Depending on the nature of the substrates used the reaction can be employed to obtain chiral lactones piperidines and azepines (vide infra)

6211 Chiral γ-substituted dihydropyranones The synthetic route to chiral butyrolactones through Cu-AAA and RCM

as described previously can be extended to dihydropyranones by application of modified substrates in the copper catalyzed allylic alkylation (Scheme 64) These six-membered lactones form a common motif in natural products including for instance neonepetalactone (7)9 and bitungolide B (8)10

Scheme 64 Naturally occurring six-membered lactones neonepetalactone (7) and bitungolide B (8) and the proposed route to chiral dihydropyranones

The substrates were synthesized from 14-dibromobut-2-ene through reaction with a deprotonated carboxylic acid in acetonitrile11 Two substrates were prepared the cinnamic acid ester 9a and the crotonic acid ester 9b The allylic bromides were subjected to the conditions described in chapter 2 (Table 61) Substitution of cinnamate 9a and crotonate 9b with MeMgBr proceeded in good yield and regioselectivity using the ligand


179


Taniaphos L1 (Scheme 63) the products 10a and 10b were obtained with 89 and 90 enantiomeric excess respectively (Table 61 entries 1 and 2) Since MeMgBr does not react with αβ-unsaturated esters under these conditions 14-addition by-products were not observed However the application of EtMgBr led to small amounts of a 14-adduct which was minimized by using a reduced excess of the Grignard reagent (105 equiv vs 12 equiv) Product 10c was obtained in good yield regioselectivity and enantiomeric excess (entry 3)

Table 61 Copper catalyzed allylic alkylation of allylic bromides 9a and 9ba

entry 9 R RrsquoMgBr product yieldb b lc eec

1 9a Ph MeMgBr 10a 91 96 4 89

2 9b Me MeMgBr 10b 94 94 6 90

3d 9b Me EtMgBr 10c 89 98 2 88 a Reaction conditions 9 (10 equiv) CuBrmiddotL1 (10 mol) RrsquoMgBr (12 equiv) CH2Cl2 minus75 degC b Isolated yield of the mixture of regioisomers c Determined by chiral GC or HPLC d EtMgBr (105 equiv)

In contrast to the formation of five-membered unsaturated lactones (section 611) the formation of six-membered lactones through ring-closing metathesis of the cinnamate ester proceeded with difficulty Heating a solution of cinnamate 10a and 10 mol Hoveyda-Grubbs 2nd generation catalyst (HG-2) in dichloromethane at reflux temperature for five days led to the formation of 12 the dimer of 10a as the major product (Table 62 entry 1) The lactone was isolated in only 25 yield Under more dilute conditions dimerisation of the substrate was less pronounced However the yield of the lactone remained low even when the reaction temperature was raised by performing the reaction in refluxing toluene (entries 2 and 3)

Chapter 6

180


Table 62 Ring-closing metathesis reactions with compounds 10a-ca

entry 10 R Rrsquo solvent conc time 11 yieldb eec

1d 10a Ph Me CH2Cl2 50 mM 5 d 11a 25e 89

2 10a Ph Me CH2Cl2 5 mM 4 d 11a 30 nd

3 10a Ph Me PhMe 5 mM 18 h 11a 35 nd

4 10b Me Me PhMe 20 mM 2 h 11a 83f 90

5 10c Me Et PhMe 20 mM 2 h 11b 71f 87 a Reaction conditions 10 (10 equiv) HG-2 (5 mol) reflux b Isolated yield after column chromatography c Determined by chiral GC or HPLC d 10 mol HG-2 used e 53 of dimerization by-product 12 was isolated f Isolated yield after chromatography but not distilled

On the other hand ring-closing metathesis of crotonate ester 10b in refluxing toluene proceeded substantially faster and led to complete conversion of the substrate in 2 h (entry 4) Lactone 11a was obtained in 83 yield and the enantiomeric excess remained 90 The ethyl substituted lactone 11b could be obtained in good yield under the same conditions also (entry 5) The remarkable difference in reactivity can be attributed to two factors Substitution of the phenyl group by a methyl group decreases the conjugation of the internal double bond and renders it more prone to metathesis In addition the side-products formed during metathesis (styrene and stilbene for 10a vs propene and 2-butene for 10b and 10c) are volatiles in the case of the crotonate esters thereby driving the reaction equilibrium towards the cyclized product


181


It has to be noted that although the products were gt95 pure as determined by NMR-spectroscopy removal of the catalyst (whose presence in the product was confirmed due to the products color) was difficult using column chromatography Kugelrohr distillation of compound 11a obtained after chromatography led to a substantially lower yield (57) and the formation of trace impurities of a new compound most likely the achiral isomeric lactone 13

6212 Chiral 5-methyl-34-dehydropiperidines Chiral piperidine rings are a common motif in natural products and

pharmaceuticals (for example compounds 2 and 6 Figure 61) The formation of dehydropiperidine analogues through diene and enyne ring-closing metathesis of N-butenyl allylic and propargylic amides respectively is well-known8 The Cu-catalyzed allylic alkylation should be an efficient method to provide enantiomerically pure precursors for these cyclizations

Substrates 14 and 15 for the allylic alkylation were prepared in two steps from allylamine and propargylic bromide respectively (Scheme 65)12 Preparation of allylic and propargylic tosylamides was followed by reaction with 14-dibromobut-2-ene to yield the allylic bromides

Scheme 65 Synthesis of substrates containing an allylic and propargylic tosylamide

Copper catalyzed asymmetric allylic alkylation of substrate 14 with methyl Grignard reagent and the ligand Taniaphos L1 provided the chiral piperidine precursor 16 in 62 yield and excellent regio- and

Chapter 6

182


enantioselectivity (Scheme 66) Subsequent ring-closing metathesis with 5 mol Hoveyda-Grubbs second generation catalyst (HG-2) provided the chiral heterocyclic compound 17 in good yield and with retention of the high enantiomeric excess Traces of a five-membered pyrrole compound which was formed through ring-closing metathesis of the linear SN2 product were removed readily through column chromatography

Scheme 66 Asymmetric synthesis of chiral piperidine 17 through Cu-AAA and RCM

Substrate 15 which contains a propargylic tosylamide was alkylated using the same conditions (Scheme 67) Product 18 was obtained in 96 yield and excellent regioselectivity and enantiomeric excess

Scheme 67 Asymmetric Cu-catalyzed allylic alkylation of substrate 15 using MeMgBr

Enyne ring-closing metathesis reactions generally provide cyclic diene compounds13 The possible use of these compounds in subsequent Diels-Alder reactions makes them highly versatile intermediates in the synthesis of bicyclic or polycyclic products The ring-closing metathesis of compound 18 was attempted with the Grubbs first generation (G-1) the Grubbs second generation (G-2) and the Hoveyda-Grubbs second generation (HG-2)


183


catalysts at different temperatures (Table 63 entries 1-3) In all three cases either conversion was low (lt10 overnight) or a complex mixture of products was obtained

Table 63 Enyne ring-closing metathesis reactions with propargylic tosylamide 18a

entry cat solvent T yieldb (ee)c

1 G-1 (5 mol) CH2Cl2 rt ndd

2 G-2 (5 mol) CH2Cl2 reflux nde

3 HG-2 (5 mol) PhMe reflux nde

4 G-1 (2 mol) CH2Cl2 (ethene) rt 90 (98)

5 G-2 (2 mol) CH2Cl2 (ethene) rt ndde

6 HG-2 (2 mol) CH2Cl2 (ethene) rt ndde

a Reaction conditions 18 Ru-catalyst (2 or 5 mol) 18 h b Isolated yield c Determined by chiral HPLC d Low conversion e Complex mixture of products

In many cases difficulties in enyne metathesis can be overcome through the use of an ethene atmosphere1314 Although the second generation catalysts provided low conversion and complex product mixtures (Table 63 entries 5 and 6) with the Grubbs first generation catalyst the reaction proceeds efficiently under an ethene atmosphere (entry 4) Heterocyclic diene 19 was obtained in 90 yield and an undiminished enantiomeric excess of 98 Here the traces of pyrrole by-product originating from the SN2 allylic substitution product could be removed readily also

Chapter 6

184


6213 Chiral 36-dimethyl-2367-tetrahydroazepine Seven-membered azacycles are components of a substantial number of

pharmaceuticals today eg diazepam (Valiumtrade) and fenoldopam mesylate (3) (Figure 61) A facile catalytic protocol for the synthesis of chiral azepine derivatives would therefore be of potential value to the pharmaceutical industry

Compound 2015 which has two allylic bromide moieties can be methylated twice using the aforementioned conditions with 4 equiv MeMgBr and 10 mol catalyst (Scheme 68) The reaction leads to three distinct products16 the chiral SN2rsquoSN2rsquo-product 21 (91 gt995 ee) the diastereomeric achiral meso-21 (4) and the SN2rsquoSN2-product 22 (5) A SN2SN2-product was not observed

Scheme 68 Double allylic alkylation of compound 20 provides three distinct products

Compound 21 (mixture of optically active and meso-compound) was subjected to ring-closing metathesis conditions ie with the Grubbs first generation catalyst (G-1) in dichloromethane and the seven-membered heterocycle 23 was obtained in 94 yield high diastereomeric ratio and enantiomerically pure

Scheme 69 Ring-closing metathesis of compound 21 to form an azepine heterocycle


185



The double bond obtained by allylic alkylation can in principle be used in a subsequent Pd-catalyzed coupling reactions in particular the Heck reaction The Heck reaction couples an aryl or alkenyl halide to a carbon-carbon double bond17 The presence of an aryl halide in the product of allylic alkylation would provide for an intramolecular Heck reaction leading to a chiral bicyclic compound

Two substrates compounds 24a and 24b which contain an bromoaryl functionality were prepared in high yield from 14-dibromobut-2-ene and o-bromophenol or tosyl protected o-bromoaniline respectively (Table 64) The subsequent enantioselective copper catalyzed allylic alkylation proceeded smoothly providing the products 25a and 25b in excellent regio- and enantioselectivity

Table 64 Asymmetric synthesis of bicyclic compounds via Cu-AAA and Heck reactiona

entry Y 24 yield 25 yieldb blc ee 25d 26 yield ee 26d

1 O 24a 95 25a 60 1000 95 26a 37 93

2 NTs 24b 81 25b 68 946 gt90 26b 62 94 a Reaction conditions 1st step 14-dibromobut-2-ene (4 equiv) K2CO3 (15 equiv) MeCN reflux 2nd step MeMgBr (12 equiv) 1 mol CuBrmiddotSMe2 12 mol L1 CH2Cl2 minus75 degC 3rd step 5 (26a) or 10 (26b) mol Pd(OAc)2 20 or 40 mol PPh3 K2CO3 (6 equiv) MeCN reflux b Isolated yield of the mixture of regioisomers c Determined by 1H-NMR-spectroscopy d Determined by chiral GC or HPLC

Chapter 6

186


The Heck reaction which connects the aromatic and the olefinic moieties thereby forming the bicyclic compound with an exocyclic double bond was performed with catalytic amounts of Pd(OAc)2 and PPh318 The chromane derivative 26a (Y = O) was obtained as a 75 25 mixture with its isomer in which the double bond has migrated to form an achiral compound with an endocyclic tetrasubstituted alkene 27a ie 34-dimethyl-2H-chromene The compounds were separable and 26a was obtained in 37 yield The reduced yield is most probably due to its volatility The quinoline derivative 26b was obtained as a 78 22 mixture with the isomeric compound 27b (Y = NTs) The presence of 27 indicates the possibility of a Pd-catalyzed allylic isomerisation of the double bond which proceeds under the reaction conditions This could explain the slightly lower enantiomeric excess of 26a compared to 25a

623 Synthesis of a chiral oxazinanone through iodo-cyclocarbamation Six-membered cyclic carbamates also known as oxazinanones are

important intermediates in the synthesis of compounds containing 13-aminoalcohols The motif can be found in pharmaceutical compounds also such as for example efavirenz 1 (Figure 61) Chiral oxazinanones can be obtained through iodo-cyclization of carbamate protected homoallylic amines19

Compound 28 which was obtained in high enantiomeric excess (95) through an enantioselective copper catalyzed allylic alkylation (see chapter 3) was subjected to iodine to yield compounds 29 in a 21 ratio (Scheme 610) The syn-diastereomer 29a which was the major product could be obtained in 55 yield and racemization of the product was not observed (95 ee)

The relative configuration of the two products was established through comparison of the corresponding NOESY spectra The assumption was made that NOE between two pseudo-equatorial substituents and between a pseudo-equatorial and a pseudo-axial substituent can be observed In compound 29b NOE were observed between the -CHCH3 protons and the -CH2I protons (eqeq) between the -CHCH3 protons and the -CH2N- protons (eqeq and eqax) and between the -CHCH3 protons and the -C(H)O- proton (eqax) and no NOE was observed between the -C(H)O- proton and the -CHCH3 proton (axax) In 29a NOE were observed between the -CHCH3


187


protons and one of the -CH2N- protons (axeq and axax) and between the -CHCH3 protons and one of the -CH2I protons (axeq) and no NOE was observed between the -CHCH3 protons and the -C(H)O- proton (axax)

Scheme 610 Iodo-cyclization of 28 leads to the syn-diastereomer as the major product

It is surprising that the syn-diastereomer is the major product since the thermodynamically favoured product is the anti-product20 It appears that the syn-diastereomer is the kinetic product This implies that the iodination is the stereodiscriminating step of the reaction However it is no trivial matter to predict the stereochemistry of this reaction In contradiction to steric arguments the double bond is preferentially eclipsed or pseudo-eclipsed with one of the allylic substituents due to orbital interactions (Scheme 611)21 Although the Felkin-Anh model cannot be applied to an electrophilic addition one would expect the addition to proceed on the least hindered face of the double bond Since the syn-diastereomer 29a is the major product the most stable or most reactive conformation has to be that in which the methyl group eclipses the olefin as opposed to the smaller hydrogen eclipsing the olefin However an explanation for this could not be established at the time

Scheme 611 Electrophilic addition to the double bond of compound 28 in the conformation which has the methyl substituent eclipsing with the alkene moiety leads to the syn-product

Chapter 6

188


624 Asymmetric synthesis of a motor upper half precursor Aside from the relevance of chiral compounds in the pharmaceutical

industry they are important in the field of nanotechnology also Many molecular devices are chiral and some of their effects are negated by the use of a racemate22 Hence there is a need to develop methods that allow asymmetric synthesis of building blocks for these compounds

The molecular light driven motors developed in the group of Feringa are a good example of chiroptic molecular devices23 They consist of an overcrowded alkene and two halves which are the same in the first generation motors and different in the second generation motors (Figure 62) The unidirectionality of the motorsrsquo rotary motion is directed by the stereogenic center in the ldquoupper halfrdquo (both halves in the case of first generation motors) Applying the rotary motion of the motors to perform work requires that they are incorporated in larger devices or arrays of multiple molecules In that case it is essential to be able to obtain the enantiomerically pure compound in sufficient quantities

Figure 62 First generation (a) and second generation (b) molecular light driven motors and the chiral ketone precursor (c)

Several methods based on resolution chiral auxiliaries and chiral pool have been applied to the asymmetric synthesis of the ketone precursors24 Asymmetric catalysis has been applied only to the ldquofive-ring upper halfrdquo-motors enantioselective hydrogenation of an αβ-unsaturated carboxylic acid gave the desired compound in 98 ee25 However this method does not allow for the enantioselective synthesis of ldquosix-ring upper halfrdquo-ketones

Enantioselective copper catalyzed allylic alkylation of compound 30 provides compound 31 in good yield and excellent selectivity (Scheme 612) Cleaving the double bond would furnish carboxylic acid 32 which is


189


a precursor to a ldquosix-ring upper halfrdquo-ketone26 This was not as easy as it seemed Ozonolysis followed by oxidation and Ru-catalyzed double bond cleavage led to complete degradation of the naphthyl moiety Os-catalyzed dihydroxylation proceeded to yield the desired diastereomeric mixture of diols however oxidative cleavage of these diols gave a complex mixture of products Oxidative cleavage of the double bond was achieved eventually using potassium permanganate under acidic conditions and provided the carboxylic acid in good yield and without loss of enantiomeric excess

Scheme 612 Catalytic asymmetric synthesis of motor upper half precursor through copper catalyzed allylic alkylation and oxidative cleavage of the olefinic bond

It has to be noted though that the second generation motors are often synthesized through a Barton-Kellogg coupling of a thioketone and a diazo compound The formation of diazo compounds from chiral ketones at present does not proceed with complete retention of stereochemistry ie optically pure compounds racemize partially under the reaction conditions24 More studies are required regarding this step of motor synthesis before catalytic enantioselective methods for the preparation of chiral precursors can be applied to the synthesis of second generation motors efficiently However first generation motors are generally prepared through a McMurry coupling of two identical chiral ketones In this case the motor synthesis proceeds with full retention of stereochemistry which makes an asymmetric catalytic method to prepare their precursors valuable

Chapter 6

190


63 Conclusions Relevant natural products and pharmaceutical compounds often contain

one or multiple heterocycles Therefore the development of catalytic asymmetric methods to obtain enantiomerically pure heterocyclic compounds is an important goal in synthetic organic chemistry

It has been demonstrated in this chapter that the enantioselective copper catalyzed allylic alkylation with Grignard reagents is an excellent method to obtain precursors to chiral heterocyclic compounds in high optical purity Several cyclization reactions were demonstrated to be applicable to the products of allylic alkylation without racemization However many more cyclization reactions could be utilized in combination with Cu-AAA and the results described in this chapter are merely an exploration into this new route to obtain heterocycles

In some cases optimization is needed to improve the routes described in this chapter The synthesis of lactones requires the enantioselectivity of the allylic alkylation to be increased and a more efficient work-up procedure is needed to obtain the lactones in high yield and purity The Heck reaction in section 622 should be improved to prevent racemization and isomerisation and increase the yield of the products If that were accomplished this innovative route into quinoline and chromane derivatives bearing an exocyclic olefin would be highly valuable

Despite the exploratory nature of these studies several important results were attained In particular the synthesis of piperidine and azepine derivatives through ring-closing metathesis the synthesis of a syn-oxazinanone through iodo-cyclization and the synthesis of a chiral benzochromenone precursor (the motor upper half) provide chiral building blocks in high enantiomeric excess These promising results open new avenues for the use of Cu-AAA in the synthesis chiral heterocyclic compounds


191



Compound 2015 allyl tosylamide12a propargyl tosylamide27 and o-bromophenyl tosylamide28 were prepared according to literature procedures The asymmetric synthesis of compound 28 is described in chapter 3 Toluene was distilled from Nabenzophenone and CH2Cl2 was distilled from CaH2 Allylic alkylations metathesis reactions and Heck reactions were conducted under a nitrogen atmosphere using standard Schlenk techniques The products 11a 11b and 32 have been described previously (see appropriate references in the following pages)

The absolute configurations of the compounds which are shown in the representations accompanying each experimental procedure are related to the enantiomer of the ligand used (based on the results obtained in preceding chapters) They are not correlated to the optical rotation by comparison to that of known literature compounds with the exception of compounds 10a 10b 11a and 29 (vide infra)

(E)-4-Bromobut-2-enyl cinnamate (9a)

NaHCO3 (15 mmol 13 g) was added to a solution of cinnamic acid (10 mmol 148 g) in MeCN (20 mL) The resulting suspension was

stirred and a solution of (E)-14-dibromobut-2-ene (15 mmol 32 g) in MeCN (10 mL) was added in one portion The reaction mixture was heated to reflux temperature for 24 h after which it was concentrated H2O (50 mL) was added and the mixture was extracted with Et2O (2 x 50 mL) The combined organic layers were dried (MgSO4) filtered and concentrated The residue was purified by flash chromatography (SiO2 298 to 1090 Et2On-pentane gradient Rf (595) = 02) which afforded 9a (42 yield 119 g) as a colourless oil 1H-NMR δ 771 (d J = 160 Hz 1H) 754-749 (m 2H) 740-735 (m 3H) 645 (d J = 160 Hz 1H) 606-598 (m 1H) 591 (dt J = 152 and 57 Hz 1H) 471 (dd J = 56 and 07 Hz 2H) 396 (d J = 72 Hz 2H) 13C-NMR δ 1662 1450 1340 1302 1297 1288

Ph O

OBr

Chapter 6

192


1287 1279 1174 633 313 MS (EI) mz 202 (8) 201 (57) 132 (10) 131 (100) 103 (34) 102 (10) 77 (24) 54 (6) 53 (11) 51 (9) MS (CI) mz 582 (6) 580 ([2M+NH4]+ 10) 578 (5) 301 (14) 300 ([M+NH4]+ 100) 299 (15) 298 ([M+NH4]+ 99) HRMS Calcd for [MminusBr]+ C13H13O2 2010916 found 2010926

(E)-4-Bromobut-2-enyl crotonate (9b)

The title compound was prepared from crotonic acid (10 mmol 086 g) and (E)-14-dibromo-2-butene (15 mmol 32 g) following the procedure

described for 9a Purification by flash chromatography (SiO2 298 to 1090 Et2On-pentane gradient Rf (496) = 02) afforded 9b (49 yield 107 g) as a colorless oil 1H-NMR δ 697 (dq J = 155 and 69 Hz 1H) 594 (dtt J = 154 69 and 11 Hz 1H) 588-579 (m 2H) 460 (app d J = 52 Hz 2H) 391 (app d J = 55 2H) 185 (dd J = 69 and 17 Hz 3H) 13C-NMR δ 1657 1452 1295 1290 1221 630 313 179 MS (EI) mz 139 (51) 69 (100) 54 (8) 53 (12) MS (CI) mz 456 ([2M+NH4]+ 8) 255 (19) 253 (19) 239 (14) 238 ([M+NH4]+ 100) 237 (14) 236 ([M+NH4]+ 100) HRMS Calcd for [MminusBr]+ C8H11O2 1390759 found 1390755

(+)-(R)-2-Methylbut-3-enyl cinnamate (10a)

In a Schlenk tube equipped with septum and stirring bar CuBrmiddot(SS)-L1 complex (1 mol 83 mg) was dissolved in CH2Cl2 (20 mL) and the solution was stirred under an argon atmosphere at

room temperature for 10 min The mixture was cooled to ndash75 oC and the methyl Grignard reagent (12 mmol 30 M solution in Et2O 04 mL) was added dropwise Allylic bromide 9a (10 mmol 281 mg) was added dropwise as a solution in 03 mL CH2Cl2 at that temperature over 15 min Once the addition was complete the resulting mixture was stirred at ndash75 oC for a further 16 h The reaction was quenched by addition of MeOH (05 mL) and the mixture was allowed to reach rt Subsequently sat aq NH4Cl (5 mL) was added and the organic layer was separated The resulting aqueous layer was extracted with Et2O (2 x 5 mL) The combined organic layers were dried (MgSO4) and concentrated to yield a yellow oil which was purified by flash chromatography (SiO2 199 to 298 Et2On-pentane gradient Rf (298) = 015) to afford a 964 mixture of 10a and its

O

OBr

Ph O

O


193


regioisomer (196 mg) as a colorless oil [91 yield 89 ee [α]D = +87 (c 10 CHCl3)] 1H-NMR δ 769 (d J = 160 Hz 1H) 756-751 (m 2H) 741-736 (m 3H) 645 (d J = 160 Hz 1H) 580 (ddd J = 174 104 and 70 Hz 1H) 515-505 (m 2H) 413 (dd J = 107 and 69 Hz 1H) 408 (dd J = 108 and 66 Hz 1H) 266-255 (m 1H) 110 (d J = 68 Hz 3H) 13C-NMR δ 1669 1447 1400 1343 1302 1288 1280 1180 1149 683 370 164 MS (EI) mz 216 (M+ 6) 148 (14) 147 (5) 132 (11) 131 (100) 104 (5) 103 (31) 102 (7) 77 (21) 68 (6) 51 (6) HRMS Calcd for C14H16O2 2161150 found 2161143 Enantiomeric excess determined for derivatized product 11a

(+)-(R)-2-Methylbut-3-enyl crotonate (10b)

The title compound was prepared from 9b (40 mmol 876 mg) following the procedure described for 10a Purification by flash chromatography (SiO2 298 Et2Opentane Rf = 02) afforded a 946 mixture

of 10b and its regioisomer (581 mg) as a colorless oil [94 yield 90 ee [α]D = +99 (c 09 CHCl3)] 1H-NMR δ 697 (dq J = 155 and 69 Hz 1H) 584 (ddd J = 155 34 and 17 Hz 1H) 575 (ddd J = 173 104 and 70 Hz 1H) 511-501 (m 2H) 404 (dd J = 107 and 69 Hz 1H) 398 (dd J = 108 and 66 Hz 1H) 260-248 (m 1H) 187 (dd J = 69 and 17 Hz 3H) 105 (d J = 68 Hz 3H) 13C-NMR δ 1664 1445 1400 1226 1148 679 369 179 163 MS (EI) mz 154 (M+ 4) 124 (7) 99 (8) 87 (6) 85 (41) 83 (62) 70 (5) 69 (100) 68 (25) 67 (7) 57 (7) 55 (6) Enantiomeric excess determined for derivatized product 11a

(+)-2-Ethylbut-3-enyl crotonate (10c)

The title compound was prepared from 9b (20 mmol 438 mg) and EtMgBr (21 mmol 07 mL) using CuBrmiddot(RR)-L1 complex following the procedure described for 10a Purification by flash

chromatography (SiO2 298 Et2On-pentane Rf = 02) afforded a 982 mixture of 10c and its regioisomer (298 mg) as a colorless oil [89 yield 88 ee [α]D = +169 (c 23 CHCl3)] 1H-NMR δ 696 (dqd J = 146 69 and 08 Hz 1H) 587-581 (m 1H) 567-557 (m 1H) 510-505 (m 2H) 410-402 (m 2H) 235-225 (m 1H) 187 (ddd J = 69 16 and 09 Hz 3H) 159-146 (m 1H) 137-124 (m 1H) 090 (dd J = 71 and 78 Hz

O

O

O

O

Chapter 6

194


3H) 13C-NMR δ 1663 1443 1387 1226 1162 666 446 238 178 112 MS (EI GC-MS) mz 168 (M+ 02) 138 (4) 99 (10) 82 (24) 70 (8) 69 (100) 67 (15) Enantiomeric excess determined by chiral GC analysis Chiraldex G-TA (30 m x 025 mm) isothermic 60 ordmC retention times (min) 682 (minor) and 702 (major)

(minus)-(R)-5-methyl-56-dihydro-2H-pyran-2-one (11a)29

Hoveyda-Grubbs 2nd generation catalyst (5 mol 72 mg) was tipped into a solution of 10b (23 mmol 357 mg) in degassed (N2-bubbling) toluene (100 mL) The resulting solution was heated at reflux temperature for 15 h after which it was allowed to cool down to rt and directly applied to a silica column Elution with

4060 Et2On-pentane afforded 11a contaminated with a residual amount of the catalyst as a dark green oil (210 mg 83 yield gt95 pure by 1H-NMR spectroscopy) Kugelrohr distillation (200-220 degC 70 mbar) of this oil yielded 11a contaminated with isomer 13 as a colorless oil (148 mg 57 yield ratio 11a13 = 973 by 1H-NMR spectroscopy30) [90 ee [α]D = minus540 (c 22 CHCl3) lit29a31 [α]D = minus60 (c 060 CHCl3)] 1H-NMR δ 676 (dd J = 98 and 35 Hz 1H) 589 (dd J = 98 and 20 Hz 1H) 434 (ddd J = 110 50 and 11 Hz 1H) 400 (dd J = 110 82 Hz 1H) 269-257 (m 1H) 108 (d J = 72 Hz 3H) 13C-NMR δ 1635 1515 1199 719 286 152 MS (EI GC-MS) mz 112 (M+ 5) 84 (41) 83 (8) 82 (100) 81 (36) 56 (19) 55 (21) 54 (42) 53 (22) 51 (9) Enantiomeric excess determined by chiral GC analysis Chiralsil Dex CB (25 m x 025 mm) isothermic 95 ordmC retention times (min) 270 (major) and 294 (minor)

5-Ethyl-56-dihydro-2H-pyran-2-one (11b)32

The title compound was prepared from 10c (13 mmol 218 mg) following the procedure described for 11a Column chromatography with 4060 Et2On-pentane afforded 11a contaminated with a portion of the catalyst as a dark green oil (154 mg gt95 pure by 1H-NMR spectroscopy) [71 yield 87 ee] 1H-NMR δ 686 (dd J = 98 and 38 Hz 1H) 598 (dd J = 98 and

18 Hz 1H) 442 (ddd J = 110 49 and 07 Hz 1H) 415 (dd J = 110 and 75 Hz 1H) 248-238 (m 1H) 169-148 (m 2H) 101 (t J = 75 Hz 3H) MS (EI GC-MS) mz 126 (M+ 2) 98 (34) 97 (13) 96 (45) 95 (8) 82 (7) 81 (100) 80 (9) 70 (27) 69 (9) 68 (17) 67 (19) 55 (16) 54 (7) 53 (22)

O

O

O

O


195


51 (5) Enantiomeric excess determined by chiral GC analysis Chiraldex B-PM column (30 m x 025 mm) 120 min isothermic 75 ordmC then 10 degCmin gradient to 175 degC retention times (min) 1254 (minor) and 1256 (major)

25-Dimethylhex-3-ene-16-diyl bis-cinnamate (12)

Hoveyda-Grubbs second gen catalyst (10 mol) was tipped into a solution of 10a (06 mmol 132 mg) in degassed

(N2-bubbling) CH2Cl2 (11 mL) The resulting solution was heated at reflux temperature for 5 d after which it was concentrated in vacuo and applied to a silica column Elution with 298 to 4060 Et2On-pentane gradient afforded 12 (66 mg 53 yield) as a colorless oil 1H-NMR δ 766 (d J = 160 Hz 2H) 752-748 (m 4H) 739-734 (m 6H) 643 (d J = 160 Hz 2H) 549 (dd J = 42 and 20 Hz 2H) 411 (dd J = 107 and 69 Hz 2H) 405 (dd J = 107 and 67 Hz 2H) 263-253 (m 2H) 108 (d J = 68 Hz 6H) 13C-NMR δ 1668 1446 1343 1323 1301 1287 1280 1180 685 362 169 MS (EI) mz 404 (M+ 04) 132 (7) 131 (76) 109 (9) 108 (100) 103 (30) 95 (8) 93 (17) 77 (10) MS (CI) mz 424 (13) 423 (29) 422 ([M+NH4]+ 100) 356 (5) 69 (10)

N-Tosyl-(E)-N-allyl-4-bromobut-2-en-1-amine (14)

To a suspension of 750 g (355 mmol) allyl tosylamide and 740 g (535 mmol) K2CO3 in 300 mL acetonitrile was added 305 g (142 mmol) 14-

dibromobut-2-ene and the mixture was heated to reflux After full conversion (24 h) the mixture was concentrated in vacuo and 30 mL Et2O was added This solution was filtered over a cake of silica on a glass filter The cake was washed with 50 mL Et2O and the the filtrate was concentrated in vacuo Column chromatography (SiO2 Rf asymp 038 EtOAcn-pentane 15) yielded 861 g (250 mmol) of the desired product as an oil 70 yield 1H NMR δ 769 (d J = 82 Hz 2H) 730 (d J = 82 Hz 2H) 582-574 (m 1H) 565-554 (m 2H) 519-513 (m 2H) 387 (d J = 72 Hz 2H) 379 (t J = 55 Hz 4H) 243 (s 3H) 13C NMR δ 1436 1374 1328 1307 1300 1299 1274 1196 499 479 316 218 MS (EI) mz 318 ([MminusC2H3]+ 01) 316 ([MminusC2H3]+ 01) 264 (100) 155 (39) 108 (12) 91 (66) 81 (11)

Ph O

OO

O

Ph

TsN Br

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196


65 (12) 53 (9) HRMS calcd for C12H15NO2SBr [MminusC2H3]+ 3160006 found 3160010

(E)-N-(4-Bromobut-2-enyl)-N-(prop-2-ynyl)-tosylamide (15)12b

A suspension of propargyl tosylamide (5 mmol 105 g) 14-dibromobut-2-ene (30 mmol 633 g) and K2CO3 (56 mmol 077 g) in MeCN (35 mL)

was heated at reflux temperature for 24 h The mixture was concentrated in vacuo and H2O (20 mL) and Et2O (20 mL) were added The organic layer was separated and the aqueous layer was extracted with Et2O (2 x 10 mL) The combined organic layers were dried filtered and concentrated in vacuo Purification by flash chromatography (SiO2 1090 Et2On-pentane Rf = 025) afforded 15 (680 mg) as an opaque oil which crystallized upon standing [40 yield mp = 763-766 degC] 1H-NMR δ 768 (app d J = 83 Hz 2H) 725 (app d J = 80Hz 2H) 589 (dtt J = 150 74 and 13 Hz 1H) 564 (dtt J = 151 66 and 10 Hz 1H) 404 (d J = 25 Hz 2H) 387 (dd J = 75 and 07 Hz 2H) 380 (d J = 66 Hz 2H) 238 (s 1H) 199 (t J = 25 Hz 1H) 13C-NMR δ 1437 1358 1314 1295 1287 1277 763 739 474 360 310 215 MS (EI) mz 264 (6) 263 (16) 262 ([MminusBr]+ 100) 155 (50) 139 (8) 107 (7) 106 (23) 92 (8) 91 (72) 79 (6) 77 (5) 65 (12) 53 (6) MS (CI) mz 363 (6) 362 (17) 361 ([M+NH4]+ 100) 360 (16) 359 ([M+NH4]+ 94) HRMS calcd for C14H16NO2S [MminusBr]+ 2620902 found 2620889

(minus)-N-Tosyl-(E)-N-allyl-2-methylbut-3-en-1-amine (16)

The title compound was prepared from 14 (50 mmol 173 g) using CuBrmiddotSMe2 and (RR)-L1 following the procedure described for 10a Purification by column

chromatography (SiO2 Rf asymp 067 EtOAcn-pentane 19) a 955 mixture of 16 and its regioisomer (087 g) as an oil [62 yield 98 ee [α]D = minus11 (c = 174 CHCl3)] 1H NMR 768 (d J = 82 Hz 2H) 729 (d J = 82 Hz 2H) 572-551 (m 2H) 516-497 (m 4H) 379 (d J = 65 Hz 2H) 308-297 (m 2H) 254-246 (m 1H) 242 (s 3H) 096 (d J = 69 Hz 3H) 13C NMR δ 1434 1413 1374 1333 1299 1274 1192 1151 529 513 368 217 176 MS (EI) mz 279 (M+ 03) 252 (03) 224 (100) 155 (59) 139 (2) 91 (70) 68 (15) HRMS calcd for C12H21NO2S 2791293 found 2791302 Enantiomeric excess determined by chiral HPLC analysis

TsN

NTs

Br


197


Chiralcel OJ-H (98 n-heptanei-PrOH) 40 oC retention times (min) 2293 (minor) and 2649 (major)

(minus)-3-Methyl-1-tosyl-1236-tetrahydropyridine (17)

In a flask fitted with a stirring bar 838 mg (0300 mmol) of 16 was dissolved in 15 mL DCM 940 mg (150 μmol) of Hoveyda-Grubbs 2nd generation catalyst was added and the mixture was stirred at rt until full conversion (25 h) was achieved The

mixture was concentrated in vacuo and column chromatography (SiO2 Rf asymp 051 EtOAcn-pentane 19) yielded 65 mg (026 mmol) of the desired product as a white solid 87 yield 97 ee mp = 75-77 oC [α]D = minus04 (c = 52 CHCl3) 1H NMR δ 767 (d J = 85 Hz 2H) 732 (d J = 83 Hz 2H) 561-557 (m 2H) 371-366 (m 1H) 344 (dd J = 105 and 40 Hz 1H) 338-333 (m 1H) 252-247 (m 2H) 243 (s 3H) 099 (d J = 69 Hz 3H) 13C NMR δ 1437 1335 1317 1299 1279 1219 496 450 305 218 185 MS (EI) mz 251 (M+ 67) 236 (14) 184 (24) 155 (37) 96 (30) 91 (58) 80 (8) 68 (100) 65 (22) 53 (10) HRMS calcd for C13H17NO2S 2510980 found 2510995 Anal calcd for C13H17NO2S C 6212 H 682 N 557 Found C 6230 H 690 N 540 Enantiomeric excess determined by chiral HPLC analysis Chiralcel AS-H (95 n-heptanei-PrOH) 40 oC retention times (min) 2122 (minor) and 2229 (major)

(minus)-N-(2-Methylbut-3-enyl)-N-(prop-2-ynyl)-tosylamide (18)

The title compound was prepared from 15 (05 mmol 171 mg) using CuBrmiddot(RR)-L1 following the procedure described for 10a Purification by flash

chromatography (SiO2 595 to 1090 Et2On-pentane gradient Rf (1090) = 035) afforded a 955 mixture of 18 and its regioisomer (133 mg) as a colorless oil [96 yield 98 ee [α]D = minus49 (c 14 CHCl3)] 1H-NMR δ 770 (d J = 83 Hz 2H) 727 (d J = 74 Hz 2H) 571 (ddd J = 178 103 and 75 Hz 1H) 510-504 (m 1H) 501 (ddd J = 103 16 and 09 Hz 1H) 413-411 (m 2H) 312-302 (m 2H) 254-243 (m 1H) 240 (s 3H) 199 (t J = 25 Hz 1H) 103 (d J = 68 Hz 3H) 13C-NMR δ 1433 1407 1358 1293 1276 1150 763 737 513 365 360 214 174 MS (EI) mz 277 (M+ 14) 224 (6) 223 (13) 222 (100) 155 (53) 91 (48) 65 (7) HRMS calcd for C15H19NO2S 2771136 found 2771153 Enantiomeric excess determined for derivatized product 19

TsN

TsN

Chapter 6

198


(+)-3-Methyl-1-tosyl-5-vinyl-1236-tetrahydropyridine (19)

Grubbs 1st generation catalyst (2 mol 43 mg) was tipped into a solution of 18 (026 mmol 73 mg) in degassed (N2-bubbling) CH2Cl2 (10 mL) The resulting solution was stirred at rt under an ethylene atmosphere (balloon pressure)

for 16 h and then concentrated in vacuo The residue was purified by flash chromatography (SiO2 595 to 1090 Et2On-pentane gradient Rf (1090) = 025) to yield 19 (66 mg) as an oil which crystallized upon standing [90 yield 98 ee [α]D = +336 (c 06 CHCl3) mp = 1076-1084 degC] 1H-NMR δ 770 (d J = 83 Hz 2H) 733 (d J = 80 Hz 2H) 624 (dd J = 178 and 110 Hz 1H) 563 (s 1H) 502 (d J = 181 Hz 1H) 498 (d J = 113 Hz 1H) 388 (d J = 153 Hz 1H) 351-344 (m 2H) 260-250 (m 1H) 249 (dd J = 109 and 77 Hz 1H) 243 (s 3H) 102 (d J = 68 Hz 3H) 13C-NMR δ 1435 1363 1333 1327 1313 1296 1276 1117 494 440 305 215 181 MS (EI) mz 277 (M+ 18) 262 (9) 155 (7) 122 (30) 121 (68) 120 (14) 106 (12) 95 (17) 94 (55) 93 (16) 92 (7) 91 (43) 80 (12) 79 (100) 78 (5) 77 (17) 67 (11) 65 (16) 55 (7) 53 (8) HRMS calcd for C15H19NO2S 2771136 found 2771144 Enantiomeric excess determined by chiral HPLC analysis Chiralcel AS-H (99 n-heptanei-PrOH) 40 oC retention times (min) 395 (minor) and 419 (major)

NN-Bis(2-methylbut-3-enyl)-tosylamide (21)

The title compound was prepared from 20 (005 mmol 22 mg) and MeMgBr (02 mmol 30 M in Et2O 67 μL) using CuBrmiddotSMe2 (10 mol 104 mg)

and (RR)-L1 (12 mol 41 mg) following the procedure described for 10a Purification by column chromatography (SiO2 Et2On-pentane 1090 Rf = 05) afforded a 9145 mixture of 21 meso-21 and its regioisomer 22 (14 mg) as an oil [92 yield gt995 ee (major diastereomer)] 1H-NMR δ 763 (d J = 83 Hz 2H) 724 (d J = 79 Hz 2H) 566-556 (m 2H) 496-489 (m 4H) 300 (dd J = 131 and 68 Hz 2H) 295 (dd J = 131 and 64 Hz 2H) 250-239 (m 2H) 237 (s 3H) 092 (d J = 67 Hz 6H) MS (EI GC-MS) mz 254 (5) 253 (13) 252 (100) 184 (11) 155 (64) 96 (11) 92 (7) 91 (72) 89 (6) 69 (10) 65 (14) 55 (15) 42 (10) 41 (8) Enantiomeric excess determined for derivatized product 23

TsN

NTs


199


(Z)-36-Dimethyl-1-tosyl-2367-tetrahydro-1H-azepine (23)

Grubbs 1st generation catalyst (25 mol 6 mg) was tipped into a solution of 21 (003 mmol 9 mg) in degassed (N2-bubbling) CH2Cl2 (3 mL) The resulting solution was heated at reflux temperature under an argon atmosphere for 16 h

and then concentrated in vacuo The residue was purified by flash chromatography (SiO2 1090 Et2On-pentane gradient) to yield a 946 mixture of 23 and its meso-diastereoisomer (8 mg) [94 yield gt995 ee (major diastereomer)] 1H-NMR δ 762 (d J = 76 Hz 2H) 725 (d J = 79 Hz 2H) 538 (d J = 12 Hz 2H) 324 (dd J = 130 and 32 Hz 2H) 298 (dd J = 129 and 87 Hz 2H) 258-247 (m 2H) 237 (s 3H) 099 (d J = 72 Hz 6H) Enantiomeric excess determined by chiral HPLC analysis Chiralcel OD-H (99 n-heptanei-PrOH) 40 oC retention times (min) 197 (meso) 212 (major) and 236 (minor)

(E)-1-Bromo-2-(4-bromobut-2-enyloxy)benzene (24a)

A suspension of o-bromophenol (10 mmol 116 mL) 14-dibromobut-2-ene (40 mmol 86 g) and K2CO3 (15 mmol 205 g) in MeCN (100 mL) was heated at reflux temperature for 7 h The reaction

mixture was then concentrated and H2O (100 mL) and Et2O (100 mL) were added The aqueous layer was separated and extracted with Et2O (50 mL) The combined organic layers were dried (MgSO4) filtered and concentrated in vacuo Purification of the residue by flash chromatography (SiO2 595 to 199 Et2On-pentane gradient Rf = 04) afforded 24a (95 yield 29 g) as a colorless oil 1H-NMR δ 750 (dd J = 78 and 16 Hz 1H) 723-718 (m 1H) 684-678 (m 2H) 611 (dtt J = 148 73 and 14 Hz 1H) 596 (dt J = 153 and 49 Hz 1H) 458 (dd J = 49 and 09 Hz 2H) 396 (d J = 74 Hz 1H) 13C-NMR δ 1547 1334 1294 1292 1284 1222 1136 1124 682 315 MS (EI) mz 308 (M+ 8) 306 M+ 15) 304 (M+ 8) 227 (5) 225 (5) 175 (6) 174 (98) 173 (9) 171 (100) 146 (9) 145 (9) 143 (8) 135 (23) 133 (24) 131 (6) 64 (7) 63 (11) 54 (13) 53 (36) HRMS calcd for C10H10

81Br2O 3079058 found 3079064 Anal calcd for C10H10Br2O C 3925 H 329 O 523 Found C 3900 H 314 O 567

TsN

O

Br

Br

Chapter 6

200


(E)-N-(4-Bromobut-2-enyl)-N-(2-bromophenyl)-tosylamide (24b)

The title compound was prepared from o-bromophenyl tosylamide (50 mmol 163 g) following the procedure described for 24a (Reaction time = 16 h) Purification by column

chromatography (SiO2 595 to 1585 Et2On-pentane gradient) yielded 24b (186 g) as a white solid [81 yield mp 903-911 oC] 1H NMR δ 766 (d J = 82 Hz 2H) 759 (d J = 82 Hz 1H) 730-724 (m 3H) 721-716 (m 1H) 711 (d J = 79 Hz 1H) 584-575 (m 1H) 568-560 (m 1H) 418 (d J = 312 Hz 2H) 380 (d J = 78 Hz 2H) 13C NMR δ 1440 1378 1369 1342 1328 1312 1302 1298 1296 1282 1259 1100 525 315 219 MS (EI) mz 459 (M+ 04) 380 (100) 378 (100) 299 (5) 224 (19) 184 (22) 182 (23) 157 (14) 155 (77) 144 (22) 139 (10) 115 (8) 91 (71) 77 (7) 65 (16) 53 (12) HRMS calcd for C17H17NO2SBr81Br79 4589326 found 4589337 Anal calcd for C17H17NO2SBr2 C 4447 H 373 N 305 Found C 4457 H 376 N 306

(+)-1-Bromo-2-(2-methylbut-3-enyloxy)benzene (25a)

The title compound was prepared from 24a (075 mmol 230 mg) using CuBrmiddotSMe2 and (RR)-L1 following the procedure described for 10a Purification by flash chromatography (SiO2 199 Et2On-pentane

gradient Rf = 065) afforded 25a (109 mg) as a colorless oil [60 yield 95 ee [α]D = +86 (c 04 CHCl3)] 1H-NMR δ 753 (dd J = 78 and 16 Hz 1H) 724 (ddd J = 82 75 and 17 Hz 1H) 687 (dd J = 82 and 14 Hz 1H) 682 (ddd J = 78 74 and 14 Hz 1H) 592 (ddd J = 173 104 and 69 Hz 1H) 517 (dt J = 173 and 15 Hz 1H) 510 (ddd J = 104 16 and 11 Hz 1H) 395 (dd J = 89 and 60 Hz 1H) 383 (dd J = 89 and 70 Hz 1H) 280-269 (m 1H) 120 (d J = 68 Hz 3H) 13C-NMR δ 1553 1401 1333 1283 1217 1149 1131 1123 733 374 165 MS (EI) mz 242 (M+ 22) 240 (M+ 23) 174 (100) 172 (87) 85 (53) 83 (76) 69 (67) 68 (38) 67 (16) 57 (22) 55 (18) 47 (16) HRMS calcd for C11H13OBr 2400150 found 2400136 Enantiomeric excess determined for derivatized product 26a

TsN

Br

Br

O

Br


201


(+)-N-(2-Bromophenyl)-N-(2-methylbut-3-enyl)-tosylamide (25b)

The title compound was prepared from 24b (10 mmol 459 mg) using CuBrmiddotSMe2 and (RR)-L1 following the procedure described for 10a Purification by flash chromatography (SiO2 1090 EtOAcpentane Rf =

065) afforded 25b (171 mg) as a white solid [68 yield gt90 ee [α]D = +16 (c 149 CHCl3) mp 78-79 oC] in 1H NMR (CDCl3) the peaks of Me and tertiary CH were split (ratio asymp 56) possibly due to the presence of 2 rotamers δ 760-754 (m 3H) 729-712 (m 5H) 574-562 (m 1H) 502-491 (m 2H) 357-346 (m 2H) 242 (s 3H) 238-230 (m minor peak 1H) 227-217 (m major peak 1H) 108 (d J = 67 Hz major peak 3H) 102 (d J = 68 Hz minor peak 3H) The coalescence temperature (Tc) of the Me and CH signals was determined through measurements in toluene-d8 at several temperatures 1H NMR (Toluene-d8 400MHz) δ 763 (d J = 80 Hz 2H) 746-724 (m 2H) 696-685 (m 1H) 682 (d J = 79 Hz 2H) 673-666 (m 1H) 580-560 (m 1H) 505-494 (m 2H) 383-361 (m 2H) 255-244 (minor) and 237-229 (major) (2 multiplets 1H Tc asymp 80 degC) 202 (s 3H) 111 (minor) and 108 (major) (2 doublets J = 67 Hz 3H Tc asymp 60 degC) ΔGDagger = 725 plusmn 11 kJ mol-1 13C NMR δ 1437 1412 1384 1368 1344 1336 1326 1298 1282 1280 1257 1150 568 372 218 180 MS (EI) mz 340 ([MminusC4H7]+ 71) 338 ([MminusC4H7]+ 69) 184 (16) 182 (11) 155 (100) 91 (70) 77 (10) 65 (13) 55 (15) HRMS calcd for C14H13NO2SBr [MminusC4H7]+ 3379850 found 3379861 Enantiomeric excess was approximated by chiral HPLC (baseline separation was not achieved) Chiralcel OJ-H (98 n-heptanei-PrOH) 40 oC retention times (min) 271 (major) and 292 (minor)

(+)-3-Methyl-4-methylenechroman (26a)

In a flame-dried Schlenk flask under a N2-atmosphere 25a (0099 mmol 238 mg) and PPh3 (20 mol 53 mg) were dissolved in anhydrous MeCN (15 mL) K2CO3 (07 mmol 95 mg) was added and the resulting suspension was degassed (N2-bubbling) Pd(OAc)2 (5 mol 112 mg) was

added and the reaction mixture was heated at reflux temperature for 17 h Subsequently Celite was added to the mixture the suspension was filtered over Celite and the filter-cake was washed with MeCN The combined filtrates were concentrated Purification by flash chromatography (SiO2 n-

TsN

Br

O

Chapter 6

202


pentane Rf = 03 Rf (isomer 27) = 025) afforded 26a (59 mg) as a colorless oil [37 yield 93 ee [α]D = +183 (c 06 CHCl3)] 1H-NMR δ 757 (dd J = 79 and 16 Hz 1H) 720-714 (m 1H) 693-685 (m 1H) 684 (dd J = 82 and 10 Hz 1H) 550 (d J = 07 Hz 1H) 494 (d J = 14 Hz 1H) 419 (dd J = 105 and 35 Hz 1H) 391 (dd J = 105 and 73 Hz 1H) 279-266 (m 1H) 120 (d J = 69 Hz 3H) 13C-NMR δ 1541 1425 1292 1248 1212 1206 1171 1052 717 340 155 MS (EI) mz 163 (7) 162 (9) 161 (14) 160 (M+ 100) 159 (23) 146 (8) 145 (68) 133 (5) 132 (8) 131 (25) 128 (5) 127 (5) 121 (6) 120 (16) 117 (7) 115 (14) 92 (6) 91 (10) 89 (5) 77 (6) 63 (6) 51 (5) HRMS calcd for C11H12O 1600888 found 1600883 Enantiomeric excess determined by chiral GC analysis Chiraldex B-PM column (30 m x 025 mm) 5 min isothermic 50 ordmC then 2 degCmin gradient to 175 degC retention times (min) 429 (minor) and 433 (major)

3-Methyl-4-methylene-1-tosyl-1234-tetrahydroquinoline (26b)

To an oven-dried Schlenk tube with a septum stirring bar and under a N2-atmosphere were added 789 mg (020 mmol) of 25b 1659 mg (120 mmol) K2CO3 208 mg (0080 mmol) PPh3 and 20 mL of degassed MeCN To this mixture was added 448 mg (0020 mmol) of Pd(OAc)2 and

the mixture was heated at reflux temperature for 17 h Subsequently Celite was added to the mixture the suspension was filtered over Celite and the filter-cake was washed with MeCN The filtrate was concentrated in vacuo and column chromatography (SiO2 Et2On-pentane 298 to 595 gradient) yielded 26b (388 mg) as an oil [62 yield 94 ee] 1H NMR δ 771 (d J = 84 Hz 1H) 752-745 (m 3H) 725-717 (m 3H) 712-707 (m 1H) 540 (s 1H) 486 (s 1H) 411 (d J = 136 Hz 1H) 333-327 (m 1H) 253 (bs 1H) 237 (s 3H) 109 (d J = 70 Hz 3H) 13C NMR δ 1437 1436 1370 1362 1296 1284 1283 1270 1250 1249 1236 1086 525 332 215 176 MS (EI) mz 313 (M+ 62) 158 (100) 155 (12) 143 (39) 130 (7) 117 (6) 115 (6) 91 (12) Enantiomeric excess determined by chiral HPLC analysis Chiralcel AD (9925 n-heptanei-PrOH) 40 oC retention times (min) 216 (major) and 246 (minor)

TsN


203


(+)-(5R6S)-6-(Iodomethyl)-5-methyl-3-tosyl-13-oxazinan-2-one (29a)

I2 (2 mmol 508 mg) was added to a biphasic system of (S)-28 (052 mmol 176 mg) CH2Cl2 (5 mL) and H2O (25 mL) and the reaction mixture was stirred vigorously at rt for 2 h Sat aq Na2S2O3 (8 mL) was added and the resulting mixture was extracted with Et2O (3 x 10 mL) The

combined organic layers were dried (MgSO4) filtered and concentrated in vacuo (ratio 29a29b = 21) Purification by flash chromatography (SiO2 1090 to 2080 EtOAcn-pentane gradient Rf (2080) = 025 (29a) 020 (29b)) afforded pure 29a (59 mg) as sticky white foam (the compound slowly forms white needle-like crystals in a mixture of n-heptane and i-PrOH) [55 yield 95 ee [α]D = +146] 1H-NMR δ 790 (d J = 84 Hz 2H) 731 (d J = 80 Hz 2H) 451 (ddd J = 93 58 and 26 Hz 1H) 406 (dd J = 123 and 27 Hz 1H) 383 (dd J = 123 and 41 Hz 1H) 329 (dd J = 104 and 58 Hz 1H) 305 (dd J = 103 and 94 Hz 1H) 272-264 (m 1H) 244 (s 3H) 095 (d J = 70 Hz 3H) 13C-NMR δ 1473 1453 1348 1294 1288 805 511 283 217 93 05 MS (EI) mz 346 (17) 345 (100) 301 (13) 259 (6) 175 (7) 174 (55) 160 (28) 155 (30) 147 (17) 133 (6) 132 (23) 120 (39) 199 (66) 118 (15) 107 (6) 92 (10) 91 (95) 90 (6) 89 (8) 65 (27) 56 (11) 55 (28) MS (CI) mz 427 ([M+NH4]+ 7) 412 (7) 411 (16) 410 ([M+H]+ 100) 345 (18) 284 (9) 240 (9) 174 (5) 119 (9) 91 (9) Enantiomeric excess determined by chiral HPLC analysis Chiralcel AD (85 n-heptanei-PrOH) 40 oC retention times (min) 242 (major) and 286 (minor) Relative configuration was determined by NOESY-spectroscopy of both diastereomers 1H-NMR (minor diastereomer 29b) δ 792 (app d J = 84 Hz 2H) 733 (app d J = 85 Hz 2H) 409 (dd J = 119 and 53 Hz 1H) 370 (dt J = 90 and 38 Hz 1H) 347 (dd J = 119 and 108 Hz 1H) 345 (dd J = 116 and 37 Hz 1H) 329 (dd J = 116 and 41 Hz 1H) 244 (s 3H) 225-215 (m 1H) 105 (d J = 67 Hz 3H)

1-Bromo-4-(2-naphthyloxy)-but-2-ene (30)

The title compound was prepared from 2-naphthol (10 mmol 144 g) following the procedure described for 24a (Reaction time = 3 h) Purification by flash column

chromatography (SiO2 05995 Et2On-pentane) afforded 30 (163 g) as a white solid [59 yield mp = 750-765 degC] 1H-NMR δ 780-772 (m 3H)

TsN O

O

I

OBr

Chapter 6

204


745 (ddd J = 82 70 and 13 Hz 1H) 736 (ddd J = 81 69 and 12 Hz 1H) 720-712 (m 2H) 619-610 (m 1H) 610-602 (m 1H) 467 (d J = 50 Hz 2H) 402 (d J = 72 Hz 2H) 13C-NMR δ 1562 1344 1299 1295 1293 1290 1276 1267 1264 1238 1188 1069 672 317 MS (EI) mz 279 (M+ 13) 277 (M+ 13) 198 (11) 197 (74) 145 (10) 144 (92) 143 (9) 135 (6) 133 (6) 127 (9) 116 (13) 115 (100) 114 (5) 89 (9) 63 (6) 54 (6) 53 (19) HRMS Calcd for C14H13OBr 27601493 found 27601614

(+)-4-(2-Naphthyloxy)-3-methyl-but-1-ene (31)

The title compound was prepared from 30 (366 mmol 101 g) using CuBrmiddotSMe2 and (RR)-L1 following the procedure described for 10a (Reaction time = 44h) Purification by flash

chromatography (SiO2 n-pentane Rf = 04 and then 6040 Et2Opentane to recover catalyst) yielded 31 (702 mg) as a colorless oil [90 yield 97 ee [α]D = + 146 (c 50 CHCl3)] 1H-NMR δ 785-779 (m 3H) 754-750 (m 1H) 744-739 (m 1H) 728-720 (m 2H) 601 (ddd J = 173 104 and 68 Hz 1H) 530-519 (m 2H)407 (dd J = 90 and 63 Hz 1H) 397 (dd J = 90 and 69 Hz 1H) 289-278 (m 1H) 129 (d J = 68 Hz 3H) 13C-NMR δ 1570 1404 1345 1293 1289 1276 1267 1262 1235 1190 1147 1066 723 373 165 MS (EI) mz 212 (M+ 24) 145 (12) 144 (100) 129 (5) 128 (7) 127 (30) 126 (8) 116 (15) 115 (65) 89 (8) 69 (11) 63 (6) HRMS Calcd for C15H16O 21212011 found 21212099 Enantiomeric excess was determined for derivatized compound 32

(+)-3-(2-Naphthyloxy)-2-methyl-propionic acid (32)26a-b

The olefin 31 (05 mmol 106 mg) was dissolved in a solvent mixture of 3 mL acetone 04 mL H2O and 025 mL AcOH KMnO4 (175 mmol 277 mg) was added slowly in small portions over

10 min while stirring vigorously and keeping the reaction mixture at rt using a waterbath After stirring at rt for 1 h the reaction mixture was filtered on a Buchner-funnel The residue was boiled in 5 mL H2O for 3 min and filtered again To the combined filtrates 10 mL aq 6N NaOH was added and the mixture was stirred for 1 h The basic solution was washed with Et2O (2 x 20 mL) and acidified carefully with conc HCl until pH lt 1 upon

O

O O

OH


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which a whitish precipitate appeared The suspension was filtered and the residue was dried in a vacuum oven (50 mbar 40 degC) overnight The residue was dissolved in Et2O and the solution was dried (MgSO4) filtered and concentrated in vacuo to yield 32 (703 mg) as a brownish-white solid [61 yield 97 ee [α]D = + 08 (c 13 MeOH) mp = 1489-1500 degC] 1H-NMR δ 778-770 (m 3H) 746-741 (m 1H) 736-731 (m 1H) 717-713 (m 2H) 433 (dd J = 91 and 68 Hz 1H) 415 (dd J = 91 and 59 Hz 1H) 312-302 (m 1H) 140 (d J = 71 Hz 3H) 13C-NMR δ 1807 1565 1344 1294 1291 1276 1267 1264 1237 1188 1069 691 397 138 MS (EI) mz 231 (8) 230 (M+ 49) 145 (11) 144 (100) 127 (7) 116 (10) 115 (26) HRMS Calcd for C14H14O3 2300943 found 2300947 Enantiomeric excess determined on esterified product A sample amount (~3 mg) was dissolved in PhMe (1 mL) and MeOH (02 mL) Slowly TMSCHN2 (02 mL 20 M in Et2O) was added dropwise and the resulting yellow solution was swirled and left standing for 20 min MeOH (05 mL) was added and the excess TMSCHN2 was quenched by adding AcOH until the yellow color disappeared (a few drops) The mixture was diluted with PhMe (1 mL) and washed with sat aq NaHCO3 (2 mL) The organic layer was dried (MgSO4) filtered and concentrated in vacuo to yield the crude methyl ester as a colorless oil which was used directly in the determination of enantiomeric excess by chiral HPLC analysis Chiralcel OD-H (98 n-heptanei-PrOH) 40ordmC retention times (min) 171 (major) and 200 (minor)

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References 1 Corey E J Czakoacute B Kuumlrti L Molecules and Medicine 2007 Wiley Hoboken 2 Murphy K E Hoveyda A H Org Lett 2005 7 1255-1258 3 a) Falciola C A Tissot-Croset K Alexakis A Angew Chem Int Ed 2006 45 5995-5998 b) Tissot-Croset K Polet D Alexakis A Angew Chem Int Ed 2004 43 2426-2428 c) Alexakis A Croset K Org Lett 2002 4 4147-4149 4 Geurts K Fletcher S P Feringa B L J Am Chem Soc 2006 128 15572-15573 5 Tava A Pecetti L Phytochemistry 1997 45 1145-1148 6 For alternative syntheses and applications in natural product synthesis see for example a) Takayama H Fujiwara R Kasai Y Kitajima M Aimi N Org Lett 2003 5 2967-2970 b) Tsuboi S Sakamoto J Yamashita H Sakai T Utaka M J Org Chem 1998 63 1102-1108 7 For reviews on metathesis reactions see a) Hoveyda A H Zhugralin A R Nature 2007 450 243-251 b) Nicolaou K C Bulger P G Sarlah D Angew Chem Int Ed 2005 44 4490-4527 c) Grubbs R H Tetrahedron 2004 60 7117-7140 d) Fuumlrstner A Alkene Metathesis in Organic Synthesis Springer Berlin 1998 8 For reviews on the application of ring-closing metathesis in the synthesis of heterocyclic compounds see a) Villar H Frings M Bolm C Chem Soc Rev 2007 36 55-66 b) Martin S F Pure Appl Chem 2005 77 1207-1212 c) Deiters A Martin S F Chem Rev 2004 104 2199-2238 9 Sakai T Nakajima K Yoshihara K Sakan T Isoe S Tetrahedron 1980 36 3115-3119 10 Sirirath S Tanaka J Ohtani I I Ichiba T Rachmat R Ueda K Usui T Osada H Higa T J Nat Prod 2002 65 1820-1823 11 See experimental part procedure based on literature report Ma S Lu X J Org Chem 1991 56 5120-5125 12 See experimental part procedures based on literature reports a) Patel M C Livinghouse T Pagenkopf B L Org Synth 2003 80 93-98 Stevens and co-workers reported the synthesis of the (Z)-isomer of compound 15 however their analytical data indicate the (E)-isomer b) Dieltiens N Moonen K Stevens C V Chem Eur J 2007 13 203-214 13 Diver S T Giessert A J Chem Rev 2004 104 1317-1382 14 Mori M Sakakibara N Kinoshita A J Org Chem 1998 63 6082-6083


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15 Cerezo S Cortegraves J Galvan D Lago E Marchi C Molins E Moreno-Mantildeas M Pleixats R Torrejoacuten J Vallribera A Eur J Org Chem 2001 329-337 16 The identity of the products was established by NMR-spectroscopy and chiral HPLC the two diastereomers of 21 can be distinguished by HPLC because a racemate and an achiral compound are obtained in the racemic reaction 17 a) Beller M Zapf A Riermeier T H Palladium-Catalyzed Olefinations of Aryl Halides (Heck Reaction) and Related Transformations in Transition Metals for Organic Synthesis 2nd Ed Eds Beller M Bolm C 2004 Wiley-VCH Weinheim Vol 1 Chapter 213 b) Brase S de Meijere A Palladium-catalyzed Coupling of Organyl Halides to Alkenes-The Heck Reaction in Metal-catalyzed Cross-coupling Reactions Eds Diederich F Stang P J 1998 Wiley-VCH Weinheim Chapter 3 and 6 18 Ma S Ni B J Org Chem 2002 67 8280-8283 19 For examples see application in the synthesis of benzoxazinones a) Kobayashi K Fukamachi S Nakamura D Morikawa O Konishi H Heterocycles 2008 75 95-105 diastereoselective formation of aliphatic oxazinones under 13-asymmetric induction b) Pattarozzi M Zonta C Broxterman Q B Kaptein B De Zorzi R Randaccio L Scrimin P Licini G Org Lett 2007 9 2365-2368 c) Davies S G Haggitt J R Ichihara O Kelly R J Leech M A Price Mortimer A J Roberts P M Smith A D Org Biomol Chem 2004 2 2630-2649 d) Jones A D Knight D W Hibbs D E J Chem Soc Perkin Trans 1 2001 1182-1203 e) Wang Y-F Izawa T Kobayashi S Ohno M J Am Chem Soc 1982 104 6465-6466 20 a) Eliel E L Wilen S H Mander L N Stereochemistry of Organic Compounds 1994 chapter 12 pp 909-910 see also b) Bartlett P A Myerson J J Am Chem Soc 1978 100 3950-3952 21 a) Kahn S D Pau C F Chamberlin A R Hehre W J J Am Chem Soc 1987 109 650-663 b) Hehre W J Salem L J Chem Soc Chem Commun 1973 754-755 22 a) Kay E R Leigh D A Zerbetto F Angew Chem Int Ed 2007 46 72-191 b) van Delden R A ter Wiel M K J Koumura N Feringa B L Synthetic Molecular Motors in Molecular Motors Ed Schliwa M 2003 Wiley-VCH Weinheim chapter 23 c) Molecular Machines and Motors Ed Sauvage J-P 2001 Springer Berlin 23 a) Pollard M M Klok M Pijper D Feringa B L Adv Funct Mater 2007 17 718-729 b) Feringa B L Acc Chem Res 2001 34 504-513 24 Pijper D PhD Thesis University of Groningen 2007 chapter 4 and references therein 25 Hoen R PhD Thesis University of Groningen 2006 chapter 5 26 Although the cyclization was not performed on this enantiomerically enriched compound it has been performed successfully on the racemate a) Geertsema E Feringa B L manuscript in preparation b) Colonge J Guyot A Bull Soc Chim Fr 1958 325-

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328 and on similar optically pure compounds without racemization c) Pijper D PhD Thesis University of Groningen 2007 chapters 4 and 7 27 Kimura M Ezoe A Mori M Tamaru Y J Am Chem Soc 2005 127 201-209 28 Krolski M E Renaldo A F Rudisill D E Stille J K J Org Chem 1988 53 1170-1176 29 a) Esteban J Costa A M Goacutemez Agrave Vilarrasa J Org Lett 2008 10 65-68 b) Dieter R K Guo F Org Lett 2006 8 4779-4782 30 1H-NMR spectroscopic data of 13 were in accordance with the data reported elsewhere Andreana P R McLellan J S Chen Y Wang P G Org Lett 2002 4 3875-3878 31 The optical rotation given in ref 29a seems to be exchanged with that of an isomeric lactone reported in the same paper which gives [α]D = minus527 (c 080 CHCl3) In response to an enquiry with the authors regarding this issue the isomeric lactone was remeasured to give an optical rotation of [α]D = minus71 (c 080 CHCl3) 32 a) Ihara M Yasui K Taniguchi N Fukumoto K J Chem Soc Perkin Trans 1 1990 1469-1476 b) Bonadies F Di Fabio R Bonini C J Org Chem 1984 49 1647-1649

Nederlandse Samenvatting Onderzoek in de synthetische organische chemie richt zich voornamelijk

op de ontwikkeling van nieuwe methodes voor het maken van organische verbindingen Organische verbindingen zijn opgebouwd uit atomen van de elementen koolstof (C) en waterstof (H) en bevatten in veel gevallen daarnaast enkele heteroatomen Dit houdt in dat organische moleculen opgebouwd zijn uit een relatief kleine hoeveelheid verschillende elementen Desondanks is er een ontzagwekkende hoeveelheid natuurlijke en onnatuurlijke organische verbindingen bekend en is het mogelijk een zelfs grotere hoeveelheid nog te ontdekken of te synthetiseren Zij verschillen van elkaar in de aantallen atomen in de bindingen tussen deze atomen en ook in de ruimtelijke orieumlntatie van deze bindingen

Chiraliteit (afgeleid van het Griekse woord χειρ = hand) is een eigenschap waarbij de spiegelbeelden van een object niet aan elkaar gelijk zijn In de organische chemie betekent dit dat de twee spiegelbeelden van een chirale verbinding enantiomeren in alles hetzelfde zijn behalve in de absolute ruimtelijke orieumlntatie van de bindingen die precies andersom is Dit is het geval wanneer een koolstofatoom aan vier verschillende groepen is gebonden die het als een tetraeumlder omringen De twee enantiomeren van bijvoorbeeld een aminozuur verschillen op geen andere wijze van elkaar dan dat ze spiegelbeelden van elkaar zijn net als bijvoorbeeld een linker- en een rechterhand (zie inzet) De fysische en chemische eigenschappen van twee enantiomeren zijn exact hetzelfde behalve in de interactie met andere chirale stoffen

Omdat in ons lichaam bijna al onze receptoren en enzymen ook chiraal zijn is de interactie hiervan met twee enantiomeren van een biologisch actieve stof zoals een medicijn vaak verschillend Om deze reden is het bijvoorbeeld voor de farmaceutische industrie van groot belang dat het mogelijk is om eacuteeacuten van de twee enantiomeren zuiver te kunnen verkrijgen Hiervoor zijn verscheidene manieren waarvan asymmetrische katalyse het onderwerp van dit proefschrift eacuteeacuten van de meest krachtige en efficieumlnte is Heteroatomen in organische verbindingen zijn atomen van een select stel andere elementen zoals bv zuurstof (O) stikstof (N) en zwavel (S)

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nederlandse samenvatting_final

Een katalysator is een stof die een chemische reactie versnelt zonder uiteindelijk zelf in het proces te veranderen Hierdoor kan een kleine hoeveelheid katalysator een grotere hoeveelheid uitgangsstof omzetten naar het beoogde product Een chirale katalysator kan bijvoorbeeld worden gebruikt om uit een niet chirale uitgangsstof selectief eacuteeacuten van de twee enantiomeren van een chiraal product te vormen De chemische reactie die het hoofdonderwerp van dit proefschrift is is de allylische alkylering (schema 1 zwarte lijnen stellen koolstofatomen en hun bindingen voor de meeste waterstofatomen worden hier voor de overzichtelijkheid weggelaten de pijl geeft het verloop van de reactie weer)

Schema 1 Een enantioselectieve koper-gekatalyseerde allylische alkylering met een Grignard reagens

In de allylische alkylering reageert een allyl bromide als uitgangsstof (links van de pijl) met een alkylmagnesium reagens een zogenaamd Grignard reagens (boven de pijl) Het broomatoom (Br) van de uitgangsstof wordt vervangen door de alkyl groep van het Grignard reagens (in schema 1 een CH3) De twee mogelijke producten staan rechts van de pijl In beide gevallen wordt het broomatoom vervangen maar de CH3 groep kan aan twee verschillende koolstofatomen van de uitgangsstof binden De katalysator die voor deze reactie wordt gebruikt is een complex van een koperatoom (Cu) met een chiraal ligand een organische verbinding die het koperatoom omringt

In schema 1 is te zien dat het linker product een koolstofatoom bevat met daaraan vier verschillen groepen verbondendagger Dit is het beoogde chirale product Een goede katalysator moet regioselectief (voornamelijk het chirale product en niet het ongewenste rechter product) en enantioselectief

dagger Driedimensionaal gezien is de dikker wordende lijn (naar de CH3) een naar voren komende binding en de gestreepte lijn (naar de H) is een naar achter staande binding


211


(voornamelijk eacuteeacuten van de twee enantiomeren van het chirale product) zijnDagger Dit proefschrift beschrijft de ontwikkeling van een nieuwe katalysator voor deze reactie en het gebruik hiervan in de synthese van relevante organische verbindingen

Hoofdstuk 1 Na een korte introductie over asymmetrische katalyse bevat hoofdstuk 1

een overzicht van katalytische enantioselectieve allylische substitutie-reacties Hierin wordt in het algemeen aangegeven wat de mogelijkheden zijn bij het gebruik van katalysatoren gebaseerd op andere metalen dan koper Vervolgens wordt een volledig overzicht gegeven van de door ons en anderen behaalde resultaten in de koper-gekatalyseerde versie van de reactie en welke speciale mogelijkheden koper biedt ten opzichte van andere metalen

Hoofdstuk 2 In hoofdstuk 2 wordt de ontwikkeling van de

nieuwe katalysator beschreven Deze chirale katalysator is gebaseerd op koper en het ligand Taniaphos (zie inzet) dat met twee fosforatomen (P) aan koper bindt Zowel de opbrengst van de reactie (gt90) als de regioselectiviteit (de verhouding van de producten is 973) en de enantioselectiviteit (de verhouding van de enantiomeren is 991) zijn hoog Vooral de introductie van een CH3 groep verloopt op een uiterst selectieve wijze Dit is van belang omdat dit een veel voorkomende groep is in biologisch actieve stoffen en omdat de introductie hiervan via allylische alkylering met behulp van de tot nu toe al bekende katalysatoren moeilijk was

Hoofdstuk 3 Een functionele groep is een deel van een molecuul waar reacties op

kunnen worden uitgevoerd Omdat het product van een enantioselectieve Dagger Deze selectiviteiten worden uitgedrukt in de relatieve percentages van beide verschillende producten (regioselectiviteit) en van de beide enantiomeren van het chirale product (enantioselectiviteit)


212


reactie meestal niet het uiteindelijke doelmolecuul is is het van belang dat dit product ten minste genoeg functionele groepen bevat om door middel van vervolgreacties het doelmolecuul te kunnen synthetiseren In hoofdstuk 3 wordt het gebruik beschreven van uitgangsstoffen in de allylische alkylering met een extra functionele groep waardoor de producten ook zorsquon extra groep bevatten (schema 2 de eerste pijl is de allylische alkylering) Vervolgens worden de producten met behulp van vervolgreacties getransformeerd tot bouwstenen met twee functionele groepen (schema 2 de tweede pijl is de vervolgreactie) Dergelijke bouwstenen zijn bijzonder bruikbaar in de synthese van relevante organische stoffen zoals medicijnen

Schema 2 De synthese in twee stappen van relevante bouwstenen met twee verschillende functionele groepen (FG en FGrsquo) met behulp van koper-gekatalyseerde allylische alkylering (stap eacuteeacuten) en bepaalde vervolgreacties (stap twee)

Hoofdstuk 4 In hoofdstuk 4 wordt de combinatie van de koper gekatalyseerde

allylische alkylering en 14-additie behandeld De 14-additie is ook een koper-gekatalyseerde enantioselectieve reactie en is op sommige punten overeenkomstig met de allylische alkylering Het is belangrijk te weten dat de producten van een allylische alkylering kunnen worden getransformeerd (schema 3 eerste stap) in moleculen die als uitgangsstof kunnen dienen in een asymmetrische 14-additie In de 14-additie wordt vervolgens opnieuw een CH3 groep geiumlntroduceerd (schema 3 tweede stap)

Schema 3 Producten van een allylische alkylering kunnen na een transformatie (stap eacuteeacuten) worden gebruikt als uitgangsstof in een 14-additie (stap twee) R is een willekeurige groep


213


Door deze combinatie van allylische alkylering en 14-additie wordt uiteindelijk een product gevormd waarin twee koolstofatomen zich naast elkaar bevinden die allebei aan vier verschillende groepen zijn gebonden In dat geval zijn er vier verschillende producten mogelijk (de twee producten in schema 3 en hun enantiomeren) De keuze van het enantiomeer van de katalysator in de allylische alkylering bepaalt de configuratie van het eerste koolstofatoom en de keuze van de katalysator in de 14-additie bepaalt de configuratie van het tweede koolstofatoom Hierdoor biedt deze nieuwe route de mogelijkheid om naar wens elk van deze vier mogelijke producten selectief te synthetiseren

De route kan nuttig zijn in de synthese van biologisch actieve stoffen Om aan te tonen dat dit daadwerkelijk mogelijk is werd de route toegepast in de synthese van twee feromonen van twee verschillende mierensoorten Beide feromonen lasiol (A) en faranal (B) bevatten hetzelfde struktuurelement van twee koolstofatomen naast elkaar met ieder een CH3 groep eraan gebonden (zie inzet)

Hoofdstuk 5 In de route beschreven in hoofdstuk 4 levert de tweede stap ons de

uitgangsstof voor de 14-additie Deze reactie heet een cross-metathese De beste resultaten in de 14-additie werden behaald met specifieke zwavelhoudende stoffen thio-esters Deze thio-esters waren echter nooit eerder gesynthetiseerd met behulp van cross-metathese In hoofdstuk 5 worden de mogelijkheden van het gebruik van cross-metathese in de synthese van deze thio-esters verkend

Hoofdstuk 6 In hoofdstuk 6 wordt het gebruik van de koper-gekatalyseerde allylische

alkylering in de synthese van heterocyclische verbindingen beschrevensect Veel biologisch actieve stoffen zijn heterocyclische verbindingen De

sect Heterocycli zijn moleculen waarvan de bindingen tussen de atomen een ring vormen waarin ook ten minste eacuteeacuten heteroatoom (eg zuurstof of stikstof) voorkomt


214


uitgangsstoffen die in hoofdstuk 6 worden gebruikt bevatten een extra functionele groep Deze groep wordt na de allylische alkylering (schema 4 stap eacuteeacuten) in een vervolgreactie gebruikt om een ringsluiting te bewerkstelligen en zo de heterocycli te vormen (schema 4 stap twee)

Schema 4 Het gebruik van de koper-gekatalyseerde allylische alkylering in de synthese van heterocyclische verbindingen De golvende lijn is een willekeurige keten van koolstof en heteroatomen

Conclusies De enantioselectieve koper-gekatalyseerde allylische alkylering is een

uiterst krachtige koolstof-koolstof bindingsvormende reactie In dit proefschrift is de ontwikkeling van een nieuwe katalysator voor het gebruik van Grignard reagentia in deze reactie beschreven Deze katalysator is gebaseerd op koper en het ligand Taniaphos De hoge regio- en enantioselectiviteit die hiermee behaald werden vooral bij de introductie van een CH3 groep maken de nieuwe katalysator complementair aan de reeds bekende katalysatoren voor deze reactie

Daarnaast is de allylische alkylering op verscheidene wijzen toegepast in de synthese van relevante organische verbindingen zoals bouwstenen met twee functionele groepen feromonen en heterocyclische verbindingen Dit demonstreert dat deze reactie daadwerkelijk een waardevolle bijdrage kan leveren aan de mogelijkheden die synthetisch organisch chemici hebben Wanneer zij chirale verbindingen willen synthetiseren zoals bijvoorbeeld medicijnen zullen zij wellicht mede dankzij dit werk eerder gebruik maken van asymmetrische katalyse dan van oudere en minder efficieumlnte methodes

English Summary The main focus of research in the field of synthetic organic chemistry is

on the development of new methods for preparing organic compounds Organic compounds consist of atoms from the elements carbon (C) and hydrogen (H) and in addition regularly contain several heteroatoms As a result organic molecules are built up from a relatively small number of elements Nevertheless an impressive number of natural and non-natural organic compounds are known to us and an even greater number can still be discovered or synthesized These compounds differ from each other in the number of atoms in the bonds between these atoms and in the spatial orientation of these bonds

Chirality (derived from Greek χειρ = hand) is the property of an object in which the mirror images are non-superimposable In organic chemistry this signifies that the two mirror images of a chiral compound enantiomers are equal in every aspect except the absolute spatial orientation of the bonds which is exactly opposite This is the case when a carbon atom is bound to four different groups that surround it like a tetrahedron The two enantiomers of for example an amino acid differ in no other way than the fact that they are mirror images of each other It is the same with for example a left and a right hand (see figure in text) The physical and chemical properties of two enantiomers are exactly the same except in the interaction with other chiral compounds

In our bodies almost all our receptors and enzymes are chiral also As a result their interaction with a biologically active chiral compound such as a medicinal drug is often different for the two enantiomers of this compound Hence it is of importance for the pharmaceutical industry among others to have access to methods for obtaining one of the two enantiomers in a pure state Several methods are available to achieve this goal Amongst these methods asymmetric catalysis the subject of this thesis is a particularly powerful and efficient one

Heteroatoms in organic compounds are atoms from a select number of other elements such as for example oxygen (O) nitrogen (N) and sulfur (S)

English Summary

216

english summary_final

A catalyst is a compound that accelerates a reaction without overall being altered by the process This allows a small amount of catalyst to transform a larger amount of substrate into the desired product A chiral catalyst can be used to convert an achiral substrate selectively into one of the two enantiomers of a chiral product The chemical reaction that is the main subject of this thesis is the allylic alkylation (Scheme 1 black lines represent carbon atoms and their bonds most hydrogen atoms are omitted for clarity the arrow indicates the direction of the reaction)

Scheme 1 An enantioselective copper catalyzed allylic alkylation involving a Grignard reagent

The allylic alkylation proceeds by reaction of an allyl bromide as a substrate (left of the arrow) with an alkylmagnesium reagent a so-called Grignard reagent (above the arrow) The bromine atom (Br) of the substrate is replaced with the alkyl group of the Grignard reagent (in Scheme 1 this is a CH3) The two possible products are seen right of the arrow Both products have had the bromine atom replaced however the CH3 group can be bound to two distinct carbon atoms of the substrate The catalyst that is used for this reaction is a complex of a copper atom (Cu) with a chiral ligand an organic compound surrounding the copper atom

Scheme 1 shows that the product on the left contains a carbon atom bound to four different groupsdagger This is the desired chiral product A good catalyst needs to be both regioselective (producing selectively the chiral product and not the undesired product on the right) and enantioselective (producing selectively one of the two enantiomers of the chiral product)Dagger This thesis describes the development of a new catalyst for this reaction and its use in the synthesis of relevant organic compounds dagger In three dimensions one must envision the bold line (to the CH3) to be standing towards the reader and the hashed line (to the H) to be standing away from the reader Dagger These selectivities are expressed in the relative percentages of the two distinct products (regioselectivity) and of the two enantiomers of the chiral product (enantioselectivity)

English Summary

217


Chapter 1 A short introduction to asymmetric catalysis is provided in chapter 1 In

addition this chapter contains an overview of catalytic enantioselective substitution reactions This overview gives a general indication of the possibilities of the use of catalysts based on metals other than copper Subsequently a review is provided of the results obtained by our group and others in the copper catalyzed version of the reaction and an explanation is given for why copper occupies a specific niche compared to the other catalytic metals

Chapter 2 In chapter 2 the development of the new

catalyst is described This chiral catalyst is based on copper and the ligand Taniaphos (see figure in text) which binds to copper with two phosphorus atoms (P) The yield of the reaction (gt90) as well as the regioselectivity (the ratio of the products is 973) and the enantioselectivity (the ratio of the two enantiomers is 991) are high Especially the introduction of a CH3 group proceeds with excellent selectivity This is important because it is a common motif in biologically active compounds and because it was difficult to introduce the CH3 group through allylic alkylation using the catalysts reported previously

Chapter 3 A functional group is a part of a molecule on which reactions can be

performed Because the product of an enantioselective reaction usually is not the final target molecule it is important that this product has sufficient functional groups to synthesize this target molecule through subsequent reactions In chapter 3 the application in the allylic alkylation of substrates with an extra functional group is described (Scheme 2 the first arrow indicates the allylic alkylation) This extra functional group is

Scheme 2 The synthesis in two steps of relevant building blocks containing two distinct functional groups (FG and FGrsquo) through copper catalyzed allylic alkylation (step one) and several subsequent reactions (step two)

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retained in the product In subsequent reactions the products are transformed into building blocks containing two functional groups (the second arrow indicates the subsequent reaction) These versatile building blocks are applicable in the synthesis of relevant compounds such as pharmaceuticals

Chapter 4 In chapter 4 the combination of the copper catalyzed allylic alkylation

and 14-addition is discussed The 14-addition is a copper catalyzed enantioselective reaction also and is somewhat similar to the allylic alkylation It is important to know that the products of an allylic alkylation can be transformed (Scheme 3 first step) into molecules that can function as a substrate in an enantioselective 14-addition Subsequently the 14-addition introduces a second CH3 group (Scheme 3 second step)

Scheme 3 After a single transformation (step one) the products of an allylic alkylation can be applied as substrates in a 14-addition (step two) R is a non-specified group

Through this combination of allylic alkylation and 14-addition a product is obtained that contains two adjacent carbon atoms which are both bound to four different groups In this case four distinct products are possible (the two products in scheme 3 and their enantiomers) The choice of the enantiomer of the catalyst in the allylic alkylation directs the configuration of the first carbon atom and the choice of the enantiomer of the catalyst in the 14-addition directs the configuration of the second carbon atom Because of this the new route allows for the preparation of each of these four possible products in a selective fashion

Such a route can be useful in the synthesis of biologically active compounds To demonstrate that this is a real possibility the route was

English Summary

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applied in the synthesis of two pheromones of two species of ants Both pheromones lasiol (A) and faranal (B) contain the same structural element two adjacent carbon atoms both with a CH3 group bound to it (see figure in text)

Chapter 5 The route described in chapter 4 contains a reaction which transforms

the product of an allylic alkylation into a substrate for a 14-addition This reaction is called cross-metathesis The best results in the 14-addition were obtained with specific sulfur containing substrates thioesters However these thioesters had not been prepared before using cross-metathesis In chapter 5 the possibilities of the use of cross-metathesis in the synthesis of these thioesters are explored

Chapter 6 In chapter 6 the use of the copper catalyzed allylic alkylation in the

synthesis of heterocyclic compounds is describedsect Many biologically active compounds contain heterocycles The substrates used in chapter 6 contain an extra functional group After the allylic alkylation (Scheme 4 step one) this functional group is used in a subsequent reaction (Scheme 4 step two) to close the ring and form the heterocycle

Scheme 4 The application of the copper catalyzed allylic alkylation in the synthesis of heterocyclic compounds The wavy line is a non-specified chain of carbon and heteroatoms

sect Heterocycles are molecules of which the bonds between the atoms form a ring that contains at least one heteroatom also (eg oxygen or nitrogen)

English Summary

220


Conclusions In this thesis the development of a new catalyst for enantioselective

copper catalyzed allylic alkylation is described The high regio- and enantioselectivity of the new catalyst in particular with the introduction of a CH3 group makes the catalyst complementary to the catalysts reported previously for this reaction

In addition the enantioselective copper catalyzed allylic alkylation was applied in the synthesis of relevant organic compounds such as building blocks containing two functional groups pheromones and heterocyclic compounds This demonstrates that this reaction can make a valuable contribution to the possibilities that synthetic organic chemists have In part due to this work they might decide on applying asymmetric catalytic methods instead of older less efficient methods when they wish to synthesize chiral compounds such as for instance medicinal compounds

Dankwoord En dan nu na vier jaar en een paar maanden als AIO en wat lijkt op een

eeuwigheid in Groningen is het eindelijk klaar Het boekje ligt er en de dag van mijn promotie komt naderbij evenals mijn vertrek uit deze mooie stad Het was wellicht soms zwaar maar zo heb ik het eigenlijk nooit ervaren Dit is mede dankzij vele anderen waar ik samen mee gewerkt gefeest en geleefd heb in deze tijd En deze anderen wil ik hier aan het einde van mijn proefschrift daarvoor hartelijk danken

Allereerst wil ik natuurlijk mijn eerste promotor Ben onze alom aan- en afwezige Prof Feringa bedanken voor de kans dit onderzoek hier in Groningen uit te voeren Bedankt voor je aanmoediging je enthousiasme en de lovende woorden die ik toch vaak hard nodig had

Ook Prof Minnaard mijn tweede promotor wil ik bedanken Adri het was altijd indrukwekkend hoe ik na bijna elk overleg met jou het gevoel had dat de problemen die ik had of voorzag reeds opgelost waren

I would like to thank the reading committee Prof Engberts Prof de Vries and Prof Chan for reading and evaluating my thesis I hope you enjoyed reading it as much as I enjoyed doing the research and Irsquom looking forward to seeing you in my opposition

Wesley Irsquod like to thank you for proofreading almost all my papers and chapters and demolishing the confidence I had in my written English Thanks for helping me turn the gibberish in some of my first drafts into clear and well-constructed articles and for teaching me to put my alsorsquos at the end of my sentences also

A few other people have contributed directly to the research described in this thesis As the first of these contributors I want to thank Fernando Without you this would have been a different thesis altogether You did most of the groundwork described in chapter 2 and started many of the projects that I have finished at a later stage I owe my thesis in part to you

Jan-Willem hartelijk bedankt voor de bijdrage die je hebt geleverd aan hoofdstuk 6 Het was me een genoegen je bij je Bachelor-project te begeleiden Wiktor Irsquod like to thank you for your contribution to chapter 4 The work you did really bulked up this chapter and clarified the scope and limitation of the protocol presented there I very much enjoyed our cooperation

Dankwoord

222

Dankwoord_2

As indirect contributors I would like to thank the entire Feringa group and in particular the ldquoAsymmetric Catalysisrdquo-subgroup for all the useful discussions and suggestions Thanks for the help solving problems I was encountering and for just pretending to care when I needed to hear myself talk about my research

Voor de hulp bij het technische en analytische gedeelte van het onderzoek wil ik Theodora Albert Wim Ebe Evert Auke en Hans bedanken En Hilda dank ik voor de hulp bij alle administratieve rompslomp

One of the reasons that I have enjoyed this period so much was the excellent atmosphere in my lab 14223Z I want to thank all the wonderful people that I have had the pleasure to share my working space with in these four years In order of appearance Javi Syuzi Jan Danny Patrick Sara Christoph Dani Diego Tim Artem Bea Tati and Lachlan I cannot begin to explain how much fun we have had all together Suffice it to say that it is important to me to have my lab represented by two lovely ladies as my paranymphs on the day of my promotion

Of course I have made many friends among my colleagues in the other labrooms also Too many to name all of them here All the coffee and lunch breaks spent together the borrels and dinners on Friday partying in het Feest (of all places) workweeks and just any other excuse to go out and do something together You know who you are Thank you

I had the pleasure to organize one of the workweeks together with Dirk and Martin (in my opinion still the best one ever the only blemish was when we lost Ben somehow) I want to thank you two for this It was a wonderful experience

Vorrei ringraziare la famiglia Pizzuti per avermi accolto nella loro famiglia con tanto calore

Ik wil mijn ouders mijn zusje en Anne bedanken gewoon omdat ze er altijd voor me waren en er altijd voor me zullen zijn And I would like to thank Gabry for everything no need to specify I love you

Toon


Table of Contents

white page

Chapter 1_final version_2b

white page




white page


white page




Dankwoord_final

Enantioselective copper catalyzed allylic alkylation using Grignard reagents

Applications in synthesis











Proefschrift




door








Prof dr A S C Chan

ISBN 978-90-367-3683-1

Table of Contents









References









7 8

10 11 14

15

16 19 20

22

24 26 27 29

35 36

37 41 45 45 50 55 56 62

65 66 67 70

Table of Contents

4

Table of Contents






References











References

71 75 75 77

77

78 81 82 97

101 102 103

105 105 107

108

112 114

114

116 116 117 118

120 124 125 147

Table of Contents

5

Table of Contents





References









ξ 153 154 155 157 157 162 163 170

173 174 175 178 178 178 181 184

185

186 188 190 191 206

209

215

221



Chapter 1

8







9






Chapter 1

10









11







Chapter 1

12







13





Chapter 1

14








15








Chapter 1

16









17







Chapter 1

18





19







Chapter 1

20









21




Chapter 1

22









23







Chapter 1

24









25




Chapter 1

26










27









Chapter 1

28






29



Chapter 1

30




31



Chapter 1

32




33






Chapter 2

36







37






Chapter 2

38







39






Chapter 2

40





41







Chapter 2

42







43





Chapter 2

44





45













Chapter 2

46














47







1 1a MeMgBr (25 eq) 2a gt98 85 15 85

2 1b MeMgBr (25 eq) 2a 29 0 100 -

3c 1c MeMgBr (25 eq) 2a 22 0 100 -

4 1d MeMgBr (25 eq) 2a lt10 81 19 58

5de 1d MeMgBr (15 eq) 2a 75 36 64 58

Chapter 2

48



7de 1e MeMgBr (15 eq) 2a 25 8 92 57

8 1b EtMgBr (115 eq) 2b 70 9 91 0

9d 1b EtMgBr (115 eq) 2b gt98 57 43 36

10de 1b EtMgBr (115 eq) 2b 96 74 26 40







49












Chapter 2

50










51














Chapter 2

52





1 1a Me

2a 91 97 3 98 (S)

2 1a Et

2b 92 81 19 95 (S)

3 1a n-Bu ( )2

2c 92 87 13 94 (S)

4 1a ( )2 ( )2

2d 93 91 9 95 (S)

5de 1a i-Bu

2e 89f 42 58 6


53


6 1f Me Cl

2f 95 99 1 97

7 1f Et Cl

2g 80 82 18 96

8 1g Me MeO2C

2h 94 98 2 97

9 1h Me

2i 87 100 0 96 (S)

10 1h Et

2j 86 87 13 90

11d 1i Me ( )3 2k 99f 100 0 92

12d 1i Et ( )3

2l 99f 100 0 93

13deg 1j Et

2m 20f 25 75 22



Chapter 2

54




55





Chapter 2

56





57








Chapter 2

58











( )2

( )2


59









Cl

Cl

Chapter 2

60










MeO2C


61









Chapter 2

62




63



Chapter 2

64






Chapter 3

66







67








Chapter 3

68








69







Chapter 3

70









71







Chapter 3

72






73






Chapter 3

74





75







Chapter 3

76




entry

substrate

FG

RMgBr

product

yieldb

() b lc

eed ()

1ef 28 BnO MeMgBr 31 94 1000 92



4f 28 BnO EtMgBr 34 98 982 94


6 28 BnO n-BuMgBr 36 93 1000 94

7 28 BnO n-PentMgBr 37 87 1000 94





77








Chapter 3

78









79






Chapter 3

80





81





Chapter 3

82









O


83







SN

OO

O

O

Chapter 3

84









SiO

O


85








O

SN

OO

O

O

Chapter 3

86








O

O


87








13C-NMR δ 1380 1284 1277 761 732 612 381 314 177 MS (EI)

O

OOH

Chapter 3

88









O

O

O OH


89






O OH

O

Chapter 3

90








NH

O

O

SN

OO

O

O O


91









SN

OO

O

O

OH

SN

OO

O

O

OH

Chapter 3

92








N

OO

O

O

OH

O

SNH

O O

O O O


93






SN

OO

O

O

O

O

Chapter 3

94








NH

O

O

O

O

SiO OH


95






SiO O

Chapter 3

96




97



Chapter 3

98




99




Chapter 3

100






Chapter 4

102







103







Chapter 4

104






105








Chapter 4

106







107









Chapter 4

108







109







Chapter 4

110






111





Chapter 4

112








113





Chapter 4

114







115




entry

R

16

Ru-cat(Figure 43)

17

yieldb

(eec)

17 18d

1 Me 16a (Y = OMe) HG-2 17a 66 nd gt97 3

2 Me 16b (Y = Me) HG-2 17b 80 (99) gt97 3

3e Me 16c (Y = SEt) HG-2 17c 74 (97) gt97 3

4 Et 16a (Y = OMe) HG-2 17d 67g (98) 80 20

5f Et 16a (Y = OMe) G-2 17d 49g (98) 90 10



Chapter 4

116









117





1 Me 17a (RS)-L3 anti-19a 81 99 1 gt995

2 Me 17a (SR)-L3 syn-19a 84 4 96 gt995

3 Et 17d (RS)-L3 anti-19b 77 91 9 gt995




Chapter 4

118






2 MeMgBr (SR)-L1 syn-20a 46 14 86 66






119















Chapter 4

120








121






Chapter 4

122







123




Chapter 4

124






125








OMe

O

Chapter 4

126






O


127








OMe

O

SEt

O

Chapter 4

128








SEt

O

OMe

O


129








OMe

O

OMe

O

Chapter 4

130








OMe

O

O


131






O

Chapter 4

132









O

O


133







SEt

O

Chapter 4

134









SEt

O

SEt

O


135






SEt

O

Chapter 4

136








SEt

O

SEt

O


137






O OMe

O

Chapter 4

138





O SEt

O


139








O SEt

O

BnOOBn

Chapter 4

140





O SEt

O


141








O H

O

O

Chapter 4

142






HO


143









O O

O

HO O

O

Chapter 4

144









I O

O

O

O


145






H

O

Chapter 4

146




147



Chapter 4

148




149



Chapter 4

150




151






Chapter 5

154








155







Chapter 5

156






157








Chapter 5

158






1 G-1 (2 mol ) rt 20 h ndb


3 G-2 (2 mol ) rt 20 h 76

4 HG-2 (2 mol ) rt 20 h 93

5 Gre-2 (2 mol ) rt 20 h 72





159






1 Ph SEt

OPh

4 1 h 95

2 Me3Si SEt

OMe3Si

5 2 h 92

3 AcO SEt

OAcO

6 4 h 86

4 MeO2C SEt

O

MeO2C 7 4 h 91

5 Ph Ph SEt

O

8 18 h 72

Chapter 5

160


6b HO2C SEt

O

HO2C 9 24 h 83

7b HO ( )3 SEt

O

HO ( )3 10 24 h 93

8b O SEt

OO

11 24 h 75

9b Br ( )3 SEt

O

Br ( )3 12 24 h 75

10b OH SEt

O

OH 13 24 h 66

11b OH

SEt

O

OH 14 24 h 71

12b TsHN SEt

OTsHN

15 24 h 59

13bc AcO OAc SEt

OAcO

16 24 h 65

14bc BrBr SEt

OBr

17 24 h 64





161



Chapter 5

162





163







S

O

Chapter 5

164











S

O

5

S

OPh

S

OMe3Si


165



1730456 found 1730449







S

OAcO

S

O

MeO2C

Chapter 5

166











S

O

HO S

O

HOS

O

O


167









S

O

Br

S

OO

H

Chapter 5

168











S

O

OH

S

O

OH

HN

S

O

SO O


169









S

OAcO

S

OBr

Chapter 5

170




171





Chapter 6

174







175







Chapter 6

176







177




Chapter 6

178










179





1 9a Ph MeMgBr 10a 91 96 4 89

2 9b Me MeMgBr 10b 94 94 6 90



Chapter 6

180







4 10b Me Me PhMe 20 mM 2 h 11a 83f 90




181








Chapter 6

182








183













Chapter 6

184









185







1 O 24a 95 25a 60 1000 95 26a 37 93


Chapter 6

186








187






Chapter 6

188









189





Chapter 6

190








191








Ph O

OBr

Chapter 6

192









O

OBr

Ph O

O


193









O

O

O

O

Chapter 6

194









O

O

O

O


195









Ph O

OO

O

Ph

TsN Br

Chapter 6

196









TsN

NTs

Br


197









TsN

TsN

Chapter 6

198








TsN

NTs


199









TsN

O

Br

Br

Chapter 6

200








TsN

Br

Br

O

Br


201








TsN

Br

O

Chapter 6

202






TsN


203








TsN O

O

I

OBr

Chapter 6

204









O

O O

OH


205



Chapter 6

206




207



Chapter 6

208








210








211










212








213










214












English Summary

216






English Summary

217









English Summary

218








English Summary

219









English Summary

220













Dankwoord

222

Dankwoord_2








Toon


Table of Contents

white page


white page




white page


white page




Dankwoord_final










Proefschrift




door








Prof dr A S C Chan

ISBN 978-90-367-3683-1

Table of Contents









References









7 8

10 11 14

15

16 19 20

22

24 26 27 29

35 36

37 41 45 45 50 55 56 62

65 66 67 70

Table of Contents

4

Table of Contents






References











References

71 75 75 77

77

78 81 82 97

101 102 103

105 105 107

108

112 114

114

116 116 117 118

120 124 125 147

Table of Contents

5

Table of Contents





References









ξ 153 154 155 157 157 162 163 170

173 174 175 178 178 178 181 184

185

186 188 190 191 206

209

215

221



Chapter 1

8







9






Chapter 1

10









11







Chapter 1

12







13





Chapter 1

14








15








Chapter 1

16









17







Chapter 1

18





19







Chapter 1

20









21




Chapter 1

22









23







Chapter 1

24









25




Chapter 1

26










27









Chapter 1

28






29



Chapter 1

30




31



Chapter 1

32




33






Chapter 2

36







37






Chapter 2

38







39






Chapter 2

40





41







Chapter 2

42







43





Chapter 2

44





45













Chapter 2

46














47







1 1a MeMgBr (25 eq) 2a gt98 85 15 85

2 1b MeMgBr (25 eq) 2a 29 0 100 -

3c 1c MeMgBr (25 eq) 2a 22 0 100 -

4 1d MeMgBr (25 eq) 2a lt10 81 19 58

5de 1d MeMgBr (15 eq) 2a 75 36 64 58

Chapter 2

48



7de 1e MeMgBr (15 eq) 2a 25 8 92 57

8 1b EtMgBr (115 eq) 2b 70 9 91 0

9d 1b EtMgBr (115 eq) 2b gt98 57 43 36

10de 1b EtMgBr (115 eq) 2b 96 74 26 40







49












Chapter 2

50










51














Chapter 2

52





1 1a Me

2a 91 97 3 98 (S)

2 1a Et

2b 92 81 19 95 (S)

3 1a n-Bu ( )2

2c 92 87 13 94 (S)

4 1a ( )2 ( )2

2d 93 91 9 95 (S)

5de 1a i-Bu

2e 89f 42 58 6


53


6 1f Me Cl

2f 95 99 1 97

7 1f Et Cl

2g 80 82 18 96

8 1g Me MeO2C

2h 94 98 2 97

9 1h Me

2i 87 100 0 96 (S)

10 1h Et

2j 86 87 13 90

11d 1i Me ( )3 2k 99f 100 0 92

12d 1i Et ( )3

2l 99f 100 0 93

13deg 1j Et

2m 20f 25 75 22



Chapter 2

54




55





Chapter 2

56





57








Chapter 2

58











( )2

( )2


59









Cl

Cl

Chapter 2

60










MeO2C


61









Chapter 2

62




63



Chapter 2

64






Chapter 3

66







67








Chapter 3

68








69







Chapter 3

70









71







Chapter 3

72






73






Chapter 3

74





75







Chapter 3

76




entry

substrate

FG

RMgBr

product

yieldb

() b lc

eed ()

1ef 28 BnO MeMgBr 31 94 1000 92



4f 28 BnO EtMgBr 34 98 982 94


6 28 BnO n-BuMgBr 36 93 1000 94

7 28 BnO n-PentMgBr 37 87 1000 94





77








Chapter 3

78









79






Chapter 3

80





81





Chapter 3

82









O


83







SN

OO

O

O

Chapter 3

84









SiO

O


85








O

SN

OO

O

O

Chapter 3

86








O

O


87








13C-NMR δ 1380 1284 1277 761 732 612 381 314 177 MS (EI)

O

OOH

Chapter 3

88









O

O

O OH


89






O OH

O

Chapter 3

90








NH

O

O

SN

OO

O

O O


91









SN

OO

O

O

OH

SN

OO

O

O

OH

Chapter 3

92








N

OO

O

O

OH

O

SNH

O O

O O O


93






SN

OO

O

O

O

O

Chapter 3

94








NH

O

O

O

O

SiO OH


95






SiO O

Chapter 3

96




97



Chapter 3

98




99




Chapter 3

100






Chapter 4

102







103







Chapter 4

104






105








Chapter 4

106







107









Chapter 4

108







109







Chapter 4

110






111





Chapter 4

112








113





Chapter 4

114







115




entry

R

16

Ru-cat(Figure 43)

17

yieldb

(eec)

17 18d

1 Me 16a (Y = OMe) HG-2 17a 66 nd gt97 3

2 Me 16b (Y = Me) HG-2 17b 80 (99) gt97 3

3e Me 16c (Y = SEt) HG-2 17c 74 (97) gt97 3

4 Et 16a (Y = OMe) HG-2 17d 67g (98) 80 20

5f Et 16a (Y = OMe) G-2 17d 49g (98) 90 10



Chapter 4

116









117





1 Me 17a (RS)-L3 anti-19a 81 99 1 gt995

2 Me 17a (SR)-L3 syn-19a 84 4 96 gt995

3 Et 17d (RS)-L3 anti-19b 77 91 9 gt995




Chapter 4

118






2 MeMgBr (SR)-L1 syn-20a 46 14 86 66






119















Chapter 4

120








121






Chapter 4

122







123




Chapter 4

124






125








OMe

O

Chapter 4

126






O


127








OMe

O

SEt

O

Chapter 4

128








SEt

O

OMe

O


129








OMe

O

OMe

O

Chapter 4

130








OMe

O

O


131






O

Chapter 4

132









O

O


133







SEt

O

Chapter 4

134









SEt

O

SEt

O


135






SEt

O

Chapter 4

136








SEt

O

SEt

O


137






O OMe

O

Chapter 4

138





O SEt

O


139








O SEt

O

BnOOBn

Chapter 4

140





O SEt

O


141








O H

O

O

Chapter 4

142






HO


143









O O

O

HO O

O

Chapter 4

144









I O

O

O

O


145






H

O

Chapter 4

146




147



Chapter 4

148




149



Chapter 4

150




151






Chapter 5

154








155







Chapter 5

156






157








Chapter 5

158






1 G-1 (2 mol ) rt 20 h ndb


3 G-2 (2 mol ) rt 20 h 76

4 HG-2 (2 mol ) rt 20 h 93

5 Gre-2 (2 mol ) rt 20 h 72





159






1 Ph SEt

OPh

4 1 h 95

2 Me3Si SEt

OMe3Si

5 2 h 92

3 AcO SEt

OAcO

6 4 h 86

4 MeO2C SEt

O

MeO2C 7 4 h 91

5 Ph Ph SEt

O

8 18 h 72

Chapter 5

160


6b HO2C SEt

O

HO2C 9 24 h 83

7b HO ( )3 SEt

O

HO ( )3 10 24 h 93

8b O SEt

OO

11 24 h 75

9b Br ( )3 SEt

O

Br ( )3 12 24 h 75

10b OH SEt

O

OH 13 24 h 66

11b OH

SEt

O

OH 14 24 h 71

12b TsHN SEt

OTsHN

15 24 h 59

13bc AcO OAc SEt

OAcO

16 24 h 65

14bc BrBr SEt

OBr

17 24 h 64





161



Chapter 5

162





163







S

O

Chapter 5

164











S

O

5

S

OPh

S

OMe3Si


165



1730456 found 1730449







S

OAcO

S

O

MeO2C

Chapter 5

166











S

O

HO S

O

HOS

O

O


167









S

O

Br

S

OO

H

Chapter 5

168











S

O

OH

S

O

OH

HN

S

O

SO O


169









S

OAcO

S

OBr

Chapter 5

170




171





Chapter 6

174







175







Chapter 6

176







177




Chapter 6

178










179





1 9a Ph MeMgBr 10a 91 96 4 89

2 9b Me MeMgBr 10b 94 94 6 90



Chapter 6

180







4 10b Me Me PhMe 20 mM 2 h 11a 83f 90




181








Chapter 6

182








183













Chapter 6

184









185







1 O 24a 95 25a 60 1000 95 26a 37 93


Chapter 6

186








187






Chapter 6

188









189





Chapter 6

190








191








Ph O

OBr

Chapter 6

192









O

OBr

Ph O

O


193









O

O

O

O

Chapter 6

194









O

O

O

O


195









Ph O

OO

O

Ph

TsN Br

Chapter 6

196









TsN

NTs

Br


197









TsN

TsN

Chapter 6

198








TsN

NTs


199









TsN

O

Br

Br

Chapter 6

200








TsN

Br

Br

O

Br


201








TsN

Br

O

Chapter 6

202






TsN


203








TsN O

O

I

OBr

Chapter 6

204









O

O O

OH


205



Chapter 6

206




207



Chapter 6

208








210








211










212








213










214












English Summary

216






English Summary

217









English Summary

218








English Summary

219









English Summary

220













Dankwoord

222

Dankwoord_2








Toon


Table of Contents

white page


white page




white page


white page




Dankwoord_final






Prof dr A S C Chan

ISBN 978-90-367-3683-1

Table of Contents









References









7 8

10 11 14

15

16 19 20

22

24 26 27 29

35 36

37 41 45 45 50 55 56 62

65 66 67 70

Table of Contents

4

Table of Contents






References











References

71 75 75 77

77

78 81 82 97

101 102 103

105 105 107

108

112 114

114

116 116 117 118

120 124 125 147

Table of Contents

5

Table of Contents





References









ξ 153 154 155 157 157 162 163 170

173 174 175 178 178 178 181 184

185

186 188 190 191 206

209

215

221



Chapter 1

8







9






Chapter 1

10









11







Chapter 1

12







13





Chapter 1

14








15








Chapter 1

16









17







Chapter 1

18





19







Chapter 1

20









21




Chapter 1

22









23







Chapter 1

24









25




Chapter 1

26










27









Chapter 1

28






29



Chapter 1

30




31



Chapter 1

32




33






Chapter 2

36







37






Chapter 2

38







39






Chapter 2

40





41







Chapter 2

42







43





Chapter 2

44





45













Chapter 2

46














47







1 1a MeMgBr (25 eq) 2a gt98 85 15 85

2 1b MeMgBr (25 eq) 2a 29 0 100 -

3c 1c MeMgBr (25 eq) 2a 22 0 100 -

4 1d MeMgBr (25 eq) 2a lt10 81 19 58

5de 1d MeMgBr (15 eq) 2a 75 36 64 58

Chapter 2

48



7de 1e MeMgBr (15 eq) 2a 25 8 92 57

8 1b EtMgBr (115 eq) 2b 70 9 91 0

9d 1b EtMgBr (115 eq) 2b gt98 57 43 36

10de 1b EtMgBr (115 eq) 2b 96 74 26 40







49












Chapter 2

50










51














Chapter 2

52





1 1a Me

2a 91 97 3 98 (S)

2 1a Et

2b 92 81 19 95 (S)

3 1a n-Bu ( )2

2c 92 87 13 94 (S)

4 1a ( )2 ( )2

2d 93 91 9 95 (S)

5de 1a i-Bu

2e 89f 42 58 6


53


6 1f Me Cl

2f 95 99 1 97

7 1f Et Cl

2g 80 82 18 96

8 1g Me MeO2C

2h 94 98 2 97

9 1h Me

2i 87 100 0 96 (S)

10 1h Et

2j 86 87 13 90

11d 1i Me ( )3 2k 99f 100 0 92

12d 1i Et ( )3

2l 99f 100 0 93

13deg 1j Et

2m 20f 25 75 22



Chapter 2

54




55





Chapter 2

56





57








Chapter 2

58











( )2

( )2


59









Cl

Cl

Chapter 2

60










MeO2C


61









Chapter 2

62




63



Chapter 2

64






Chapter 3

66







67








Chapter 3

68








69







Chapter 3

70









71







Chapter 3

72






73






Chapter 3

74





75







Chapter 3

76




entry

substrate

FG

RMgBr

product

yieldb

() b lc

eed ()

1ef 28 BnO MeMgBr 31 94 1000 92



4f 28 BnO EtMgBr 34 98 982 94


6 28 BnO n-BuMgBr 36 93 1000 94

7 28 BnO n-PentMgBr 37 87 1000 94





77








Chapter 3

78









79






Chapter 3

80





81





Chapter 3

82









O


83







SN

OO

O

O

Chapter 3

84









SiO

O


85








O

SN

OO

O

O

Chapter 3

86








O

O


87








13C-NMR δ 1380 1284 1277 761 732 612 381 314 177 MS (EI)

O

OOH

Chapter 3

88









O

O

O OH


89






O OH

O

Chapter 3

90








NH

O

O

SN

OO

O

O O


91









SN

OO

O

O

OH

SN

OO

O

O

OH

Chapter 3

92








N

OO

O

O

OH

O

SNH

O O

O O O


93






SN

OO

O

O

O

O

Chapter 3

94








NH

O

O

O

O

SiO OH


95






SiO O

Chapter 3

96




97



Chapter 3

98




99




Chapter 3

100






Chapter 4

102







103







Chapter 4

104






105








Chapter 4

106







107









Chapter 4

108







109







Chapter 4

110






111





Chapter 4

112








113





Chapter 4

114







115




entry

R

16

Ru-cat(Figure 43)

17

yieldb

(eec)

17 18d

1 Me 16a (Y = OMe) HG-2 17a 66 nd gt97 3

2 Me 16b (Y = Me) HG-2 17b 80 (99) gt97 3

3e Me 16c (Y = SEt) HG-2 17c 74 (97) gt97 3

4 Et 16a (Y = OMe) HG-2 17d 67g (98) 80 20

5f Et 16a (Y = OMe) G-2 17d 49g (98) 90 10



Chapter 4

116









117





1 Me 17a (RS)-L3 anti-19a 81 99 1 gt995

2 Me 17a (SR)-L3 syn-19a 84 4 96 gt995

3 Et 17d (RS)-L3 anti-19b 77 91 9 gt995




Chapter 4

118






2 MeMgBr (SR)-L1 syn-20a 46 14 86 66






119















Chapter 4

120








121






Chapter 4

122







123




Chapter 4

124






125








OMe

O

Chapter 4

126






O


127








OMe

O

SEt

O

Chapter 4

128








SEt

O

OMe

O


129








OMe

O

OMe

O

Chapter 4

130








OMe

O

O


131






O

Chapter 4

132









O

O


133







SEt

O

Chapter 4

134









SEt

O

SEt

O


135






SEt

O

Chapter 4

136








SEt

O

SEt

O


137






O OMe

O

Chapter 4

138





O SEt

O


139








O SEt

O

BnOOBn

Chapter 4

140





O SEt

O


141








O H

O

O

Chapter 4

142






HO


143









O O

O

HO O

O

Chapter 4

144









I O

O

O

O


145






H

O

Chapter 4

146




147



Chapter 4

148




149



Chapter 4

150




151






Chapter 5

154








155







Chapter 5

156






157








Chapter 5

158






1 G-1 (2 mol ) rt 20 h ndb


3 G-2 (2 mol ) rt 20 h 76

4 HG-2 (2 mol ) rt 20 h 93

5 Gre-2 (2 mol ) rt 20 h 72





159






1 Ph SEt

OPh

4 1 h 95

2 Me3Si SEt

OMe3Si

5 2 h 92

3 AcO SEt

OAcO

6 4 h 86

4 MeO2C SEt

O

MeO2C 7 4 h 91

5 Ph Ph SEt

O

8 18 h 72

Chapter 5

160


6b HO2C SEt

O

HO2C 9 24 h 83

7b HO ( )3 SEt

O

HO ( )3 10 24 h 93

8b O SEt

OO

11 24 h 75

9b Br ( )3 SEt

O

Br ( )3 12 24 h 75

10b OH SEt

O

OH 13 24 h 66

11b OH

SEt

O

OH 14 24 h 71

12b TsHN SEt

OTsHN

15 24 h 59

13bc AcO OAc SEt

OAcO

16 24 h 65

14bc BrBr SEt

OBr

17 24 h 64





161



Chapter 5

162





163







S

O

Chapter 5

164











S

O

5

S

OPh

S

OMe3Si


165



1730456 found 1730449







S

OAcO

S

O

MeO2C

Chapter 5

166











S

O

HO S

O

HOS

O

O


167









S

O

Br

S

OO

H

Chapter 5

168











S

O

OH

S

O

OH

HN

S

O

SO O


169









S

OAcO

S

OBr

Chapter 5

170




171





Chapter 6

174







175







Chapter 6

176







177




Chapter 6

178










179





1 9a Ph MeMgBr 10a 91 96 4 89

2 9b Me MeMgBr 10b 94 94 6 90



Chapter 6

180







4 10b Me Me PhMe 20 mM 2 h 11a 83f 90




181








Chapter 6

182








183













Chapter 6

184









185







1 O 24a 95 25a 60 1000 95 26a 37 93


Chapter 6

186








187






Chapter 6

188









189





Chapter 6

190








191








Ph O

OBr

Chapter 6

192









O

OBr

Ph O

O


193









O

O

O

O

Chapter 6

194









O

O

O

O


195









Ph O

OO

O

Ph

TsN Br

Chapter 6

196









TsN

NTs

Br


197









TsN

TsN

Chapter 6

198








TsN

NTs


199









TsN

O

Br

Br

Chapter 6

200








TsN

Br

Br

O

Br


201








TsN

Br

O

Chapter 6

202






TsN


203








TsN O

O

I

OBr

Chapter 6

204









O

O O

OH


205



Chapter 6

206




207



Chapter 6

208








210








211










212








213










214












English Summary

216






English Summary

217









English Summary

218








English Summary

219









English Summary

220













Dankwoord

222

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Table of Contents

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Dankwoord_final

Table of Contents









References









7 8

10 11 14

15

16 19 20

22

24 26 27 29

35 36

37 41 45 45 50 55 56 62

65 66 67 70

Table of Contents

4

Table of Contents






References











References

71 75 75 77

77

78 81 82 97

101 102 103

105 105 107

108

112 114

114

116 116 117 118

120 124 125 147

Table of Contents

5

Table of Contents





References









ξ 153 154 155 157 157 162 163 170

173 174 175 178 178 178 181 184

185

186 188 190 191 206

209

215

221



Chapter 1

8







9






Chapter 1

10









11







Chapter 1

12







13





Chapter 1

14








15








Chapter 1

16









17







Chapter 1

18





19







Chapter 1

20









21




Chapter 1

22









23







Chapter 1

24









25




Chapter 1

26










27









Chapter 1

28






29



Chapter 1

30




31



Chapter 1

32




33






Chapter 2

36







37






Chapter 2

38







39






Chapter 2

40





41







Chapter 2

42







43





Chapter 2

44





45













Chapter 2

46














47







1 1a MeMgBr (25 eq) 2a gt98 85 15 85

2 1b MeMgBr (25 eq) 2a 29 0 100 -

3c 1c MeMgBr (25 eq) 2a 22 0 100 -

4 1d MeMgBr (25 eq) 2a lt10 81 19 58

5de 1d MeMgBr (15 eq) 2a 75 36 64 58

Chapter 2

48



7de 1e MeMgBr (15 eq) 2a 25 8 92 57

8 1b EtMgBr (115 eq) 2b 70 9 91 0

9d 1b EtMgBr (115 eq) 2b gt98 57 43 36

10de 1b EtMgBr (115 eq) 2b 96 74 26 40







49












Chapter 2

50










51














Chapter 2

52





1 1a Me

2a 91 97 3 98 (S)

2 1a Et

2b 92 81 19 95 (S)

3 1a n-Bu ( )2

2c 92 87 13 94 (S)

4 1a ( )2 ( )2

2d 93 91 9 95 (S)

5de 1a i-Bu

2e 89f 42 58 6


53


6 1f Me Cl

2f 95 99 1 97

7 1f Et Cl

2g 80 82 18 96

8 1g Me MeO2C

2h 94 98 2 97

9 1h Me

2i 87 100 0 96 (S)

10 1h Et

2j 86 87 13 90

11d 1i Me ( )3 2k 99f 100 0 92

12d 1i Et ( )3

2l 99f 100 0 93

13deg 1j Et

2m 20f 25 75 22



Chapter 2

54




55





Chapter 2

56





57








Chapter 2

58











( )2

( )2


59









Cl

Cl

Chapter 2

60










MeO2C


61









Chapter 2

62




63



Chapter 2

64






Chapter 3

66







67








Chapter 3

68








69







Chapter 3

70









71







Chapter 3

72






73






Chapter 3

74





75







Chapter 3

76




entry

substrate

FG

RMgBr

product

yieldb

() b lc

eed ()

1ef 28 BnO MeMgBr 31 94 1000 92



4f 28 BnO EtMgBr 34 98 982 94


6 28 BnO n-BuMgBr 36 93 1000 94

7 28 BnO n-PentMgBr 37 87 1000 94





77








Chapter 3

78









79






Chapter 3

80





81





Chapter 3

82









O


83







SN

OO

O

O

Chapter 3

84









SiO

O


85








O

SN

OO

O

O

Chapter 3

86








O

O


87








13C-NMR δ 1380 1284 1277 761 732 612 381 314 177 MS (EI)

O

OOH

Chapter 3

88









O

O

O OH


89






O OH

O

Chapter 3

90








NH

O

O

SN

OO

O

O O


91









SN

OO

O

O

OH

SN

OO

O

O

OH

Chapter 3

92








N

OO

O

O

OH

O

SNH

O O

O O O


93






SN

OO

O

O

O

O

Chapter 3

94








NH

O

O

O

O

SiO OH


95






SiO O

Chapter 3

96




97



Chapter 3

98




99




Chapter 3

100






Chapter 4

102







103







Chapter 4

104






105








Chapter 4

106







107









Chapter 4

108







109







Chapter 4

110






111





Chapter 4

112








113





Chapter 4

114







115




entry

R

16

Ru-cat(Figure 43)

17

yieldb

(eec)

17 18d

1 Me 16a (Y = OMe) HG-2 17a 66 nd gt97 3

2 Me 16b (Y = Me) HG-2 17b 80 (99) gt97 3

3e Me 16c (Y = SEt) HG-2 17c 74 (97) gt97 3

4 Et 16a (Y = OMe) HG-2 17d 67g (98) 80 20

5f Et 16a (Y = OMe) G-2 17d 49g (98) 90 10



Chapter 4

116









117





1 Me 17a (RS)-L3 anti-19a 81 99 1 gt995

2 Me 17a (SR)-L3 syn-19a 84 4 96 gt995

3 Et 17d (RS)-L3 anti-19b 77 91 9 gt995




Chapter 4

118






2 MeMgBr (SR)-L1 syn-20a 46 14 86 66






119















Chapter 4

120








121






Chapter 4

122







123




Chapter 4

124






125








OMe

O

Chapter 4

126






O


127








OMe

O

SEt

O

Chapter 4

128








SEt

O

OMe

O


129








OMe

O

OMe

O

Chapter 4

130








OMe

O

O


131






O

Chapter 4

132









O

O


133







SEt

O

Chapter 4

134









SEt

O

SEt

O


135






SEt

O

Chapter 4

136








SEt

O

SEt

O


137






O OMe

O

Chapter 4

138





O SEt

O


139








O SEt

O

BnOOBn

Chapter 4

140





O SEt

O


141








O H

O

O

Chapter 4

142






HO


143









O O

O

HO O

O

Chapter 4

144









I O

O

O

O


145






H

O

Chapter 4

146




147



Chapter 4

148




149



Chapter 4

150




151






Chapter 5

154








155







Chapter 5

156






157








Chapter 5

158






1 G-1 (2 mol ) rt 20 h ndb


3 G-2 (2 mol ) rt 20 h 76

4 HG-2 (2 mol ) rt 20 h 93

5 Gre-2 (2 mol ) rt 20 h 72





159






1 Ph SEt

OPh

4 1 h 95

2 Me3Si SEt

OMe3Si

5 2 h 92

3 AcO SEt

OAcO

6 4 h 86

4 MeO2C SEt

O

MeO2C 7 4 h 91

5 Ph Ph SEt

O

8 18 h 72

Chapter 5

160


6b HO2C SEt

O

HO2C 9 24 h 83

7b HO ( )3 SEt

O

HO ( )3 10 24 h 93

8b O SEt

OO

11 24 h 75

9b Br ( )3 SEt

O

Br ( )3 12 24 h 75

10b OH SEt

O

OH 13 24 h 66

11b OH

SEt

O

OH 14 24 h 71

12b TsHN SEt

OTsHN

15 24 h 59

13bc AcO OAc SEt

OAcO

16 24 h 65

14bc BrBr SEt

OBr

17 24 h 64





161



Chapter 5

162





163







S

O

Chapter 5

164











S

O

5

S

OPh

S

OMe3Si


165



1730456 found 1730449







S

OAcO

S

O

MeO2C

Chapter 5

166











S

O

HO S

O

HOS

O

O


167









S

O

Br

S

OO

H

Chapter 5

168











S

O

OH

S

O

OH

HN

S

O

SO O


169









S

OAcO

S

OBr

Chapter 5

170




171





Chapter 6

174







175







Chapter 6

176







177




Chapter 6

178










179





1 9a Ph MeMgBr 10a 91 96 4 89

2 9b Me MeMgBr 10b 94 94 6 90



Chapter 6

180







4 10b Me Me PhMe 20 mM 2 h 11a 83f 90




181








Chapter 6

182








183













Chapter 6

184









185







1 O 24a 95 25a 60 1000 95 26a 37 93


Chapter 6

186








187






Chapter 6

188









189





Chapter 6

190








191








Ph O

OBr

Chapter 6

192









O

OBr

Ph O

O


193









O

O

O

O

Chapter 6

194









O

O

O

O


195









Ph O

OO

O

Ph

TsN Br

Chapter 6

196









TsN

NTs

Br


197









TsN

TsN

Chapter 6

198








TsN

NTs


199









TsN

O

Br

Br

Chapter 6

200








TsN

Br

Br

O

Br


201








TsN

Br

O

Chapter 6

202






TsN


203








TsN O

O

I

OBr

Chapter 6

204









O

O O

OH


205



Chapter 6

206




207



Chapter 6

208








210








211










212








213










214












English Summary

216






English Summary

217









English Summary

218








English Summary

219









English Summary

220













Dankwoord

222

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