Department of Chemistry Imperial College London South Kensington Campus London SW7 2AY (UK)

Synthesis and

modif ication of

paracyclophanes

A thesis presented by

Cristina Lecci

In partial fulfilment of the requirements for the degree of

DoCtor of Philosophy

of the University of London

Department of Chemistry Imperial College London South Kensington Campus London SW7 2AY (UK)

October 2005

rat. Alkstract&&j

Two main research topics are discussed in this thesis: a) the synthesis and reactivity of small and medium size paracyclophanes; b) the synthesis and applications of new classes of chiral macrocycles derived from amino acids.

The first chapter is a concise review on the synthesis and use of [2.21paracyclophane derivatives as ligands in asymmetric catalysis and molecular recognition processes, with particular emphasis on tricarbonylchromium(O) complexes of [2.21paracyclophane.

In the second chapter the synthesis and reactivity of tricarbonyl chromium (0) complexes of small and medium size paracyclophanes towards asymmetric derivatisation is described. Various synthetic systems have been examined in asymmetric deprotonation/quench sequences directed towards obtaining enantioenriched derivatives by a procedure that would provide an alternative to more classical methods such as enzymatic and chemical resolution.

The third chapter is a comprehensive critical review of the applications of chiral macrocycles derived from amino acids in areas as diverse as ion transport across membranes, catalysis, development of new antibiotics and new materials.

The fourth chapter describes the synthesis of two new classes of chiral macrocycles via a versatile route, which potentially gives diverse and useful systems. The structure of the synthetic macrocycles, whose chirality is derived from the incorporation of amino acids as building blocks, has been examined by X-ray analysis. This led to the prediction that the presence of hydrogen bond donors and acceptors in the structure of these systems plays an important role in determining the interaction of such macrocycles with guest candidates. This chapter also details a study of the host properties of the synthetic macrocycles towards organic and metal guests.

The fifth chapter contains the experimental details of the work described in chapters 2 and 4. The appendix (Chapter

6) contains supporting information for the X-ray analyses performed during the course of the work while Chapter 7 provides the reader with full bibliographic details. Acknowledgements

I would like to thank my supervisor Professor Sue Gibson for her continuous support throughout my PhD experience and

for always seeing the bright side of things.

I would like to thank Jon Cobb at King's College London and

Pete Haycock at Imperial College London for their great NMR

service. I also wish to thank the Mass Spectrometry Service at King's College and at Imperial College, Dr. Andrew White at Imperial College for the X-ray analyses and Stephen

Boyer at London Metropolitan University for the elemental analysis service.

I also would like to thank the past and present members of the Gibson group and my friends at King's College and at

Imperial College, who have made these three years enjoyable and stimulating either from the scientific and the human point of you. I am indebted to Aaron, Karina, Ayako and

Paolo for carefully and helpfully proof-reading this thesis. I am particularly grateful to Paola, Matt, Nello,,

Andrea,, Patsy and Jamie for being very good friends and terrific companions inside and outside the work environment.

And finally I would like to thank my parents, my sisters and Paolo for being my constant moral support and for always believing in my capabilities. Table of contents

Abbreviations v

Chapter I

Synthesis and applications of [2.21paracyclophane derivatives

Introduction 2

1.2 Synthesis of enantioenriched paracyclophanes 2

1.3 [2.2]Paracyclophane derivatives in asymmetric catalysis 5 1.4 Bioactive [2.2]paracyclophanes 8

1.5 Synthesis of tricarbonylchromium(O) complexes of paracyclophanes 10

1.6 Reactivity of tricarbonylchromium(O) complexes of [2.21paracyclophane 13

Chapter 2

Synthesis and modification of small and medium-size paracyclophanes 18

2.1 The proposal 19

2.1.1 Desy=etrising paracyclophanes 19 2.2 Reactivity of [2.21paracyclophane 22

2.2.1 Studies of achiral deprotonation 22

2.2.2 Studies of enantioselective deprotonation 27 2.3 2,11-Dithia[3.3]paracyclophane and related systems 37

2.3.1 Synthesis of sulfur-containing paracyclophanes 37

2.3.2 Synthesis and reactivity of tricarbonylchromium(O)

complexes of sulfur-containing paracyclophanes 41 2.3.3 Reactivity of complexes 84 and 85 44

2.4 Synthesis and reactivity of a medium-size paracyclophane 53 2.5 Summary 54

i 0 Chapter 3

Amino-acid derived macrocycles -an area driven by synthesis or application? 55

3.1 Introduction 56

3.2 Transport across membranes 59 3.2.1 Introduction 59

3.2.2 Transport of small molecules across a lipidic membrane 61

3.2.3 Transport of small molecules across a chloroform/water membrane 67 3.3 Catalysis mediated by amino acid-derived macrocycles 69 3.4 Gelators 75

3.5 Organic nanotubes 77

3.6 Recognition of biologically important molecules 79 3.6.1 Introduction 79

3.6.2 Recognition of amino acid and peptide derivatives 82 3.6.3 Recognition of carboxylic anions 85

3.6.4 Recognition of steroids and purine derivatives 87

Chapter 4

Synthesis of new classes of chiral macrocycles derived from amino acids 90

4.1 The proposal 91

4.2 Synthesis of a novel class of macrocycles with

an increased number of nitrogen atoms 96

4.2.1 Synthesis of the appropriate aldehyde 96 4.2.2 Synthesis of chiral aminoalcohol 165 97

4.2.3 Synthesis of new alkene acceptors containing

the (S)-proline unit 98 4.2.4 Testing the Heck macrocyclisation on substrate 160 107

4.2.5 The Heck macrocyclisation on substrate 162

4.2.6 Synthesis of amine 170 and introduction of

(S)-valine into the picture 113

4.2.7 The Heck macrocyclisation on substrates 168 and 169 118

11 4.2.8 An experimental assessment for the selective formation of "dimers" during the

macrocyclisation step 121 4.3 Synthesis of a novel class of pyrrole-containing macrocycles 123

4.3.1 Background to the introduction of pyrroles 123

4.3.2 Synthesis of the appropriate aldehyde 125 4.3.3 Synthesis of a proline-derived alkene precursor 127

4.3.4 Synthesis of a valine-derived alkene precursor 130 4.3.5 The Heck macrocyclisation on substrates 188 and 193 134

4.3.6 Attempts to remove the benzyl protecting group from macrocycles 194 and 195 137

4.4 Application of the synthetic macrocycles: host-guest chemistry 140 4.4.1 Introduction 140

4.4.2 Investigation of the host properties of the

synthetic macrocycles 143 4.5 Application of the synthetic macrocycles:

asymmetric catalysis 146 4.5.1 Introduction 146

4.5.2 Testing the synthetic macrocycles as chiral

ligands in the RE (OTf) 3-catalysed Mukaiyama aldol reaction 148

4.5.3 Assessment of the nature of the interaction between the ligand and the metal 153

4.6 Summary and outlook 156

Chapter 5

Experimental 158

5.1 General Experimental 159

5.2 Experimental of Chapter 2 162

5.3 Experimental of Chapter 4 178

5.3.1 Experimental of Section 4.2 towards the synthesis of alkenes 160,162,168 and 169 178

111 5.3.2 Experimental of Section 4.3 towards the synthesis of alkenes 188 and 193 197

5.3.3 Typical procedure for the Heck coupling reactions 213 5.3.4 Experimental of Section 4.4 220

Chapter 6

Appendix 223

6.1 Crystal data for macrocycle 158 224 6.2 Crystal data for macrocycle 179 230

6.3 Crystal data for complex 204 233

Chapter 7

References 243

iv Abbreviations

a selectivity factor

Ac acetyl

Ala alanine

atm. atmosphere(s)

Ar aryl Bn benzyl

Boc tert-butoxycarbonyl Bu butyl

nBu normal-butyl tBu tert-butyl

C concentration

OC degrees centigrade cal calories CI Chemical Ionisation

cm centimetre(s) COSY Correlated Spectroscopy

mCPBA meta-chloroperbenzoic acid CSP Chiral Stationary Phase

dba trans, trans-dibenzylideneacetone DCM dichloromethane

d. e. diastereomeric excess

DEAD diethyl azodicarboxylate

dec. p. decomposition point DEPT Distortionless Enhancement by Polarization Transfer

DIPEA di-iso-propylethylamine

DMAP 4-N, N-dimethylaminopyridine

DME 1.2-dimethoxyethane

DMF AT,AT-dimethylf ormamide DMSO dimethyl sulfoxide

DNA deoxyribonucleic acid dppf 1,1'-bis(diphenylphosphino)ferrocene

V d. r. diastereomeric ratio e. e. enantiomeric excess EEDQ 2-ethoxy-l-ethoxycarbonyl-1,2-dihydroquinoline

EI Electron Impact eq. equivalent(s) ESI Electronspray Ionisation

Et ethyl FAB Fast Atom Bombardment

FT Fourier Transform

G molar free energy (Gibb's energy) Gln glutamine

Glu glutamic acid GPC Gel Permeation Chromatography h hour(s)

h-v light

a-HL a-hemol_ysin HETCOR Heteronuclear Correlation

HPLC High-Pressure Liquid Chromatography

HRMS High-Resolution Mass Spectroscopy

Hz Hertz

IR Infra Red

i coupling constant in Hz

K partition coefficient

k' capacity factor

Kass association constant KC1-Tris tris(hydroxymethyl)aminomethane potassium chloride LDA lithium diisopropylamide

ln natural logarithm Ln lanthanide

M molar

M+ molecular ion MALDI Matrix Assisted Laser Desorption/Ionization

Me methyl MHz MegaHertz

vi min. minute(s) M. P. melting point MS Mass Spectrometry

M/Z mass/charge

NAD + nicotinamide adenine dinucleotide

NADH hydrogenated nicotinamide adenine dinucleotide

NADP + nicotinamide adenine dinucleotide phosphate

NADPH hydrogenated nicotinamide adenine dinucleotide

phosphate

NHCs AT-heterocyclic carbene ligands nm nanometre(s) NMR Nuclear Magnetic Resonance

NOESY Nuclear Overhauser Effect Spectroscopy

ORTEP Oak Ridge Thermal Ellipsoid Plot

PDC Pyridinium Dichromate

Ph Phenyl

PPM parts per million

Pr propyl iPr iso-propyl psi pounds per square inch RE Rare Earth

Rf retention factor rt room temperature SBPs Steroid-Binding Proteins

SEC Size Exclusion Chromatography

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC Thin Layer Chromatography

TMEDA N, N, N", N"-tetramethylethylenediamine

TMS trimethylsilyl o-Tol ortho-tolyl p-Tol para-tolyl tR retention time

Ts para-toluensulfonyl

Vil UV Ultra V'Vet

volume V vibrational frequency (cm-1)

W/w weight per weight

Vill Chapter 1

Synthesis and applications of [2.2]paracyclophane derivatives

1 1.1 Introduction

There has been growing interest in the synthesis of chiral paracyclophanes in the last ten years given their potential in a wide range of applications, ['] such as the preparation of chiral ligands for asymmetric catalysis [ 21 or as chiral auxiliaries in stoichiometric asymmetric synthesis. [31

The introduction of chirality into the structure of paracyclophanes has been the focus of extensive research

since the synthesis of 12.21paracyclophane, the simplest [ 41 unsubstituted paracyclophane, was reported in 19,5 1. In particular, much effort has been devoted to synthesising planar chiral derivatives of [2.21paracyclophane, which are very interesting chiral scaffolds since they undergo

racemisation only at high temperatures and are stable ['] towards oxidants, light, acids and bases.

1.2 Synthesis of enantioenriched paracyclophanes

In the absence of efficient methods for the direct

enantioselective derivatisation of [2.2]paracyclophane via

asymmetric transformations, resolution techniques,

involving either asymmetric interconversion of functional

groups within a cyclophane structure or the use of enzymes as chiral catalysts, represent the best method to access [51 enantioenriched paracyclophanes.

(±)-4- For example, the asymmetric reduction of (S)-2 acetyl[2.2]paracyclophane 1 with enantiopure catalyst 3 4 afforded a 2: 1 mixture of diastereomeric alcohols and in good enantiomeric excesses (64 and >99% e. e., ['] respectively) (Scheme 1).

2 H( )H

BH3*SMe2 (0.6 eq. ) + + IN (S)-2 (15 mol%) THF, 0 'C, 100 min. (Rp)-l (R, Rp)-3 (R, Sp)-4 (Spo 85% conversion 64% e. e. >99% e. e.

d. r. = 2/1 (3/4) H C-N Ph Ph B-0 Me (S)-2

Scheme 1. Kinetic resolution of -1 with chiral catalyst (S)-2. (61

The unreacted starting material (Sp) -1 was recovered at the end of the reaction in 95% e. e., meaning that a kinetic resolution of the two enantiomers of 1 had occurred during the (S)-2 catalyzed asymmetric reduction, which is reflected in the diastereomeric ratio between the two products of the reaction.

More recently, the planar chirality of [2.21paracyclophane derivatives 9 has been resolved via conversion of (±)-4- bromo[2.2]paracyclophane 5 into the corresponding sulfoxides using commercially available Andersen's reagent 71 (lR, 2S, 5R) -(-)-menthyl (S)-p-toluenesulfinate (Scheme 2)

The stereospecific sulfinylation produced diastereoisomeric products 6 and 7, which differ only by the planar chirality of the [2.2]paracyclophane moiety, in 1: 1 ratio. These were readily separated by flash column chromatography, allowing the resolution of the planar chirality, and subjected to sulfoxide-metal exchange with various organometallic reagents to produce compounds 8, which were not isolated but immediately quenched with a variety of

3 electrophiles to afford 4-substituted [2.2]paracyclophanes 9 in yields of up to 90%.

0 1) (1.05 s Br nBuLi eq. ), THF, -78'C "Tol 2) (S,,)-menthyl p-toluenesulfinate, THF 0'/ sr-,A . Tol *

(±)-5 (Rp, Ss)-6 (Sp, Ss)-7

Yield = 61% (6/7 = 1: 1)

R'M (Sp, Ss) RX -7 10 THF, 'C -78 M] R

(Sp)-8 (Sp)-9 Yield up to 90%

R'M = nBuLi, EtMgBr, tBuLi, tBuMgBr

RX = DMF, Mel, TMSCI, C02, B(OMe6 Ph2P(O)Cl, Ph2PC', TsN3

Scheme 2. Planar resolution via stereospecific sulfinylation followed by sulfoxide-metal exchange and electrophilic quench. [71

The lipase from Candida Rugosa is one of the most versatile and widely used enzymes for the preparation of optically active compounds from either racemic. or prochiral substrates. [83 This enzyme has been shown to be capable of hydrolysing selectively the (Rp) -enantiomer of racemic (±) - 4-acetyl[2.2]paracyclophane 1, affording high enantiomeric excess of (+) - (Rp) -4 -hydroxy [ 2.21 paracyclophane 10 and (Sp) (Scheme 3) 19,10] unreacted - -1 .

4 Candida Rugosa H OAc 50 OC,H20,8 h +

W-l (+)-(Rp)-10 (+)-(Sp)-l

e. e. = 82% e. e. = 85% Scheme 3. Candida Rugosa-mediated E91 resolution of (±) -1.

1.3 [2.2]Paracyclophane derivatives in asymmetric catalysis

The possibility of accessing enantioenriched

[2.21paracyclophane derivatives either by chemical or enzymatic resolution as discussed in the previous section has opened the way to their use as chiral ligands for asymmetric catalysis. [21

For example, [2.2]paracyclophane-based N, O-ligands 11-12 have been used in the asymmetric addition of dialkylzincs to N-protected imines to ultimately afford enantioenriched secondary amines. E111 The reaction is believed to proceed via deprotonation of the N-formyl-(x-(p-tolylsulfonyl) benzylamine 13 (Scheme 4), followed by elimination of the sulfinate to form the prochiral N-formyl imine 14; this undergoes enantios elective conversion to AT-formyl amine 15, which can be hydrolysed to the corresponding primary amine

16 without loss of optical purity and nearly quantitatively. Ligand (Rp, S)-12, known for its broader substrate tolerance, [121 was demonstrated to be capable of inducing e. e. 's of up to 95%.

5 000 )l )l HN N NH Zn Et2 HN 2 ZnEt2 (3 eq. ) HCI S02Tol 0/x- Et Et ligand (2-5 mol%) rl RRRR I 13 14 15 16

Yield >99% Yield 95% e. e. = 95% e. e. 95% R=H, 4-Cl, 4-OMe, 4-COOMe, 2,6-Cl, 4-tBu, 4-Me, 3-Cl, 3-Me

4 ýH ýN OH N 0

(Rp, S)-ll (sp,S)-i 1 (Rp, S)-12 (Sp, S)-l 2

Scheme 4. Enantioselective addition of dialkylzinc to aldehydes catalyzed by AT,O-ligands 11-12. ý111

Planar chiral imidazolium salts 17 and 18, synthesised from enantiopure dibromide (Rp) -19 employing the reaction sequence depicted in Scheme 5, have been used as precursors for N-heterocyclic carbene ligands (NHCs) in the rhodium- catalyzed addition of arylboronic acids to aromatic aldehydes. [ 131 This study was triggered by previously reported work in which [2.2]paracyclophane-based NHCs ligands were used in asymmetric hydrogenation reactions [ 141 achieving e. e. 's of up to 89%. Catalysts derived from phosphinoyl imidazolium salts 17 gave better results than those obtained from methoxy-substituted paracyclophanes 18

(29% VS 10% maximum e. e. rs obtained when 4- chlorobenzaldehyde 27 was used as substrate).

6 a 0 b,c- e Br ( Br

20: 60% dC 21 (X=OH): 78% 17a-d 22 (X=Br): 52% Br

19 ro- f e 0 Iýv Br x Br

23 (R=H): 93% 25 (X=OH): 63% 18a-c 24 (R=Me): 87% 26 (X=Br): 82%

17a: R=Me (69%); 17b: R=(S)-CHMePh (50%); 17c: R=(R)-CHMePh (83%); 17d: R=Mesityl (35%); 18a: R=Me (99%); 18b: R=(S)-CHMePh (89%); 18c: R=(R)-CHMePh (93%).

Reagents and conditions: a) nBuLi, TMEDA, THF, -78 'C, then P(O)Ph2CI; b) tBuLi, THF, -78 "C, then DMF; c) NaBH4, H20, MeOH; d) PBr3, THF; e) imidazoles, DMF, 80- 100 f) OC; nBuLi, THF, -78 'C, then B(OMe)3, H202, NaOH; g) Mel, K2CO3, acetone, reflux; h) nBuLi, THF, -78 OC,then (CH20)x, 0 OC;i) PBr3, pyridine, DCM.

OH PhB(OH)2 5 mol% Rh/ligand ci---o 1,ýl- cl NaOMe, 60 OC DME/H20 27 28

Yield (%) e. e.

(Rp)-1 7a 72 20(S) (S, Rp)-17b 84 29(S) (R, Rp)-17c 63 3(R) (Rp)-17d 90 24(S) (Rp)-18a 80 2(R) (S, Rp)-18b 75 6(S) (R, Rp)-l 8c 57 1O(R)

Scheme 5. Synthesis of [2.21paracyclophane-based NHCs

ligands 17-18 and their use in the asymmetric addition of

arylboronic acids to aromatic aldehydes. [131

Although the e. e. 's obtained are quite low, these results [ 151 appear promising when compared to other published data and represent an interesting application of

7 [2.21paracyclophane-containing ligands to the relatively unexplored rhodium-catalyzed addition of arylboronic acids to aromatic aldehydes.

1.4 Bioactive [2.21paracyclophanes

A few studies concerning the biological activity of paracyclophanes are described in the literature, [ 161 and in it particular has been reported that indolocyclophane (±) - 29, obtained by a Buchwald variant of the Fisher indole synthesis, displayed substantial dopamine receptor affinity, demonstrating that sterically demanding paracyclophane derivatives are able to recognize highly transmembrane binding 17] To specific receptor sites .[ study the dopamine binding profile of the two enantiomers (Rp)-29

and (Sp)-29, the two antipodes were synthesised from

racemic acetyl. derivative (±)-l, employing a Candida

c_ylind-racea lipase-catalysed kinetic resolution to separate unreacted (Sp)-l and hydroxy derivative (Rp) -10 (Scheme 6) [18] Saponif ication (Sp) f . of -1 af orded enantiomerically pure (Sp) -10. The two hydroxy derivatives were subjected separately to a reaction sequence (shown in Scheme 6 only identical f or antipode (Rp) -10 but carried out in an way with (Sp) -10) involving triflation (a), palladium-catalysed cross-coupling reaction with benzophenone hydrazone (b), conversion to derivative 32 (c), Fisher cyclisation (d) and reductive amination (e) to afford enantiopure (Rp)-29 and

(Sp) -29.

8 Candida ý-,, I-Izl ý-, "IN, cylindracea NaOH 85 'C, 3h OAC AcO - 0H AcO HO (Rp)-l (sp)-l (Rp)-l 0 (Sp)-i (Sp)-i 0

ab c 0. llýN ý-, N. Ph -NNý 0H COTf NPh N COOEt H H (Rp)-10 (Rp)-30 (Rp)-31 (Rp)-32

HN COOEt N"^ýN'aClNS; (Rp)-33 (Rp)-29

Reagents and conditions: a) Tf20, pyridine, 0 'C to rt, 2 h, (85%); b) tBuONa, benzophenone hydrazone, dppf, Pd2(dba)3, toluene, 100 'C, 48 h (58%); c) 1. TsOHOH20, ethylene glycol, HCl/EtOH, reflux, 24 h; 2. Ethyl pyruvate, EtOH, 70 OC,3h (62%); d) TsOH, benzene, 100 OC, 45 min. (42%); e) LiAIH4, (4-chlorophenyl)piperazine, THF, rt to reflux, 75 min. (53%).

Scheme 6. indolocyclophanes Synthesis of (Rp) -29 and (Sp) -

29, which were tested for dopamine receptor binding [181 properties.

Both enantiomers (Rp) -29 and (Sp) -29 were evaluated in

vitro for their ability to bind to cloned human dopamine [ 191 receptors, and their affinity for the D4 receptor was

found to be comparable to that of the anti-psychotic drug

clozapine. Stereodifferentiation between the two enantiomers was also observed since (Rp) -29 showed significantly higher affinity than that displayed by (Sp)-

29 for all the receptor subtypes investigated. Given their promising biological activity, it can be envisaged that these compounds may serve as pharmacophoric building blocks

9 for the synthesis of neuroreceptor ligands with enhanced selectivities.

1-5 Synthesis of tri carbonyl chromium (0) complexes of paracyclophanes

Tricarbonylchromium(O) complexes of strained paracyclophanes have been known for decades and have been the subject of many investigations given their interesting [201 physical and chemical properties. The presence of the metal renders them crystalline and makes them ideal for carrying out X-ray crystallographic analysis. [211 The metal also induces an anisotropy effect that causes an upfield shift of the arene protons in the NMR spectra. (221

Pioneering studies on tricarbonylchromium(O) complexes of paracyclophanes soon revealed that each aromatic ring behaved like a single n system. [2 31 In fact, only monometal complexes 34 could be formed from [m. n1paracyclophanes with

ý 4 (Figure 1) the is deactivated m. n :! , as second ring towards complexation by the electron-withdrawing character of the tricarbonylchromium-bearing first ring. In contrast,

[4.5]- and [6.6]paracyclophanes formed both mono- and bis-

Cr(CO)3 derivatives 35f depending on the number of equivalents of the tri carbonyl chromium (0) source employed.

These results demonstrated that the transannular electronic interaction between the aromatic rings in the ligand cyclophanes, which increases with shortening of the alkyl bridges, plays an important role in determining the

Cr(CO)3/arene ring stoichiometry of the complexes.

10 Cr(CO)3

(C 2) (C 'ýt m 2)n

ur(Uo)3 Cr(UU)3

34 m, n<4 35 m, n=4,5 m, n=6,6

C6 6r r 36 37

Figure 1. The structure of mono-complex 34, bis-complexes [23,2 51 35 and "sandwich" complexes 36 and 37.

Later on, with the development of methods f or generating (241 single metal atoms, it became possibl E to synthesise sandwich compounds in which the chromium is encapsulated by the two rings of [2.21paracyclophane as in complex 36, which resembles the structure of bis(benzene) [251 tricarbonylchromium(O) complex 37.

In 1977 the synthesis and characterisation of mono- and bis-tricarbonylchromium complexes of multilayered

[2.21paracyclophanes was reported with the aim of further investigating their physical properties and the nature of [2 61 the electronic interactions between their benzene rings.

Mono-complexes 38-40 and bis-complexes 41-43 were prepared by treatment of the corresponding cyclophanes with an by flash excess of hexacarbonylchromium(O), and purified 41 column chromatography (Figure 2). Bis-complex was obtained in only 8% yield by use of a two molar ratio of

Cr(CO)6 to [2.21paracyclophane, while the similar complex better (29%). It is 42 could be prepared in a yield important to point out that bis-complex 43 with a formed in the quadruple-layered paracyclophane was even

11 case of equimolar amount of Cr(CO)6 and cyclophane. These results indicate that the first tricarbony1chromium group to coordinate exerts less of a transspacial electronic interaction on the other external benzene ring as the layer number increases.

qr(CO)3

Cr(CO)3

38 39 40

Cr(CO)3 Cr(CO)3 qr(CO)3 II

Cr(CO)3

41 Cr(CO)3

42 Cr(CO)3

Figure 2. Synthesis of mono- and bis-tricarbonylchromium(O) [2 61 complexes of multilayered [2.2]paracyclophanes.

12 1.6 Reactivity of tri carbonyl chromium (0) complexes of [2-21paracyclophane

The efficient electron withdrawal from the 6n-arene system exerted by the -Cr(CO)3 moiety increases the acidity of the complexed ring protons and allows their abstraction with strong bases such as nBuLi preferentially over the protons the of uncomplexed ring. The resulting (ri - aryllithium)Cr(CO)3 complexes can be quenched with a variety of electrophiles. [271

4,7-Dialkoxy[2.2]paracyclophanes 44a-b and the

corresponding 1,9-dienes 45a-b have been shown to undergo

selective complexation on their less substituted benzene [281 moiety (Scheme 7). The tricarbony1chromium complexes

46a-b and 48a-b were formed by reacting 44a-b and 45a-b in with (EtCN) 3Cr (CO) 3 in dioxane (method A) or Cr (CO) 6 dibutylether/tetrahydrofuran 10: 1 (method B). It is noteworthy that all these complexations occurred [291 selectively at the less substituted benzene ring except

for that of 44b with (EtCN)3Cr(CO)3; in this case the ratio between the -Cr(CO)3 complexed to the more substituted ring less and the -Cr(CO)3 complexed to the substituted ring was almost one.

13 qr(CO)3 Cr(CO)3 OR method A or B RO 7

R R

44a R= Me 46a-b 47a-b 44b R =nBu Yield Yield (%)

from 44a method A from 44a 54% trace method B from 44b 40% 39% method A

qr(CO)3 Cr(CO)3 OR method A or B -09 of + Ro'i I RO R

48a-b 45a R =Me 49a-b 45b R =nBu Yield (%) Yield (%)

from 45a 75% 5% method A from 45a 37% - method B from 45b 73% 5% method A

method A: (EtCN)3Cr(CO)3, dioxane; method B: Cr(CO)6, nBU20/THF (10/1)

Scheme 7.4,7-Dialkoxy[2.2]paracyclophanes 44a-b and 1,9- dienes 45a-b undergo selective complexation on their less [281 substituted benzene moiety.

Deprotonation followed by electrophilic quench of complexes

46b and 48a-b led to arene and bridge substitution, respectively, and an analogous behaviour was observed for tricarbonylchromium[2.2]paracyclophane 52 and for its 1,9- diene 56 (Scheme 8).

14 qr(CO)3 Cr(C0)3 Cr(C0)3 Me3Si Me3Si e --ýý, SiMe3 axbb. LIEI1 ,x xx

46b (X= OnBu) 50b (X= OnBu): 65% P-51b (X OnBu) 52 (X H) = = 53 (X = H): 90% 54 (X=H): 72%, p/m=1.33

qr(CO)3 qr(CO)3

Me3Si c SiMe3 x x

x x 48a (X = OMe) 55a (X= 0Me): 43% 48b (X= OnBu) 55b (X = OnBu): 80% 56 (X = H) 57 (X = H): 41 %

Reagents and conditions: a) X= OnBu : 1.10 eq. nBu Li/TM EDA, TH F, OC,40-50 h; 2. TMSCI; X=H: -78 1.5 eq. nBuLi/TMEDA, THF, -78 'C, 41 h; 2. TMSCI; b) 1.10 eq. nBuLifTMEDA, THF, -78'C, 40-50 h; 2. TMSCI; X=H: 1.10 eq. nBuLi/TMEDA, THF, h; -78 OC, 14 2. TMSCI; c) 1.5 eq. nBuLi/TMEDA, THF, -78 'C, 2 h; 2. TMSCI.

Scheme 8. Reactivity of complexes 46b, 52,48a-b and 56. [281

In contrast to the lithiation/silylation of complexes 48a- b, which gave almost exclusively the 1,10-bistrimethylsilyl

product 55a-b, the saturated complex 46b was metalated at

the tricarbonylchromium-complexed benzene ring. Only a

mono- lithiation/silylation was achieved in this case,

however, even with a tenfold excess of nBuLi after more than 40 h. Reacting the monosilylated complex 50b again

with 10 equivalents of nBuLi/TMSC1 gave the para- bissilylated complex p-51b. The striking selectivity for bridge metalation in 48 and ring attack in 46 cannot be

caused by the alkoxy substituent as this is also observed for the parent complexes 56 and 52 which predominantly give the 1,10-bissilylated 57 and the p- and m-bissilylated complexes plm-54, respectively. As ligands 51b, 54,55a-b by and 57 can be liberated from the -Cr(CO)3 moiety oxidation in trifluoroacetic acid, the three step sequence

15 of complexation, lithiation and electrophilic substitution opens a new route to compounds possessing an electron rich and an electron poor ring. These compounds could potentially exhibit useful intramolecular charge transfer features.

In 1991 an interesting intramolecular competition experiment for complexation of planar versus distorted benzene rings revealed that upon reaction of 1,2: 9,10- dibenzo[2.2]paracyclophane-1,9-diene 58 with 3 equivalents of (EtCN)3Cr(CO)3, only complex 59 could be formed (Figure [301 3). With an increased excess of (EtCN) 3Cr (CO) 31 59 reacted further to give the bis(tricarbonylchromium) complex 60 with both the -Cr(CO)3 units attached to the cyclophane-arene rings. This result was consistent with what Cram et al. had already deduced from the enhanced stability of the [2.2]paracyclophane-tetracyanoethylene complex: the bent arene groups in such systems are stronger

Tc-bases than undistorted arenes because the n-electron density is compressed between the rings and pushed outward [ 311 accordingly. Even in the dibenzo[2.2]paracyclophane-1,9- diene 61, with its four additional phenyl groups bearing in electron-donating t-butyl groups, the bent arenes the 3 skeleton win when it comes to complexation. With 62 traces equivalents of (EtCN)3Cr(CO)3,61 yields only and of the bis-complex 63.

16 Cr(CO)3

Cr(CO)3 Cr(CO)3 58 59 60

62 Cr(CO)3

Cr(CO)3

Figure 3. Intramolecular competition experiment for complexation of planar versus distorted benzene rings. [301

This outcome must be due solely to the relative n-basicity of the phane-arene moieties, since the t-butyl and the phenyl groups on the outer rings would not prevent the attachment of a -Cr(CO)3 unit for steric or electronic reasons, given that tricarbonylchromium(O) complexes of t- butylbenzene, biphenyl and even 1,3,5-tri-t-butylbenzene [321 are formed without difficulty.

17 Chapter 2

Synthesis and modification of small and

medium-size paracyclophanes

18 2.1 The proposal

In spite of the increasing interest in the synthesis and characterisation of chiral cyclophanes, there have been few surprisingly new approaches to generating non-racemic chiral In cyclophanes. particular, no chiral-base mediated has chemistry been applied so far to the enantioselective synthesis of this class of compounds.

At the time it is same known that complexation of an arene ring to the tricarbony1chromium fragment changes the

reactivity of the aromatic system and allows transformations that are otherwise inaccessible to become feasible. [3 31 it is anticipated that conversion of cyclophanes into the corresponding chromium complexes enhances the acidity of the aromatic and benzylic hydrogen [3 41 atoms; therefore their abstraction should be made easier at the low temperatures usually required for enantioselective deprotonation by a chiral base.

This is the starting point for the development of the

present project,. which concerns the investigation of the reactivity of paracyclophane-tricarbonylchromium(O)

complexes in deprotonation reactions employing non-racemic

chiral bases in an effort to ultimately achieve the

synthesis of substituted, enantioenriched paracyclophanes.

2.1.1 Desymmetrising paracyclophanes

According to the definition given by Cram, [ 351a cyclophane is a compound in which two or more atoms of an aromatic ring are incorporated into a larger ring system. In particular, for a pa-ra-system, the aromatic ring is incorporated via two carbons pa-ra to each other (64, Figure 4). [2.2]Paracyclophane 65 is the simplest unsubstituted

19 in paracyclophane which two benzene rings are connected to each other by two alkyl bridges.

(CH2

64 65

Figure 4. General structure of a paracyclophane (64) and [2.2]paracyclophane 65. [ 351

Systems like 65 are achiral since they exhibit three planes of symmetry,, one containing the two alkyl bridges and twc perpendicular to themselves and to the first plane. The presence of an ortho-substituent -X on the ring makes the system chiral, as it is no longer superimposable on its image (A, Figure ). [363 The is due to mirror '5 chirality not the presence of a tetrahedral asymmetric atom but to the presence of a chiral plane of symmetry (the substituted benzene ring), hence this particular kind of chirality is [3 61 referred to as planar chirality.

LII1 x

Figure 5. A representation of planar (A) and tetrahedral [361 (B) chirality for [ 2.2 ] paracyclophane derivatives.

in Alternatively, a paracyclophane can be desymmetrised a introduction tetrahedral more classical way by the of a in the benzylic centre of chirality, for example position.

20 Once the again molecule obtained is chiral as the two mirror images cannot be superimposed (B).

Both elements of chirality (planar and tetrahedral) can in be introduced principle stepwise or in a one-pot procedure. In the stepwise approach it is envisaged that the second element of chirality can be diastereoselectively introduced relying on the absolute configuration of the pre-existing one. [ 371

[341 As mentioned before, complexation of an aromatic ring to chromium(O) enhances the acidity of benzylic and aromatic hydrogen atoms. If the t ri carbonyl chromium (0) moiety is attached to only one of the two aromatic rings of [2.21paracyclophane, the base, either chiral or achiral, will selectively deprotonate this complexed ring or its benzylic protons leaving the other ring untouched.

Sequential deprotonation/quenching steps can in theory allow the introduction of different functionalities on the ring and in the benzylic position (Scheme 9). The introduction of the same substituent in the two positions is nevertheless also highly desirable. For example, by employing E= E' PPh2 and liberating the resulting system f rom the -Cr (CO)3 moiety, it could be possible to obtain diphosphine 68 which is an isomer of [2.2]PHANEPHOS 69, successfully used as a ligand in Rh-catalysed asymmetric [361 hydrogenation reactions.

21 1) deprotonation 1) deprotonation

2) EX 2) E'X E E Cr(CO)3 Cr(CO)3 Cr(CO)3

38 66 67

PPh2 PPh2 PPh2 68 E= E'= PPh2 69 [2.2]PHANEPHOS

Scheme 9. Derivatisation of the tricarbonylchromium complex [2.21paracyclophane of to obtain an isomer of [2.21PHANEPHOS 69. [381

With larger paracyclophanes, where the two benzene rings are far apart from each other, obtaining bis-

tricarbony1chromium complexes should be reasonably [231 straightforward. Therefore it may be possible to

deprotonate one or both of the arene rings in a chiral

fashion by employing the required number of non-racemic base equivalents in each step.

2.2 Reactivity of [2.21paracyclophane

2.2.1 Studies of achiral deprotonation

In an effort to combine tricarbony1chromium

complexation/activation and asymmetric deprotonation

reactions in a successful multi-step synthesis of

enantioenriched paracyclophanes, the reactivity of diverse

systems was explored. The preliminary investigation started with [2.2]paracyclophane 65, the simplest unsubstituted paracyclophane. As the complexation of [2.2]paracyclophane [23,3 91 and the achiral deprotonation of

22 the resulting [281 complex are well documented in the literature, a complexation/asymmetric deprotonation sequence employing a non-racemic chiral base was attempted on this system.

With this in mind, commercially available [2.21paracyclophane 65 heated was with one equivalent of Cr(CO)6 in dry di-n-butyl ether/THF mixture for 48 h (Scheme 10 40] After crystallisation of the crude yellow solid from nitrogen saturated dichloromethane/hexane 38 mixture, complex was obtained in 80% yield as yellow crystals.

Cr(CO)6 (1 eq.)

"INN nBU20fTH F (10/1) 135 OC,48 h Cr(CO)3

65 38

Yield = 80% [39,4 01 Scheme 10. Synthesis of complex 38.

1H 13C The NMR,, NMRf IR,, low resolution mass spectra and melting point of complex 38 matched the data reported in [391 1H the literature. The NMR spectrum of compound 38 shows separate multiplets for the two different types of benzylic protons and separate singlets for the two different types of aromatic protons. While the benzylic protons next to the complexed ring give a multiplet between 2.79 and 2.83 ppm due to the shielding properties of the -Cr (CO) 3 unit,, the other benzylic protons give a multiplet between 3.20 and

3.25 ppm. Similarly, the aromatic protons belonging to the complexed ring give a singlet at 4.67 ppm while the uncomplexed ring's ones give their signal at 6.81 ppm.

23 The reactivity 38 towards of deprotonation was initially tested employing nBuLi as base a and N" N' - tetramethylethylenediamine (TMEDA) as an additive, conditions drawn from chemistry which had already been successfully to applied the synthesis of similar arene- chromium [281 complexes. Iodomethane was chosen as the quenching electrophile in this preliminary study because the signal of the methyl group would be easy to locate in the NMR spectrum.

When five equivalents of nBuLi and five equivalents of TMEDA dropwise were added to a solution of 38 in dry THF at 'C, the -78 reaction mixture, kept at -78 'C, turned orange over a period of 40 h (Scheme 11). After adding 10

equivalents of iodomethane in one portion, the colour of the solution changed from orange to yellow.

1) nBuLi/TMEDA (5 eq. ) THF, OC,40 h -78 starting material 2) Mel (10 eq. ), -78 OC,2h 3) MeOH, OC->rt -78 H3C Cr(CO)3 Cr(CU)3

38 70

Scheme 11. Incomplete conversion of complex 38 into methylated compound 70.

Hydrolysis with nitrogen saturated methanol after 2h and flash column chromatography of the crude yellow material offered an inseparable 1: 1 mixture of the starting material and the methyl-substituted derivative 70. All efforts to separate the two compounds by flash column chromatography or by crystallisation failed, due to their very similar polarity and solubility.

24 Reaction parameters were altered in an attempt to achieve higher conversions. Switching from ten to twenty equivalents iodomethane of and using longer reaction did help, periods not as again only a 1: 1 starting material/methylated product mixture was obtained.

A crucial parameter proved eventually to be the temperature the is at which anion formed: when the mixture of 38 and

nBuLi/TMEDA was allowed to stir at -40 OC for 3 h, the solution turned deep red (Scheme 12), suggesting a higher degree deprotonation. of Quenching with 20 equivalents of iodomethane 'C, at -40 hydrolysis with MeOH, and flash

column chromatography of the crude product offered, to our delight, pure methylated compound 70 in 78% yield. No trace of the starting material 38 was detected.

1) nBuLi/TMEDA (5 eq. ) TH F, -78 'C-> -40 'C, 3h NNII 2) Mel (20 eq. ), -40 OC,2h - 3) MeOH, OC->rt -78 H3C" 1 Cr(CO)3 Cr(CO)3

38 70

Yield = 78% Scheme 12. Complete conversion of complex 38 into methylated compound 70.

1H The structure of novel compound 70 was determined by

NMR 13C NMR, IR, low and high resolution mass spectra and 1H elemental analysis. The NMR spectrum of compound 70 is particularly indicative of the high degree of asymmetry possessed by the system. The methyl group gives a singlet at 1.96 ppm, while all the benzylic protons give a very complicated multiplet between 2.53 and 3.15 ppm (Figure 6).

25 13 12 5:"" 10 14 15 16 87

--3 -6 9 H3 C45 Cr(CO)3

Figure 6. The structure of novel compound 70.

The signals of the complexed ring's protons all fall between 4.28 and 4.64 ppm. Proton 5 gives a doublet at 4.28 ppm, due to the coupling with proton 7. The latter gives a doublet of doublets at 4.48 ppm, and the coupling constants demonstrate that it couples with both 8 and 5. Finally, proton 8 gives a doublet at 4.64 ppm. The non-complexed ring's protons give four doublets of doublets between 6.60 and 6.89 ppm, and their coupling constants show that there are strong ortho- and para-couplings (respectively J=7.9 1.7 Hz) and .

To check whether an effective deprotonation was possible without TMEDA, an experiment employing only nBuLi was (Scheme 13) Since 83: 17 (estimated from 1H carried out . an NMR peaks intensity) inseparable mixture of 70 and 38 was obtained under these conditions, it was concluded that

TMEDA was necessary for complete conversion of the starting material into its methylated product.

1) nBuLi (5 eq. ) TH F, 'C-> 'C, 6h -78 -40 starting 0- material 2) Mel (20 eq. ), -40 cC, 15 h 3) MeOH, -78 OC->rt Cr(CO)3 Cr(CO)3

38 70

83 17

Scheme 13. TMEDA is necessary to achieve complete conversion of 38 into 70. 26 2.2.2 Studies of enantioselective deprotonation

Once it had been ascertained that complex 38 could successfully react with a strong, achiral base and undergo aromatic deprotonation, an asymmetric version of this sequence was attempted. The non-racemic chiral amine employed was (S, S) -1,2-diphenyl-N, N'-bis-[ (R) - (+) -1- phenylethyl I -ethane- 1,2 -diamine 72 (Scheme 14), which has been proven to be of significant use in the asymmetric functionalisation of tricarbonylchromium(O) complexes of [4 11 arenes.

This amine was obtained in two steps via the diimine [42,4 31 derivative 71, according to the literature procedure.

Glyoxal, (R)-(+)-l-methylbenzylamine, formic acid and magnesium sulfate were stirred in dichloromethane at room temperature for 20 minutes, and the brown oil resulting from the evaporation of the solvent was dissolved in hexane and dried over magnesium sulfate. Evaporation of the solvent afforded N, AP-bis E (R) - (+) -1-phenylethyll -1,2- its ethanediimine 71 in 92% yield as an orange oil, and structure was confirmed by the usual spectroscopic [421 means.

27 0

H)tyH 0 cI ) NH2 eq.

lsýl HCOOH, MgS04, CH2CI2, 20 71 eq. ) rt, min.

Yield = 92%

Ph Ph aNH PhMgBr (4.5 eq. ) HNb

Et20, -78 OC->rt, 10 h 72

Yield = 20% [42,431 Scheme 14. Synthesis of diamine 72.

Phenylmagnesium bromide was added dropwise at -78 OC to a stirred solution of diimine 71 in dry diethyl ether, and

the resulting solution was stirred for a further 10 h at room temperature. The brown oil obtained after hydrolysis,

extraction, and evaporation of the solvent was purified by

flash column chromatography followed by crystallisation

from hexane/dichloromethane. Compound 72 was obtained as colourless crystals with low yield (20%), which is reported to be typical of this reaction. [431 Its spectroscopic data matched those reported in the literature. [431

Chiral diamine 72 was employed in deprotonation experiments with complex 38, but disappointingly did not afford any derivatisation (Scheme 15, A) Using TMEDA (B) product . and changing the temperature (C) served to prevent the decomplexation of the starting material to

[2.21paracyclophane, but not to enhance the power of nBuLi as base and/or to induce enantioselectivity in the deprotonation of 38. These experiments were performed by pre-forming the dianion of 72 by nBuLi or by nBuLi/TMEDA at OC 38 -40 in THF and adding a THF solution of complex to

28 this mixture at 'C. -78 It was clear, from the colour change of the 72/nBuLi/TMEDA solution to red, that lithiation of 72 had proceeded without any difficulty, so the failure of this sequence was ascribed to the inability of the so-formed chiral dianion to deprotonate 38.

1) 72 (1 eq. ), nBuLi (2 eq.) TH F, 'C-> T, -78 -40 6'h starting material 2) Mel (20 eq.), -78 OC,15 h 3) MeOH, -78 'C->rt ur(ý; U)3 3 1 38

1) 72 (1 eq.), nBuLi/TMEDA (2 eq.) THF, 'C--> -78 -40 OC,6h starting material 'INN 2) Mel (20 eq.), -78 OC,15 h 3) MeOH, -78 OC->rt L; r((; L))3

38 31

1) 72 (1 eq.), nBuLi/TMEDA (2 eq. ) THF, 'C-> 0 'C, 3h C -78 starting material 2) Mel (20 eq.), -78 OC,15 h 3) MeOH, -78 OC->rt Cr(CO)3

38 Ph Ph

NH HN

Scheme 15. Studies of enantioselective deprotonation of complex 38 with diamine 72.

As TMEDA had been demonstrated to play a role in the deprotonation step for the preparation of 70, it was thought that a non-racemic additive structurally similar to

TMEDA and exhibiting the same elements of chirality as those of 72 may induce an asymmetric deprotonation of complex 38 if used together with nBuLi. Since chiral base

29 72 possesses two nitrogen atoms liable to methylation, it was planned to synthesise system 73 (Figure 7), which exhibits structural features similar to TMEDA.

Ph Ph Ph Ph ý4 NH HN lr---\ N\/ N- Me-N N-Me II Me Me

72 73 TMEDA

Figure 7. Chiral diamine 73 exhibits structural features similar to TMEDA.

Many experimental conditions were tried in the attempt to synthesise compound 73, but they were all unsuccessful.

Deprotonation at low temperature with sodium hydride

followed by quenching with iodomethane [441 only led to the

recovery of unreacted starting material, while

deprotonation with potassium hydride/18-crown-6 at high

temperature or with nBuLi at -78 OC afforded only decomposition products.

On the other hand, classical reductive amination reactions employing aqueous formaldehyde and sodium cyanoborohydride in the presence of acetic acid, (451 or Eschweiler-Clarke methods [4 61 with formaldehyde and formic acid, led to interesting, although undesirable, results. When a solution of 72 was added dropwise at 0 OC to an aqueous stirred solution of formic acid and formaldehyde and the resulting mixture was refluxed for 14 h, the only product obtained after hydrolysis, extraction and evaporation of the solvent was imidazolidine 74 (Scheme 16).

30 Ph Ph Ph,,, Ph 1) HCOOH, HCHO, THF/H20 0 'C->rt then reflux, 14 h NHHN-b NN 2) NaOH(aq. )

72 74

Yield = 94% Scheme 16. Synthesis of imidazolidine 74.

Novel aminal 74 was characterised by 1H NMR, 13C NMR,, determination of its melting point and optical rotation,,

IR, low and high resolution mass spectra and elemental analysis.

Although compound 74 is not the desired dimethylated compound 73, it is interesting in itself because of its potential role as an additive in deprotonation reaction. In fact,, it is a C2-symmetric compound with chiral elements identical to those of 72, but without the liability to deprotonation by nBuLi. Its performance in the derivatisation of complex 38 was therefore explored.

An experiment carried out using 5 equivalents of nBuLi and 5 equivalents of aminal 74 and then quenching with 20 equivalents of iodomethane only afforded unreacted starting material (Scheme 17, A), while lowering the amount of the aminal to one equivalent and keeping 5 equivalents of nBuLi produced complete conversion of 38 into 70, which was isolated in 90% yield after column chromatography (B).

31 1) nBuLi/74 (5 eq. ) THF, A -78 'C--> -40 'C, 3h 0. starting material 2) Mel (20 eq. ), -78 OC,14 h 3) MeOH, -78 OC->rt L; r(CO)3

1) 74 (1 eq. ), nBuLi (5 eq. ) B TH F, -78 'C--ý -40 T, 5h 0 2) Mel (20 eq.), -78 IC, 14 h 3) MeOH, OC-->rt I -78 H3C' I Cr(CO)3 Cr(CO)3

38 70

Yield = 90% racemic

Scheme 17. Attempted enantioselective deprotonation with

aminal 74.

Unfortunately the product of the latter reaction proved to be a racemic mixture of enantiomers (by measurement of its

optical rotation), and the two results put together seem to

imply that a possible 1: 1 complex between nBuLi and aminal 74 is not able to deprotonate compound 38.

Naturally occurring alkaloid (-) -sparteine 75, which has been successfully used in the asymmetric deprotonation of

ferrocenyl derivatives [471 and arene tri carbonyl chromium (0) [481 complexes, was also tried in the effort to enantioselectively functionalise compound 38. This bidentate ligand is able to form, with Li+,. the cation

+" is known to [Lie (-) -sparteine) which recognise enantiotopic sides of carbanions and enantiotopic hydrogens (471 in acidic carbon-hydrogen bonds.

In our experiment, nBuLi and (-)-sparteine were added 'C 38 in dropwise at -78 to a stirred solution of complex OC THF (Scheme 18) Over a period of 6h at -40 the reaction mixture turned deep red. Iodomethane was added 32 and, after hydrolysis, evaporation of the solvent and flash column chromatography, compound 70 was obtained in quantitative but yield again as a racemic mixture of enantiomers.

1) nBuLi/75 (5 eq. ) THF, -78 OC-->-40 OC,6h 0- 2) Mel (20 eq. ), -40 OC,14 h 3) MeOH, -78 OC->rt (; H3C I r(CO)3 Cr(CO)3

38 H 70 CN 7N Yield = 99%

wH racemic 75

(-)-sparteine

Scheme 18. Attempted enantioselective deprotonation of

complex 38 with (-) -sparteine 75.

With the aim of determining whether the lack of any

enantioselectivity in the deprotonation/quench sequence

could be due to the reaction temperature of -40 OC, a similar experiment was carried out keeping the temperature

at -78 'C during a 48 h deprotonation step and in the quenching step. In this case only the starting material was

recovered, with no trace of any derivatised product.

These results point to the conclusion that (-) -sparteine

might be acting as an additive at -40 OC, but that at this temperature chirality cannot be induced in the deprotonation of 38.

The possible influence of the nature of the electrophile on

the outcome of the reaction was then explored, and benzaldehyde was chosen in place of iodomethane for the

quenching step. It is in fact known that, employing chiral

33 diamine 74, the enantioselectivity of the deprotonation/quench sequence is induced during the [4 11 deprotonation step, and therefore the presence of a coordinating atom like oxygen in the structure of the

electrophile may favour the formation of more-ordered and differently stabilised transition states. This could lead

to well-differentiated diastereoisomeric pathways and [4 11 ultimately to good enantioselectivities.

A mixture of complex 38 and nBuLi/TMEDA was thus stirred at 'C benzaldehyde -40 for 6 h, after which an excess of was OC added and stirring was continued for 18 h at -78 (Scheme 19).

Ph Cr(CO)3 Cr(CO)3

76 1) nBuLi/TMEDA (5 eq. ) (50%) THF, -78 'C->-40 OC,6h

2) PhCHO (20 eq. ), -78 'C, 18 h 3) MeOH, -78 'C->rt Cr(CO)3

38 )H H(

I Ph Cr(CO)3 Cr(CO)3

77 (49%)

overall yield 99% 76 77. Scheme 19. Synthesis of diastereomeric compounds and

34 After addition of nitrogen-saturated MeOH and flash column chromatography, two yellow crystalline solids with remarkably different retention factors (Rf r see Experimental) were obtained in respectively 49% and 50% yield, with an overall yield of 99% which corresponds to quantitative conversion of starting material 38 into its substituted derivatives. These two novel compounds were 1H 13 characterised by NMR, C NMR, melting point, IR, low and high resolution mass spectra and elemental analysis, and a diastereomeric, relationship was established. The relative planar/tetrahedral configuration of these two diastereoisomers is not known. They will be referred to as 76 and 77 throughout this manuscript for the sake of clarity, but no direct relationship between the depicted and the actual (unknown) structure should be inferred.

Having ascertained that benzaldehyde functions as an electrophile in this transformation, the possibility of carrying out a selective version was examined. The use of chiral diamine 72 in this attempt resulted only in the recovery of unreacted starting material. Therefore the same reaction was repeated employing (-) -sparteine as the chiral additive (Scheme 20), but again a 1: 1 mixture of the two diastereoisomers was obtained in high yield.

35 Cr(CO)3 Cr(CO)3 76 1) nBuLi/(-)-sparteine (5 eq. ) THF, (49%) -78 'C--> -40 OC, 4.5 h 2) PhCHO (20 eq.), -40 'C, 14 h 3) MeOH, -78 *C-->rt Cr(CO)3

)H H

0) Cr(CO)3 3 77 (48%)

overall yield 97%

Scheme 20. The use of (-)-sparteine resulted in the formation of a 1: 1 mixture of diastereoisomers, each of which resulted to be a racemic mixture of enantiomers.

Although no diastereoselectivity had been achieved during the reaction, the question regarding the enantioselectivity of the process was still open. Disappointingly, polarimetric measurements confirmed that both compounds had again been obtained as a racemic mixture of enantiomers, confirming that replacing iodomethane with benzaldehyde did not influence the enantioselectivity of the process.

36 2.3 2,, 11-Dithia[3.3]paracyclophane and related systems

2.3.1 Synthesis of sulfur-containing paracyclophanes

The disappointing results obtained in the studies on [2.21paracyclophane derivatives led to the conclusion that 72, 74 chiral amine aminal and (-)-sparteine 75 were not for the suitable enantioselective derivatisation of 38, least compound at within the range of conditions and electrophiles examined. On the other hand, the fact that it had not been possible to achieve any sort of benzylic

functionalisation raised the concern that the highly

reduced conformational flexibility of this class of

compounds could in some way impede the stabilisation of a

possible benzylic anionic intermediate, known to rely on a flat transition state. [4 11

It is also known that the presence of heteroatoms such as

oxygen, nitrogen or sulfur, next to the benzylic position

can favour the alkylation of this specific site by nBuLi

followed by quenching with a range of alkylating 11 reagents. 4 Moreover, once this kind of derivatisation is

complete, the benzylic electron donating atom can direct

the next deprotonation to the o-rtho- position of the 91 ring. [4

In light of the above, the new goal became the synthesis of more conformationally flexible thiacyclophane 78 and oxacyclophane 79 (Figure 8). and the assessment of the reactivity of the corresponding chromium complexes in both achiral and enantioselective deprotonation reactions.

37 S S \ j

78 79 Ficjure 8. New synthetic targets: compounds 78 and 79.

Compound 78 is particularly interesting given the possibility of sulfur extrusion by photolysis with trialkylphosphites, [501 [511 by treatment with Fe (CO)5 or by [521 pyrolysis of its sulfone analogue. Extrusion of the sulfur atoms from enantioenriched substituted 2,11- dithia[3.3]paracyclophanes could provide a novel route to the corresponding enantioenriched substituted [2.2]paracyclophanes.

[531 Whereas the synthesis of 78 and the preparation of its 41 tri carbonyl chromium (0) complex [5 is known, the synthesis of compound 79 has not been reported. Following the literature procedure for the synthesis of 78, [531a dilute equimolar mixture of 1,4-benzenedimethanethiol 80 and cc, oc'-dibromo-p-xylene 81 in ethanol was added dropwise to a dilute solution of potassium hydroxide in ethanol at room temperature over a period of 6h (Scheme 21). A white solid precipitated and the mixture was stirred at room temperature for 14 h. After evaporation of the solvent, work-up, and recrystallisation of the white crude solid from toluene, compound 78 was obtained in 70% yield as colourless crystals and its structure was confirmed by the [531 usual spectroscopic and analytical means.

38 HS Br

KOH (2 eq. ) + 1ý S\ EtOH, h S rt, 14 \L / SH Br

80 81 78 ) eq eq. Yield = 70%

Scheme 21. Synthesis of thiaparacyclophane 78.

The application of the same procedure to the synthesis of

79 was ineffective, and many other different experimental

conditions (solvents, bases, reactions temperatures, and

reaction times) were tried. The use of NaH as base in DMF

only afforded polymeric products, even at high dilutions,

while with aqueous K2CO3 or KOH and a phase transfer

catalyst (either nBU4NC1 or 18-crown-6) only by-products or

starting materials were obtained, even at high

temperatures. It was concluded that 79 is a kinetically and

thermodynamically unfavoured compound, possibly because the

two oxygen atoms are not large enough to prevent repulsion

between the two electron-rich aromatic rings, thus

rendering its synthesis unfeasible under conventional [551 laboratory conditions.

Attention then turned to the possibility of manipulating

compound 78 in order to access derivatives 82 and 83

(Figure 9), whose electron-withdrawing sulfoxy- and

sulfonyl-groups were anticipated to facilitate benzylic deprotonation. Besides, as already mentioned earlier, disulfone 83 has been reported to undergo pyrolysis with release of sulfur dioxide and concomitant formation of a [2.2]paracyclophane backbone, [521 which expands the scope of applications of this particular derivative. At the same time, if it was possible to obtain an enantioenriched derivative of 82, oxidation to an enantioenriched

39 disulfone, or reduction to an enantioenriched thiaparacyclopane, could afford enantioenriched [2.21paracyclophanes after sulfur extrusion.

02S S02 os' so

82 83

Figure 9. Disulfoxide 82 and disulfone 83.

To synthesise disulfoxide 82, aqueous hydrogen peroxide was added dropwise to a stirred solution of 78 in chloroform and acetic acid at 10 'C, and the mixture was allowed to stir at room temperature for 40 h (Scheme 22). After work- up, novel disulfoxide 82 was obtained as a mixture of diastereoisomers in 86% yield, and was characterised by 1H

NMR,, 13C NMR,, IR,. melting point,, low resolution and high resolution mass spectrometry and elemental analysis.

T -rt, 40 h os so

78 82

Yield = 86%

Scheme 22. Synthesis of disulfoxide 82.

Disulfone 83 was synthesised following the reported [5 21 literature procedure: a mixture of 78 and m- chloroperbenzoic acid (mCPBA) was stirred at room temperature for 48 h, and 83 was recovered by filtration in 23). Its 70% yield as a colourless solid (Scheme data in spectroscopic and physical matched those reported [ 521 the literature.

40 mCPBA (4 eq. ) 02S S02 CHC13, rt, 48 h

78 83

Yield = 70% Scheme 23. Synthesis of disulfone 83. [ 521

2.3.2 Synthesis and reactivity of tr i carbonyl chromium (0) complexes of sulfur-containing paracyclophanes

With compounds 78,82 and 83 in hand, their reactivity towards a source of chromium(O) became the subject of investigation.

The synthesis of complex 84 had been reported in 1989 by [541 Mitchell et al., but several attempts to reproduce their

results failed to afford an appreciable amount of the desired compound.

After modifications which included the unfruitful use of (CH3CN) (CO) [561 3Cr 3 as a more reactive source of -Cr (CO) 3r

the reaction temperature proved to be the crucial

parameter. In fact when a suspension of

hexacarbonylchromium(O) and 78 were refluxed for 18 h at

145 OC rather than 135 OC, as reported in the literature [541 procedure, flash column chromatography of the yellow crude afforded complex 84 in 72% yield as a yellow crystalline solid (Scheme 24). Its spectroscopic and analytical data matched those reported in the literature. [541

41 Cr(CO)3

ý F-'LL: Cr(CO)6 (1 ) .1 eq. SIS0. SS+SS nBU20fTH F (10/1) 145 T, 18 h

ur(UU)3 Cr(UU)3 78 84 85 Yield = 72% Yield = 11% Scheme 24. Synthesis of complexes 84 and 85. [541

It is worth noting that, even if only a slight excess of Cr(CO)6 was used, a considerable amount of dicomplex 85 was formed. also This more polar complex was isolated as a

yellow solid and fully characterised by the usual means. [541

Increasing the amount of Cr (CO) 6 employed only served to increase the yield of dicomplex 85 (with 1.5 eq. of

Cr(CO)6,37% yield of 84 against 38% yield of 85 was

obtained), and conversely by lowering the equivalents of

Cr(CO)6 to equimolar amount in order to minimise the amount

of 85 formed, no trace of dicomplex was detected while the

yield of 84 dropped to 30%. Interestingly, dicomplex 85

proved to be remarkably unstable, decomposing to green

material even when stored in the dark under an atmosphere

of dry nitrogen. The reason for this instability was

ascribed to the fact that 85 might readily lose one of the

tricarbonylchromium(O) units with generation of oxidised

chromium species.

Once it had been established that compound 78 could undergo

complexation on one or both aromatic rings, a similar set of conditions was applied to the conversion of disulfoxide 82 into the corresponding chromium complex. Unfortunately it soon became clear that this particular compound involving the undergoes a redox reaction reduction of

42 sulfoxide moieties with concomitant oxidation of the Cr(O) source.

In fact, when a mixture of disulfoxide 82 and 1.1 equivalents of Cr(CO)6 135 'C was stirred at for 18 h, a large amount of oxidised chromium material precipitated out of the solution (Scheme 25). Filtration of the crudp product and flash column chromatography led to the isolation identification and of reduced compounds 78 and 86 (1H NMR and MS).

F-ýý F

+S S \-ý

ca. 20%

Scheme 25. Disulfoxide 82 undergoes a redox reaction under

complexation conditions.

Leaving aside compound 82 because of its liability to act

as an oxidising reagent towards chromium(O) sources, the

reactivity of disulfone 83 was next taken into

consideration. In this case the very poor solubility of 83

in all common organic solvents, including those usually

employed in complexation reactions, proved to be a real

issue. it was thought, nonetheless, that a tricarbony1chromium derivative of disulfone 83 may be more soluble than 83 itself in the organic solvents needed for further manipulation.

43 Given the insolubility of 83 in nBU20/THF, an alternative procedure involving the pre-formation of active species (CH3CN)3Cr(CO)3 [561 was attempted. 1.5 Equivalents of Cr(CO)6

were refluxed in anhydrous acetonitrile for 3 days, then

one equivalent of 83 suspended in acetonitrile was added to

the deep yellow solution and the reflux was continued for 30 minutes (Scheme 26) It is known that the very reactive

species (CH3CN)3Cr(CO)3, unlike Cr(CO)6, is able to undergo

CH3CN/arene ligand-exchange in a matter of minutes, leading

to very fast formation of arene-tricarbonylchromium

complexes. [571

(CH3CN)3Cr(CO)3 1) CH3CN, 3 d, 80'C Cr(CO)6 2) 83 (1 eq. ), 30 min., 80 OC (1.5 eq. ) starting material

Scheme 26. Attempted complexation of 83 employing reactive

species (CH3CN)3Cr(CO)3-

Unfortunately, filtration of the green crude mixture and

evaporation of the solvent afforded only (CH3CN)3Cr(CO)3 in

almost quantitative yield.

2.3.3 Reactivity of complexes 84 and 85

The exploration of the reactivity of complex 84 began by

subjecting it to very strong deprotonating conditions. Treatment with an excess of tBuLi did not produce any

conversion and led to the quantitative recovery of (Scheme 27, A) On the unreacted starting material . other hand, treatment with an excess of nBuLi promoted an

uncontrolled multi-deprotonation process which, after in quenching with iodomethane, resulted a complex mixture to identify (B). of compounds, not easy to separate or

rý 1) tBuLi (4.2 eq. ) A THF, -78 OC, 2h starting material 2) Mel (20 eq. ), -78 "C, 14 h 3) MeOH, -78 OC->rt Cr(CO)3

1) nBuLi (5 eq. ) THF, -78 'C, 1.5 h complex mixture of compounds 2) Mel (20 eq. ), -78 OC, 1.5 h 3) MeOH, -78 OC->rt ur(ý; Uh

Scheme 27. Preliminary investigation of the reactivity of complex 84.

Nevertheless, these preliminary results confirmed that

nBuLi could be used to convert complex 84 into some sort of 1H derivatised products since NMR spectrum of the crude product of reaction B clearly showed the incorporation of

one or more methyl groups into the cyclophane backbone.

After much optimisation, it was discovered that an excess

of nBuLi/TMEDA was able to convert starting material 84

into a novel methylated compound (Scheme 28).

1)nBuLi/TMEDA (5 eq. ) THF, -78 OC,3h 2) Mel (20 ), 'C, 1h CH3 eq. -78 , 3) MeOH, -78 'C-->rt uqý; Uh (; r(uu)3

84 87

Yield = 30%

Scheme 28. Synthesis of compound 87.

TMEDA Five equivalents of nBuLi and an equimolar amount of 84 in were added dropwise to a stirred solution of complex OC, 3h the turned THF at -78 and over a period of solution the deep red. An excess of iodomethane was then added and 45 reaction mixture was stirred at -78 OC for a further hour, before adding nitrogen-saturated MeOH. Evaporation of the solvent and flash column chromatography of the crude afforded a single compound as a yellow crystalline solid in 30% yield.

1H The NMR spectrum this of species showed the presence of a 2.16 sharp singlet at ppm, which is a typical shift for methyl groups directly bound to sulfur atoms. It was that [581 postulated a Wittig-type rearrangement,. rather than a simple benzylic deprotonation/quench sequence, had taken place. The product of this reaction was therefore believed to have structure 87, obtained from the base-mediated Wittig rearrangement on compound 84 (Scheme 28a, pathway A).

deprotonation The of compound 84 could also trigger an

alternative rearrangement involving the generation of a carbene species (pathway B), which would then undergo a C-H

insertion and ultimately lead to the formation of compound 87a, in which the sulfur atom is bound to the benzylic carbon next to the non-complexed ring. Although this mechanism could also be operating in the present case in place of the Wittig rearrangement mechanism, the examination of the proton NMR of the actual compound obtained (see below) does not match the expected NMR for compound 87a. In fact, it is anticipated that protons 10 in

87a (easily located on the 1H NMR spectrum given their clear and unique coupling with proton 11) and benzylic protons 2 in compound 87b (obtained by double Stevens 6_ rearrangements on tricarbonyl(q s_yn-2,11-dithia [3.3]metacyclophane)chromium(O)) [ 601 should display very similar shifts, as also proton 11 in 87a should have a very 1 in 87b Since the similar shift to the one of proton .

46 base

(Wittig rearraingement, pathway A) Cr(CO)3 Cr(CO),

84 base

(pathway B)

S\ S N-1 E) ur((; ())3

H /-ýý E) SS (; r(uU)3

C-H insertion E)

Is ur((; U)3 e / Mel Me[ Cr(CO)3 CH3 3.24 and 2.23 ppm S, 4.27 ppm S-CH3 Cr(CO)3 L; r(L; U)3

87a 87

3.84 ppm / 3.43 and 2.13-2.26 ppm S\ H3C" 4.42 ppm , -S-CH3 2 ur((; 0)3 3.53 and 2.98 ppm 87b

Scheme 28a. Mechanisms of the Wittig rearrangement to form

compound 87 (pathway A) and alternative carbene-generating mechanism (pathway B) to form 87a.

47 observed 1H NMR is completely consistent with structure 87 but not entirely with structure 87a, the Wittig mechanism is here proposed to take place preferentially to the carbene-involving pathway.

This is result not without precedent: 2,11- dithia [591 [ 3.3 ] metacyclophane and its tricarbonyl chromium(O) [601 known complex are to undergo Wittig and Stevens rearrangement under basic conditions. A similar behaviour of a tricarbonylchromium complex of 2,11- dithia[3.3]paracyclophane is unprecedented, as is the

possibility of carrying out the rearrangement only on one side of the cyclophane, leaving the other bridge intact.

16 17 1 15

S 14 13 98 7 10 CH3 34-, S., 56 Cr(CO)3

Ficjure 10. Wittig-type rearrangement product 87.

In the 1H NMR spectrum of 87 (Figure 10) apart from the singlet discussed above which accounts for the methyl protons, a doublet of doublets at 2.23 ppm is assigned to one of the two diastereotopic protons 11. The determination of the coupling constants for this doublet of doublets

(13.7 and 6.2 Hz) renders particularly easy the location of the remaining proton 11 and of proton 10: the former gives a doublet of doublet at 3.24 ppm with J values of 13.7 and 9.8 Hz (geminal and vicinal coupling constant, respectively), while the latter gives another doublet of doublets at 4.27 ppm, with vicinal J values of 9.8 Hz and 6.2 Hz. The methylenic protons on the unaffected bridge

48 doublet. give each a The two doublets at 3.41 and 3.45 ppm, integrating each for one proton and exhibiting a coupling 14.5 constant of Hz, are assigned to protons 3 (which are in close proximity to the complexed ring); the two doublets at 3.87 and 3.94 ppm, exhibiting J= 15.3 Hz, are therefore assigned to protons 1. The four protons of the complexed aromatic ring give four distinct doublets of doublets between 4.56 and 4.90 ppm, with clearly resolved ortho- (J

= 6.7 Hz) and meta- (J = 1.5 Hz) couplings in each case, while the protons of the uncomplexed ring give a multiplet between 6.74 and 7.29 ppm.

Novel compound 87 was characterised also by 13C NMR,, IR,, determination of the melting point, low resolution and high resolution mass spectrometry and elemental analysis.

An interesting reactivity of compound 84 towards strong bases was thus starting to emerge, and the possibility of taking advantage of it in an asymmetric fashion became the

focus of the ensuing investigations. The 1,2-Wittig rearrangement has been reported to proceed with

stereospecificity both at the migrating centre and at the [ 611 metal terminus. In our particular case, the metal bearing centre would be a sulfur atom which does not give rise to any stereochemical issue; conversely, an trigger enantioselective benzylic deprotonation that could the a rearrangement with retention of configuration at migrating centre would ultimately produce an enantioenriched paracyclophane.

be to To test whether chiral diamine 72 could used realise the of 87 this goal, an asymmetric version of preparation 29). was attempted (Scheme

49 .11" 1) 72 (1.1 eq. ), nBuLi/(2.2 eq. ) LiCl (1 eq. ), THF, -78 'C, 3.5 h

2) Mel (20 eq. ), -78 'C, 16 h 3) MeOH, C-*rt CH3 -78: s , Cr(CO)3 Cr(CO)3

84 87

Yield = 70% Scheme 29. Attempted enantioselective synthesis of 87 employing diamine 72.

nBuLi was added dropwise to a stirred solution of diamine 72 in THF at -78 OC. The chiral diimide was allowed to form at room temperature, then the deep pink solution was re- cooled back to -78 'C and a solution of heat-gun dried [ 62 lithium chloride was added, followed by a solution of complex 84 in THF. Iodomethane was added to the deep orange

solution after 3.5 h and, to our delight, after quench with MeOH, evaporation of the solvent and flash column chromatography, Wittig-type rearrangement product 87 was isolated in 70% yield. Unfortunately, the product of this reaction proved to be a racemic mixture of enantiomers (chiral HPLC determination), and therefore no enantioselection had been induced by the chiral lithium diamide 88 (Figure 11) generated from 72 and nBuLi.

Nonetheless, these were the highest yielding of the many reaction conditions investigated in the pursuit of converting 84 into 87.

Since no enantioselection had been achieved in the formation of 87 with diamide 88 (and using nBuLi/(-)- the sparteine only unreacted 84 was recovered), plan to 87, switched to developing a high-yielding route which further The could become the subject of manipulation. 88 in deprotonating 84 efficiency of chiral diamide was but the low indeed a very interesting and promising result, encountered yield and the practical purification problems

50 during the synthesis of diamine 72 make it not particularly ideal for reactivity screening.

This triggered the search for a structurally related but diamide achiral that would give a good conversion of 84 into 87. racemic The choice settled on Cnmmprr!,; ýIIV aval able diamine 89 (Figure 11), which, like diamine 72, possesses two hydrogen atoms available for deprotonation by a strong base.

Ph Ph

N N-b NH HN II Li Li

88 89

Figure 11. Achiral diamine 89 can form a diamide structurally related to diamide 88.

The reaction carried out with amine 72 was attempted with compound 89. In this case there was no enantioselectivity issue to impose an upper limit to the reaction temperature, and therefore the reaction mixture was allowed to reach room temperature and stirred for 3h before the addition of iodomethane (Scheme 30).

1) 89 (1 eq. ), nBuLi(2 eq. ) THF, -78 'C-->rt, 3h (20 ), 18 h 2) Mel eq. rt, CH3 3) MeOH , -,, I Cr(CO)3 Cr(CO)3

84 87

Yield = 21%

Scheme 30. Synthesis of compound 87 employing diamine 89.

Quenching with MeOH, evaporation of the solvent and flash 21% 87, column chromatography afforded only a yield of

51 confirming that all the structural features of chiral diamine 72 were essential to achieve high yield and conversion.

To complete the study of the reactivity of t ri carbonyl chromium (0) complexes of small paracyclophanes, the behaviour of dicomplex 85 towards strong bases had to be ascertained. With this aim, 85 was subjected to deprotonation with chiral diamide 88, believing this base could perform more efficiently compared to nBuLi/TMEDA and nBuLi/89. The product resulting from treatment with nBuLi/72 and quenching with iodomethane proved to be composed mainly of compounds 84 and 87 (1H NMR spectrum of the crude product mixture), together with unreacted starting material (Scheme 31).

Cr(CO)3

1) 72 (2 eq. ), nBuLi ý(4eq. ) LiCl (1 ), THF, 3 h, OC eq. -78 +

2) Mel (20 eq. ), 1 h, -78 OC 3) MeOH, -78 OC->rt Cr(CU)3 L; r(uU)3 84 85

unreacted starting material s CH3 s Cr((; 0)3

Scheme 31. Reactivity of dicomplex 85 towards deprotonation conditions.

This was ascribed to the inherent instability of complex

85, which readily loses one of the tricarbonylchromium towards moieties to generate 84, whose chemistry nBuLi/72 has already been examined.

p 2.4 Synthesis and reactivity of a medium-size paracyclophane

The possibility of carrying out chromium complexation on a larger cyclophane has been also explored. Compound 90, a crown-ether type paracyclophane, was chosen because it can be easily from synthesised inexpensive starting materials (Scheme 32) According to the procedure Gray 631 . of et al. f[ diethylene glycol 91 was heated with potassium t-butoxide f or 1h 60 'C. at aal-Dibromo-p-xylene 92 was added and the stirring was continued at 60 OC for 4 h. After filtration to remove polymeric products, flash column chromatography of the crude afforded crown-ether 90 in 21% yield as a yellow oil.

c r, o, 'ý tBuOK (2.1 eq. ) OH OH Br/ 00 toluene, 60 OC,4h 91 92

(1 eq. ) (1 eq. )

Yield = 21 %

Scheme 32. Synthesis of crown-ether type paracyclophane go. [631

Compound 90 was characterised by 1H NMR,, 13C NMR,, IR,, low

resolution and high resolution mass spectrometry, and the

data collected matched those reported in the literature. [ 631

Unfortunately, every attempt to obtain a tricarbonylchromium(O) complex of 90 failed, as only

unreacted starting material and oxidised chromium species were isolated in all the experiments carried out. These results suggest that the formation of a chromium complex

53 could be disfavoured by the dominant ability of the crown- ether to act as a cage for the metal. Therefore rather then complexing the chromium via the arene ring, paracyclophane

90 prefers to host the metal in its cavity, forming very unstable species that ultimately lead to chromium oxidation and to the recovery of starting material.

2.5 Sunuuary

A systematic exploration of the reactivity of tricarbony1chromium complexes of [2.21paracyclophane and 2,11-dithia[3.3]paracyclophane has demonstrated that they can be functionalised via a dep rotonation/electrophilic quench sequence using diff( ýrent types of bases and electrophiles.

No enantioselective derivatisation of complexes 38 and 84 has been achieved within the range of conditions taken into consideration, but a very interesting reactivity of compound 84 has emerged.

Crown-ether type paracyclophane 90 has been successfully synthesised, but it could not be converted into the corresponding tricarbonylchromium(O) complex, possibly because of its strong tendency to form host-guest aggregates with the metal during the attempted complexation step.

54 Chapter 3

Amino-acid derived macrocycles

an area driven by synthesis or application?

55 3.1 Introduction

The synthesis, structure and physical properties of macrocycles have fascinated chemists for many years. Their inherent properties make them useful in areas as diverse as ion transport across membranes, development of new antibiotics, and catalysis. In this review a cross-section of macrocyclic chemistry containing non-peptidic amino-acid

derived molecules has been taken and analysed in terms of

function, rather than structure or synthesis.

Before discussing how synthetic non-peptidic macrocycles

derived from amino acids are being used in a range of

applications in Sections 3.2-3.6, it is instructive to look

at the functions performed by naturally occurring

macrocycles of this type.

Diazonamide A (641 93 (Figure 12) is a potent inhibitor of

the assembly of tubulin in human carcinoma cells, and even

though its overall mode of action is unclear, several

hypotheses about the nature of its interaction with tubulin

have been formulated. [ 651 For example, it has been proposed

that diazonamide A binds to tubulin at a site remote from it has been the one where the Vinca alkaloids bind; also tubulin but proposed that it binds weakly to unpolymerized [ 65 Cryptophycin-1 94, the strongly to microtubule ends. from Mostoc sp. major cryptophycin extracted cyanobacterium tubulin GSV224, is also a potent inhibitor of is believed to have therapeutic polymerization and (taxolo) ý66] Examination of the advantages over paclitaxel . with tubulin in vitro effects of incubating cryptophycin-1 form bond led to the hypothesis that 94 does not a covalent reactive to the protein, despite the presence of a very [ 66c] epoxide ring.

56 Some naturally occurring amino acid-containing macrocycles 1 C2ýCZ derive their biological activity from the proposed or proven formation of complexes with metal cations. The biaryl ether K-13 95, isolated from the culture broth of

Micromonospora halophytica subsp. exilisia K-13, is an inhibitor of angiotensin I converting enzyme, a member of [ 671 the family of zinc metalloproteinases. Its mechanism of inhibition is believed to rely on its coordination to the 2+ Zn ion in the active site of angiotensin I. The Li+ complex of jaspamide (jasplakinolide) 96, isolated from the marine sponge Jaspis johnstoni, has been the subject of extensive recent investigations as a model for cation-a interactions which are acknowledged to be important in [ 681 protein-DNA complexes, and which may explain the anticancer activity of jaspamide and how it stabilises actin polymerization. Ascidiacyclamide 97, isolated from ascidian Lissoclinum patella found on the Great Barrier

Reef, [ 691 features a hydrophobic pocket capable of accommodating two copper ions, a metal whose concentration

S 105 fold higher in the ascidian organisms than in the

C02 surrounding sea water, and which is able to capture and 2-. C03 This cyclic peptide may therefore be involved in the 2- C02/CO3 uptake and transport Of in ascidians, which are [701 C03 2- known to concentrate in their spicules. Frangufoline (sanjoinine A) 98 is an alkaloid isolated from (711 the seeds of Zizyphus vulgaris. It is reported to [721 possess ionophore activity and to be an effective 2+_ inhibitor of calmodulin-induced activation of Ca [731 ATPase.

57 HO H HN- 0 HN Cl 0 0 ): 0 -N, N cl %-/, 0c 0cc N 0 OMe H N NH H cryptophycin-1 94 diazonamide A 93 OH

OH 0 0

Br HN 0 0H0 N HN N, N'ýý N0 HOOC H0H

H K-13 95 jaspamide (jasplakinolide) 96

0 0< ": Ns ý H NH NN HN HN00 0 0 N1HHNLj NMe2

N H N S, 0 frangufoline (sanjoinine A) 98 ascidiacyclamide 97

Figure 12. Some naturally occurring macrocycles derived

[ 64 -7 31 from amino acids.

58 3.2 Transport across membranes

3.2.1 Introduction

Increasing attention has been devoted in recent years to the development of synthetic systems that mimic the ionophore activity of membrane proteins. Valinomycin, a cyclopeptide obtained from Streptom_yces fermentation, is a much studied natural ion carrier which derives its antibiotic properties from its specific binding to ions. potassium Normal cells contain a high concentration ions of potassium and a low concentration of sodium ions, and thus the specific binding and transport of potassium from the inside to the outside of the cell operated by valinomycin causes the death of the cell. Unfortunately

valinomycin, along with other naturally occurring ionophore

peptides, shows no selective toxicity for bacterial cells

over mammalian cells and is therefore useless as a ý741 therapeutic agent. Synthetic low molecular weight

compounds which could be tailored to produce well-defined

ion transport properties across model membranes would therefore represent a useful alternative to natural ion channels.

Two main methods have emerged over the years for modelling

in vitro the conditions for transport of small molecules

across natural biological membranes.

The simplest one, introduced by Cram and co-workers in the

late 70's, but still considered a benchmark in this area

uses a chloroform/water interface as a model for a liquid [751 membrane. The transport experiments are usually

conducted in a U-tube to assess for example the differential transport of a racemic mixture of enantiomeric salts by a single enantiomer of the host,. or in a W-tube 59 both when enantiomers of the host are employed in the differential, simultaneous transport of both enantiomers of the P 5b] guest. In the U-tube experiment, a chloroform solution of the host is stirred at the bottom of the tube; a solution of the guest and LiPF6 in water floats on the CHC13 P001 in one of the arms, and a water solution floats on the CHC13 in the remaining arm. The rates of transport of the hexafluorophosphate salt of each guest from one arm of the tube to the other are measured by monitoring the increase in absorbance (with time) of the UV spectrum of the solution in the receiving arm. When a racemic mixture of enantiomers is used as the guest, the optical purity of the guest transported to the receiving arm may be determined polarimetrically. [75b]

A more advanced model which resembles more closely naturally occurring lipid bilayers is based on a study published in the mid 70's. [7 61 In this report the changes in the spectral properties (e. g. fluorescence) of several cyanine dyes upon association with red blood cells and the natural ionophore valinomycin were examined, and various hypotheses were put forward to explain how the dye "senses, " the change in the membrane potential induced by valinomycin. Given the poor reproducibility of some spectroscopic experiments performed on blood cells, the authors turned their attention to a model synthetic membrane, which was obtained by sonicating a mixture of phosphatidylcholine, cholesterol and KC1-Tris to obtain a vesicle suspension. A cyanine dye was added to this suspension and the fluorescence emission of the resulting system was recorded. Upon addition of valinomycin, the fluorescence of the dye decreased sharply. The authors postulated that this was the result of membrane transport polarization induced by valinomycin-mediated of this leads to potassium ions out of the vesicles; an

60 -increased concentration of the dye on the inner membrane surface with subsequent formation of dye multimers which are known to quench fluorescence. A variant of this type of model membrane has been developed in order to perform [771 planar lipid bilayer studies, but the procedure already (761 described, along with the use of valinomycin and a

fluorescent dye as a standard reference, has remained basically unchanged to date.

3.2.2 Transport of small molecules across a lipidic membrane

Although this review is focussed on nonpeptidic amino acid-

derived macrocycles, this section begins with a report on

the modification of ion transport channels by synthetic

cyclopeptides in order to place the subsequent work with 81 non-peptidic molecules in perspective. In this worký7

synthetic cyclopeptides 99-102 were used to modify the pore

of staphylococcal a-hemolysin (aHL), a 239-residue

exotoxin that forms a mushroom-shaped heptameric, pore (100 ý791 A-long0 channel) in lipid bilayers (Figure 13).

61 R Ph Hi 0 0 HY HR N]Lz %'k N NN-0 /U H, H, N0 H H N- N- 0 0N Ph

Ph//A N N- N ý, H

0, N- IN. 0 N10 N H 0 ýHl fT R0Ph

NH2

101 99 R= 'Jý R -X""'N NH2 H 0

100 R= ll-ýýO- 102 R

Figure 13. Synthetic macrocycles used to modify the (xHL [78 pore.

Cyclopeptides 99-102 do not form channels by themselves but

rather are designed to alter the conductance and ion

selectivity of the (xHL pore. In fact while lodged in the

channel lumen (the authors propose that the peptides are held at a single binding site within the protein), the two positively charged peptides 99 and 101 increase the natural ý801 anion selectivity of allL,, while the negatively charged peptide 100 converts (xHL into a weakly cation-selective pore. Peptide 102 gave different results depending on the intensity of the reversal potential applied. This study also demonstrated that the positively charged peptides 99 and 101 are able to bind to various polyanions which block 1811 the channel and reduce the channel current (small polyanions like 1,2,3,4,5,6-benzenehexacarboxylic acid, L- m_yo-inositol 1,4,5-tris-phosphate hexapotassium salt and D- m_vo-inositol 1,4,5-tris-phosphate hexapotassium salt were used as blockers). This result reinforces the idea that the

62 use of noncovalent adapters is a versatile way of programming the properties of (xHL and perhaps other channel pores.

The ion-transporting properties of nonpeptidic serine-based

macrocycles incorporating an adamantane moiety have been

the focus of extensive research over the last decade. [ 821

Using the fluorescent dye method described previously, and

valinomycin as a standard reference, [7 61 it was found that although macrocycle 103 did not transport any ions, [831 the

larger macrocycles 104-108 were all effective in

translocating Na+,, Mg+ and Ca 2+ ions across model membranes

(small unilamellar vesicles) (Figure 14). [82c] Macrocycle 106, featuring two exocyclic (S)-leucine residues, showed

maximum efficiency and was demonstrated to be almost as

efficient as valinomycin in quenching the fluorescence of the dye. Interestingly, studies conducted on similar

macrocycles featuring only one adamantane unit were found

to be completely devoid of any ion-transport capability, in

spite of containing strong metal-complexing moieties in their cyclic framework.

63 by0

0 00 (00 0- MeO OMe ýy NH HN Me0 0Me 00 Y', "CoNH HN 0 0 0 R NH HN 'R ojvo ovo

103

104 R= -ýx 105 R

0H0A0H0 N0 NA MeO NH HN OMe 00 00Dy NH HN - 0v00A0

Meo11-w 0WKI)11ý OMe 11 \COO11111N ri 11 u0 106 00 HN"' 00 NH O_i Dh--/ " '--Ph

OMe 00 I OMe 00 107 0 NH HN 0

0 NH HN 0 O, O 0 r),,,, V, OMe 0 co OMe

108

Figure 14. Serine-derived macrocycles 103-108 incorporating [82c] an adamantane moiety.

64 In a more recent development from the same group, (82d] serine based 20-membered macrocycles 109a-c and cystine based 15-membered macrocycles 110a-c (Figure 15) were synthesised and it was shown that 109c and 110c were capable of transporting Na+ across a lipid bilayer. None of the prepared macrocycles in this case was able to transport 2+ Ca and Mg2+ ions, which highlights how a judicious choice of complexing moieties on the ring can effectively tune the performance of synthetic systems.

001NH

HNýO O'OlNH R ooet //"r, HN'CO

)000 IrR 00

109a R= OMe 110a R= OMe

109b R= LeuOMe 11 Ob R= Leuffle

109c R= 110c R= ýNe H H

Figure 15. Serine-derived 20-membered macrocycles 109a-c and cystine-derived 15-membered macrocycles 110a-c. [82d]

Calixarene-like macrocycles 111-117 (Figure 16) form ion channels in bilayer membranes by the creation of tail-to- tail dimers and the alignment of their hydrophobic alkyl 2). [841 chains (R How the nature of an amino acid residue (R1) the length the (R 2) the , of alkyl chain and size of the macrocycle (n) affected the activity of the ion channel has been assessed.

65 Rl J, H0 N, yN,, 0 n HN 0 'ýf R2

111 R'=CH3, R2=nCgHlg, n=3 112 Rl = CH3, R2 = nCgHlg, n=4 113 Rl = CH3, R2 = nC15H31, n4 114 Rl = CH3, R2 = nC15H31, n5 115 Rl = CH2COO-, R2 = nC15H31, n=4 116 Rl = (CH2)4NH3', R2 = nC17H35, n=4 117 Rl = CH20H, R2 = nC17H35, n=4

Figure 16. Calixarene-like macrocycles 111-117. ý841

The synthetic macrocycles 111-117 show similar conductance,

charge (K+ over Cl-) and cation (K+ over Na+) selectivity in

spite of their quite different structures. The authors

ascribe this quite surprising result to the fact that the

rate determining step for ion permeation through all these channels is migration through the hydrophobic alkyl chain

region. The current of an ion permeating across a channel

is an integration of the whole energy profile the ion

experiences during the permeation. [851 Therefore, it was

reasoned, the alkyl chain region, which is much longer than

the amino acid containing region, contributes significantly

to the current,, and therefore to the conductance, of the

channel. Altering the length of the alkyl chain, though,

did not produce any effect on the conductance; this

apparently unexpected behaviour was rationalized by

assuming that the degree of ordered interaction between the

alkyl chains increases with increasing chain length. This produces a more ordered pore which facilitates ion permeation.

66 3.2.3 Transport of small molecules across a chloroform/water membrane

The undeniable practicality of the U-tube liquid membrane over the lipidic membrane experiment for assessing the transport properties of synthetic macrocycles has certainly contributed to its popularity as an initial screen for transport properties. Several amino acid-derived macrocycles of various size and nature have been used as hosts to extract metal ions or charged organic species from an aqueous to a chloroform layer.

It has been reported both for chiral guests (861 and f or [871 metal ion guests that the presence of a cage in the macrocyclic backbone enhances the liPophilicity and hence the transport ability of the resulting system. In light of this, macrocycles derived from (S)-a-phenylglycine 118

(Figure 17) and (S)-valine 119 and incorporating a pent a cycl ounde cane backbone have been studiedý88] using the

U-tube transport experiment and measuring the optical rotation in the receiving arm of the tube. [75b] Using (±)- methyl-a-phenylglycinate hydrochloride as guest in the transport experiment, macrocycles 118 and 119 showed a moderate enantioselectivity for the (R)-enantiomer (29% and 68% Analogous e. e. respectively) . macrocycles containing a pyridine ring in place of the pentacycloundecane moiety displayed poor transport ability, probably due to their low lipophilicity.

67 R (H oN 0

118 R= Ph 119 R= tPr

Figure 17. Macrocycles 118-119 containing a pentacycloundecane unit. ý883

Studies on the differential transport of amino ester hydrochlorides and various amines through a liquid membrane have shown that macrocycles 120-121 (Figure 18) containing predominantly aromatic or exclusively alkyl side chains display increased affinity for organic molecules with matching substituents. E89J The smaller macrocycle 122 showed selective transport properties towards K+ and Na+ across a liquid membrane, and a degree of preference for M+ over M2+ cations was established. ý901 Chiral dithia-tetrahomodiaza- calix[4]arene 123 in which four methylene bridges (-CH2-) were replaced by two epithio (-S-) groups and two dihomoaza bridges (-CH2-NRCH2-) proved capable of extracting Zn 2+

(percent extraction: 61%) and Cu 2+ (83%) from water to chloroform. E911 Given that the parent calixarene did not this that the extract any metal -ions, result suggested epithio groups and the dihomoaza bridges contained in 123 may play an important role in determining the host-guest properties of the synthetic macrocycle.

68 00 Ph Ph ý-NH HN--\ 010 0_:: 5ý 00 Rl 14. N2 H0 NH 1ý0 HN ý-ýO"'ý0-) 00 122

X,-NH HN 04 1-- Rl"' 0 \\l NH 0'/ "*R 2 'N' 0 'OH HO- Rl 0 COOMe 120 Rl = Bn, R2= ýCH21Pr 121 Rl CH21Pr zs =R2= s

eOOC HO (-OH N, - 123

Figure 18. Macrocycles 120-121 transport organic molecules with matching substituents. ý893 Macrocycles 122 ý90ý and 123 ý913 transport metal ions selectively.

3.3 Catalysis mediated by amino acid-derived

macrocycles

Synthetic macrocyclic ligands derived from amino acids offer an attractive way of holding chiral groups in close proximity to each other to create a situation that resembles the chiral environment surrounding the metal in many metalloenzyme-catalysed reactions. [ 921 In designing potential ligands for catalytically active transition metals the ligand should: a) be capable of sustaining a range of metal oxidation states, b) feature readily available and modifiable chiral residues close to the metal, capable of influencing the stereoselective approach of a substrate, and c) be sufficiently stable to allow

69 multiple turnovers under a range of catalytic reaction conditions.

The first example of the synthesis and application of amino acid-containing macrocycles to an asymmetric transformation [ 931 dates back to 1979. In this report (S) -valine was used as the starting material for the synthesis of a 1,4-

dihydropyridine-containing system 124 (Scheme 33) capable 2+ of encapsulating Mg and catalysing the asymmetric

reduction of ketones to alcohols at room temperature. Upon

hydride transfer from the dihydropyridine ring to the

carbonyl moiety, 124 is oxidised to the corresponding

pyridinium salt 125 which is reduced back to 124 with

Na2S204 without loss of optical purity (measured

polarimetrically). The reduction proceeds with asymmetric

induction of up to 86%, and this result represented at the

time one of the highest asymmetric inductions ever achieved

with a 1,4-dihydropyridine.

70 Na2'5204

10 Mg(CI04)2"1.5H20 OH

124 + Rl R2 Rlý'R 2 125

Rl = C6H5, R2 = CF3 ee up to 86% (S)-enantiomer Rl ý CA5, R2 = C02C2H5 Rl = C6H5, R2 = CONH2 Rl = C6H5, R2 = CONHC2H5

ro-, ^ý) ro-"*ý) 000 00H H, 'o H H, To N' N N' N, 'I", r

00 0+0

N N C104- 6H3 6H3

124 125

Scheme 33. Compounds 124 and 125 and the proposed catalytic cycle for the reduction of ketones to alcohols. [931

Based on 1H NMR shielding studies, the consistent formation of the (S)-enantiomer of the alcohol product was attributed to a transition state in which the Mg2+ coordination site was close to the diethylene glycol bridge. This initial hypothesis was reformulated, however, in light of further 94 studies. [ 1 In a second report the consequences of changing the configuration and the structure of the amino acid along with the length of the bridge embedded in the macrocycle were assessed. "Open" analogues 129-130 (Figure 19) of the synthetic macrocycles 126-128 were also prepared in order to evaluate the effect of the cyclic structure on the enantiomeric excess of the alcohol product.

71 rEýi)OITO r'ýO-"ý 0*10 I" R NH HN 1,R HH rH 00

N N 6H3 6H3

126 R= Pr 128 127 R= Bn 0HH0 bridge = -(CH2)20(CH2)2- RO N0R 44 -(CH2)20(CH2)20(CH2)2- 0H0 H -(CH2)2(0(CH2)2)3- N -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)8-, 6H3 -(CH2)10-, -(CH2)12-,-mCH2C6H4CH2-

129 R CH3 130 R CH2CH20CH3

Figure 19. Macrocycles 126-128 and ""open" analogues 129-

130. ý941

Good to excellent enantiomeric excesses (up to 90%) of the

alcohol were obtained with compounds 126-127, which feature

a wide range of bridges. Consistent formation of the (S)-

enantiomer indicated that the length and the nature of the

bridge were not crucial in determining the stereochemical

course of the reaction. This led to the conclusion that the

magnesium ion does not bind to the bridge in the complex

formed prior to hydride transfer. Remarkably, proline-

derived macrocycle 128 was the only system that failed to

transfer chiralitY, affording a 50% yield of racemic

alcohol. Finally, "open"" derivatives 129-130 gave very low

excesses (10 and 18% e. e., respectively) of alcohol

product, which confirmed that the presence of a bridge is a minimum requirement for good transfer of chirality. These [ 93,941 reports represent important milestones towards the development of quite simple systems that resemble the

structure and the selectivity of the naturally occurring redox systems NAD"-/NADH and NADP+/NADPH.

72 An iron (III) complex of chiral macrocycle 131 (Scheme 34) has been shown to catalyse the conversion of alkenes to the corresponding epoxides in the presence of iodosylbenzene as [ 951 terminal oxidant. Cyclooctene gave exclusively epoxidized product in a reasonable yield (relative to iodosylbenzene amount employed), while styrene produced its epoxide and benzaldehyde. Analysis of the styrene epoxide using a chiral shift reagent [961 revealed an essentially racemic. product, which suggested minimal chiral interactions had occurred between the alkene and the metal- bound oxidising reagent.

0 D Fe(CI04)3 / 131 (5 mol %) IN 0 PhIO (40 mol%)

Yield = 55% 0 Fe(CI04)31131 (5 mol %) 0 Ph"'ý - Ph""ý Ph'1ý1 H PhIO (40 mol%)

Yield = 10% Yield = 20%

«NN OYH

0 H N)-NH

131

Scheme 34. Macrocycle 131 and its application to the epoxidation of alkenes (yields are based on iodosylbenzene). [ 951

Dioxycyclam macrocycles 132a-b (Scheme 35) form catalytically active complexes with N i2+ for the conversion of tran3-p-methylstyrene to the corresponding epoxide using [971 sodium hypochlorite as terminal oxidant.

73 Ni(OAc)2 /132 (12.5 mol%) 00 )ý Ph Ph"ýý + Ph H NaOCI (4.5 eq. ) P,hCH2NMe3+Br- (5 mol%) Yield = 51 % 23% (132a) CH2C'2, rt 26% 9% (132b) 1% 2% (132c)

NH HN,, ,

R'. NH HN "R

0-ýýýo

132a R= Bn 132b R= CH2JPr 132c R= /Pr

Scheme 35. Dioxycyclam macrocycles 132a-b and their application to the epoxidation of t-rans-p-methylstyrene. [97)

The phenylalanine-derived macrocycle 132a afforded complete conversion of the substrate into the corresponding epoxide and benzaldehyde. [ 971 Leucine-derived complex 132b showed only moderate activity while valine analogue 132c gave very low conversions. Spectroscopic investigation (chiral shift reagent) of the epoxide product obtained with 132a revealed its racemic nature which was ascribed to the low steric demands of the benzyl side chain. Previous studies had proven that simple nickel salts such as Ni (OAc) 2 are inactive as oxidation catalysts with NaOCl alone and that no epoxidation occurred in the absence of aN i2+ /cyclam complex; ý981 hence the presence of the dioxocyclam ligand was considered essential for the reactivity.

74 3.4 Gelators

In the last decade a large number of low molecular weight

compounds capable of reversibly forming gels in both

organic liquids and water have been reported. ý99' 1001 These

compounds are able to self-assemble into fibres of

considerable length (several micrometers) that crosslink

and entrap solvent molecules thus forming a soft, solid-

like material. Given their interesting physical and

chemical properties, organic gelators have been studied for [101] use in drug delivery processes, responsive materials [ 1021

and catalysis. [ 1031

Amino acid-derived building blocks have been widely used

for the construction of low molecular weight compounds that

are able to form gels in organic solvents. E1041 The first

example of amino-acid containing systems capable of

gelating both polar (acetonitrile, water) and nonpolar

(diethyl ether, dichloromethane) solvents was reported in ý1051 1993 (133 and 134, Figure 20). More recent studies show

that in some cases the chirality of the system is expressed

at a supramolecular level by the formation of helical [ 1061 architectures. In fact, scanning electron microscopy of

the gel formed by macrocycle 135a (n=l) revealed the presence of isolated right-handed twisted ribbons several [106a] micrometers long. The self-assembly of chiral cyclophanes 135a-c, and of their analogues containing different amino acid side chains, was proven to be very sensitive to small structural changes (the nature of the amino acid residue or of the aromatic moiety, the length of the [106b1 These factors have important aliphatic spacer) . an influence on the conformational preference of these type of molecules as well as on their supramolecular self-assembly.

75 0 0 HN NH NH 0-"'ýrHN k, 0 0 -:::: NH HN 0 0- 0 o 0ý, y 0 133 134

HH NN

NHnHN

135a-c, n= 1,2,4

Figure 20. Cyclic compounds 133-134 are capable of gelating polar and nonpolar solvents (1051 and 135a forms

supramolecular right-handed twisted ribbons. 1106a]

The relationship between the absolute configuration of the chiral macrocycle used to form the gel and the handedness of the resulting helix has also been studied. [106c3 The two

enantiomers of compound 135a contain helicoidal aggregates

of opposite handedness in their benzene gels. Results

obtained with nonenantiopure mixtures, though, suggest that under these conditions compound 135a could self-assemble

into enantiopure crystalline conglomerates disrupted by

racemic aggregates, or could be made up by layers of

opposite enantiomers stacking on top of each other to form a meso aggregate. In either case, the presence of the other enantiomer results in a reduction of the size of the aggregates and the prevention of gelation.

76 3.5 Organic nanotulbes

Synthetic nanotubes have been the subject of extensive investigations over the last few years given their potential utility in chemical, biological and material ý1071 science. The hypothesis that cyclic peptides having an

even number of alternating (R) - and (S) -amino acids should stack through backbone-backbone hydrogen bonding to form

hollow cylinders was first formulated in 1974. ý1081 Almost decades two later this concept was put into practice with the synthesis of octapeptide cyc1o[-((S)-Gln-(R)-Ala-(S)-

Glu-(S)-Ala)2-1 136 (Figure 21), which provided the first

example of a self-assembling nanotube formed by ring stacking of cyclic (R), (S)-peptides. [ 1091

HR0 0'* % ý H R N -J-. 0HH00HH0 H- HR N N- IIII 0 RN N, ONI NN 000 o Tj N 10 Rj oII 0HH00 0 IH N- H Hb 0HH00 HA 111, N ý11ý R oo* N 0 RNNNN '00ý, RH IT H0R HPH0

OHHO OHHO 136 IIII RN R SNI0ý-*. ,IN *INN ll**ý, NN 40 'r, N 1ý1ONI H 0HH0H 0H HO 0H HO ýý I^II HbH 0HH00 N Nloý R N '00 N N Io0H IN RNN HH HO 0 0HH00HH0

Figure 21. The first example of a self-assembling nanotube based on cyclic (x-peptide 136. Some of the R- groups have [1091 been removed for clarity.

More recently, the high efficacy of this class of materials against lethal methicillin-resistant Staphilococcus aureus

77 (MRSA) infections in mice has been reported, revealing that (R) (S) , -a-peptides are attractive alternatives to naturally derived antibiotics. ["Oj

Nonpeptidic synthetic macrocycles have also been shown to

form tubelike structures by stacking one on top of another through hydrogen bonds or n-n interactions between aromatic [107c, 1113 rings. For example, serine-based cyclophane 137

(Figure 22) self-assembles into a supramolecular structure containing two tubes. (1121

Meo Ft OMe J, NN 0 Ný 0 00 >-N-0- 0 __p-z; ýý-ýN N-7- oý 0 H 137 0

0 N- ov

N -i- On n0 0H R 0 H0

Figure 22.18-membered serinophane 137 containing pyridyl and phenyl rings as bridges and schematic representation of [1121 the multiple n-n stacks in the self-assembly.

A crucial requirement for n-n stacking between the aromatic and pyridyl bridging units is the presence of the pyridyl unit next to the amide moiety; this locks the amide NHs into NH ... N hydrogen bonding creating an almost flat ring conformation, a prerequisite for vertical stacking.

78 3.6 Recognition of biologically important molecules

3.6.1 Introduction

Many biological processes vital to life involve

interactions between the active sites of receptor proteins and relatively small molecules such as carbohydrates, amino acids, peptides, glycoconjugates and hormones. Specific molecular recognition phenomena also play an important role

in the highly selective chemical reactions that occur in living systems. Much attention has thus been devoted in

recent years to the study of synthetic models that could provide a understanding of these processes. [1131

NMR spectroscopy and High Performance Liquid Chromatography

(HPLC) are important techniques for studying the binding of synthetic receptors to substrates of biological interest.

In both cases the molecular recognition process is translated into a physical phenomenon (shift of NMR peaks or separated peaks in the chromatogram) which expresses and

quantifies the free energy of formation of the

supramolecular aggregates.

Upon interaction with a receptor R. two dif erent substrates A and B might temporarily form 1 :1 complexes RA and RB. A difference in the stability of the complexes arising from the different way in which each substrate associates with the receptor results in different association constants Kass, defined as shown in Equations 1 and 2 (Scheme 36).

79 R+A RA

Kass [RAI (PA) [R] [A]

AGass =- RTlnKass (RA) (RA)

R+B RB (2)

Kass [RBI (RB) [R] [B]

AG =- RTlnKass(RB) ass (RB)

A(AGass) AGass A'Gass = (RA) - (RB) =

RTln (Kass lKass ) - (RA) (RB)

Scheme 36. Quantification of the relative stabilities of two different complexes.

The binding constant for a given complex can be obtained using solution NMR spectroscopy. Addition of a substrate to a receptor held at constant concentration, observation of the change in chemical shift between the uncomplexed and complexed substrate, and analysis of the data by linear regression best-fit procedure provides the constant 114 Kass [ 1 Once the value of the binding constant is known for each substrate, the difference between their molar free energy of associations [A(AGass)] can be calculated.

If the receptor is anchored to an inert solid support and the recognition process is studied in a solid-liquid system, the different stability of the adsorbates RA and RB formed by interaction of the analytes with the stationary phase results in different retention times (tRA and tRB) f or [115 3 the two substrates in the HPLC chromatogram. For each is in analyte, the partition coefficient K defined as

80 Equations 1-2 in Scheme 37f where CS is the molar analytical concentration of the solute in the stationary phase and cm is its analytical concentration in the mobile phase. The capacity factor k' is defined as in Equations 3-

4,, where Vm and Vs are the total volumes of the mobile and the stationary phases in the column and tm is the retention time of the species which is not retained by the column

(usually the solvent in which the sample is dissolved to the HPLC 1161 The carry out analysis) .[ chromatographic parameter a (selectivity factor) is the ratio between the partition coefficients KA and KB for the formation of the

two adsorbates and can be calculated directly from the times tRA, t tm (Equation 5) This retention RB and . allows the direct A (AGass) in this calculation of r which case corresponds to the difference between the molar free

energies of absorption of A and B on the stationary phase

containing R (Equation 6).

(1) Kjý = CsA/ CMA

KB = CsBICMB (2)

KAVS tRA - tM MA (3) vm tm

KBVS tRB - tM MB (4) vm tm

tRA - tM UAB =: KA/K3 = tRB - tM

A(AG RTlnoýAB ass) =-

Scheme 37. Quantification of the relative stabilities of by HPLC [1151 receptor-substrate complexes resolution.

81 It is of note that even a small A(AGass) value is enough to observe a good separation on HPLC. For example, when A(AGa, 50 s) = cal/mol, (x = 1.09, which corresponds to well resolved peaks on the chromatogram. [ 1151

The general considerations discussed above are applicable of course to molecular recognition processes that involve enantioselective interactions between the receptor, for example a chiral macrocycle, and the substrate. In this

case, enantiodifferentiation between two optical antipodes in solution by a chiral macrocycle will result in the

generation of different NMR signals for each diastereomeric

complex; similarly in HPLC experiments performed with a

stationary phase bearing a chiral macrocycle, differential

interactions with enantiomeric analytes will result in different retention times for the two optical antipodes.

3.6.2 Recognition of amino acid and peptide derivatives

Amino acid residues in a receptor molecule and/or a

substrate molecule play a significant role in artificial

systems since they can be arranged to form multipoint binding sites thus mimicking many naturally occurring receptors and enzymes. The tertiary structure and function of complex biological molecules such as enzymes rely strongly on noncovalent, specific inter- and intramolecular interactions that involve amino acids residues, is and the binding between a substrate and a receptor is significantly enhanced when the receptor structure inherently complementary to that of the substrate. The development of synthetic systems derived from amino acids derivatives is and capable of binding amino acid or peptide therefore a powerful tool for understanding the phenomena in biological which govern molecular recognition [1171 environments. 82 The C3-symmetric receptor 138ý1181 (Figure 23) features a concave, rigid binding site and an array of hydrogen bond donors and acceptors located around the macrocycle periphery. It has been anchored to silica to obtain a Chiral Stationary Phase (CSP) which showed exceptional for affinity the (S)-enantiomer of N-Boc-amino acid methylamides. [1191

HN HN Zýo0

NH 0--0 s 0, 5ý1ý1 s

N H

9%090

Figure 23. The CSP derived from macrocycle 138 readily separates simple amino acid derivatives. 11191

((XRS) An enantioselectivity factor of 43 was obtained for the enantiomers of threonine, corresponding to a difference

A(AGass) in binding affinities of -2.2 kcal/mol.

NMR titration has been used to explore the binding properties of another tyrosine-derived macrocycle. Compound 139 (Figure 24), which is a superior version to a [1201 previously reported receptor, exhibited enantioselectivity for the (S)-enantiomer of acetylalanineamides (for Ac-(S)-Ala-NHBn, AGass -2.36 kcal/mol whereas for Ac-(R)-Ala-NHBn, AGass -1.36 kcal/mol, A(AGass) -1.0 kcal/mol) and alanine dipeptides

83 between ý12 11 -0.8 and -1.3 kcal/mol) . A series of experiments performed with structurally different alanine derivatives (obtained by varying the nature of the protecting groups at the C- and N- termini) showed that the binding properties of the receptor are a direct consequence of a good match between the substituents on the host and the guest and therefore of their capability to give rise to stable interactions.

N- o NHH NBn BnN-

000 ý--N "k N-ý \-i

139

Figure 24. Macrocycle 139 selectively binds the [1211 enantiomer of acetylalanineamides.

Cage-like selectors 140-141 (Figure 25), showed good kcal/mol] enantio selectivity [A(AG,,,,, ) between -0.6 and -1.1 in f or the (S)-enantiomer of AT-protected amino acids solution, but they were unable to resolve the same class of [ 1221 The (S)- compounds when anchored to silica. 142, designed to phenylalanine-derived macrocycle carefully feature a diamidopyridine unit that ser-ý , es as a carboxylic biaryl fragment to acid binding site and to contain a rigid hold open the binding cavity, shows some enantioselectivity for the (S)-antipode of dipeptides with a carboxylic acid [A (AGass) terminus. [ 1231 Although the observed binding kcal/mol] is not comparable with the between -0.1 and -1.0 for peptide high enantioselectivities observed some other

84 binding (1241 systems [A(AG,,,, ) between and kcal/mol] -2 -3 " it is surprisingly good given the minimal chirality incorporated in the macrocycle.

// 0 -0-\NH HN

NH R-' N c0 0 10 HNA 0 HN R HN Ph b \'\, HH 0 NH N, N-ý I" 0

140 R= CH21Pr 141 R= Bn 142

E1221 Figure 25. Cage-like macrocycles 140-141 and a [ 123 1 macrocycle with minimal chirality 142 are selective

towards AT-protected amino acids and dipeptides respectively.

3.6.3 Recognition of carboxylic anions

Carboxylate anions are involved in several processes of biological interest. A much-studied example is carboxypeptidase A,, an enzyme that coordinates to the C-

terminal carboxylate group of polypeptides by the formation

of an arginine-aspartate salt bridge, and then catalyzes

the hydrolysis of the C-terminal residue. [ 1251 Carboxylate

anions also play a special role in the biological activity [ 1261 of the vancomycin family of glycopeptide antibiotics. Vancomycin, produced by the microorganism Am_ycolatopsis

orientalis, is widely prescribed for infections arising from Staphylococcus au-reus; it is known to bind to bacterial cell wall mucopeptide precursors (intermediates [ 127 in the process of bacterial cell-wall biosynthesis) by 85 forming three hydrogen bonds with the carboxylate anion of the C-terminal (R)-alanine. The enantioselective [128,1291 recognition and separation of chiral carboxylates is also an important goal because several pharmaceutical

compounds possess this functional group.

Chiral C2-symmetric macrocycles 143-144 are examples of

synthetic receptors for carboxylates derived partially from (Figure 26) [130 The this natural amino acids . potential of type of compound is demonstrated by the fact that 143

behaves as a vancomycin mimic, showing promising antibiotic

activity toward Gram-positive bacterial strands due to its

ability to bind the (R)-alanyl-(R)-alanine terminus of [1311 peptoglycans.

/--\ r--\ X NH NH0 0, NH H 0 o-, H

HN NH HN NH

jf0 0"'ýu

143 144a X= CH 144b X=N (1311 Figure 26. Macrocycle 143 behaves as a vancomycin mimic

and macrocycles 144a-b selectively bind carboxylate [ 130) anions.

A preliminary screening of the binding properties of

macrocycles 144a-b was performed by mass spectrometryf for which has become a powerful tool the characterization development of noncovalent adducts since the of mild [ 1321 ionization techniques like FAB, MALDI and ESI. In fact, be if supramolecular entities can successfully charged and transferred into the gas phase without destruction, then

86 mass spectrometry has clear advantages over other methods such as vapour-phase osmometry, Size Exclusion Chromatography (SEC), Gel Permeation Chromatography (GPC), or light scattering, all of which give only estimates of molecular weights. Macrocycles 144a-b showed good

selectivity for organic carboxylates over inorganic anions such as Cl- and N03- in the gas phase. Subsequent NMR investigations confirmed that 144b had a high affinity for

"Y"-shaped anions such as carboxylate anions, with

particularly strong binding to benzoate. Disappointingly, 144a-b showed only a very modest enantioselectivity for the

(R)-enantiomer of N-acetyl amino acid carboxylates.

3.6.4 Recognition of steroids and purine derivatives

Steroid recognition by protein receptors has several [ 1331 essential and diverse roles in eukaryotic cells.

Steroid-binding proteins (SBPs) exhibit a wide range of

affinities (Kassý' 105_1010 M-1) depending on their involvement [ 134] in steroid transport, metabolism or gene regulation.

The development of water-soluble synthetic steroid

receptors featuring rigid cavities, known to be present

also in steroid-binding proteins, may help to elucidate the SBPs. mechanism of recognition of naturally occurring

Water-soluble cage-type enantiomeric macrocycles (-)-145

and (+)-145 have been used for the selective uptake of (a- steroid hormones containing an aromatic moiety 148, Figure 27) estradiol 146, P-estradiol 147 and estriol fully but proved incapable of binding a aliphatic guest 149) 135,13 61 NMR studies revealed that the (testosterone -[ (-)-145 binding constant for complexation of with (x- for P- estradiol is greater than the corresponding constant 0.34 kcal/mol) the situation is estradiol (A (AGass) = , and (+)-145 to these two epimers. reversed for the binding of

87 NN -N

0N 00-A %WeNJ; 7-- o N-CH3 CH 3 (Y4f""R HN NH NI

+1 H3C-N H3C-N Yý \ý \ Zi , Z, - N N

(+)-145 Pr (-)-1 45

H3C OH H3C PH

HO' HO

cc-estradiol 146 P-estradiol 147

H3C OH H OH ,

H 1-21 H

estriol 148 testosterone 149

Figure 2 7. Enantiomeric macrocycles (+) -145 and (-)-145 show diastereoselective binding for steroids. [1351

Studies of the selective complexation of purines and

pyrimidines by synthetic host compounds may lead to a better understanding of noncovalent interactions involving

nucleic acids, which contain purines and pyrimidines as structural building blocks. Very recently the binding properties of synthetic macrocycles 150-152 towards purine derivatives have been (Figure 28) 1371 Although reported .[

88 the binding to be (Kassýý10 M-1) proved weak , these macrocycles exhibit an interesting framework derived from amino acids and sugars whose potential has yet to be fully exploited.

H HO, r

-ty H0 N, ý HN7N _, "jq 0 0ý RH HN -oFfkuU, wo 0 MeO ýýWe (Do 10 HN HR000 9 'ý,, NH _ýN 'ý'ýN 0H

OH H

150 R= tyrosine side chain 151 R= CH2CH2COOH 152 R= CH2CH2CH2NHC(NH)NH2

Figure 28. Macrocycles 150-152 bind weakly to purine

derivatives. [ 1371

89 Chapter 4

Synthesis of new classes of chiral macrocycles derived from amino acids

90 4.1 The proposal

The interest within the group in using the intramolecular Heck [ 13 81 reaction to synthesise medium-sized rings recently led to the serendipitous discovery of a "head-to-tail"

coupling reaction involving two units of alkene precursor (Scheme 38). [ 13 91

BNoc Pd(OAc)2 (10 Molo/') COOMe 0.1 n 1 NBoc nBU4NCI, NaHC03 DMF (0.05 "II COOMe 110 'C, 20 h MeOOC- 'N- Boc n

Yields = 28-30% (n = 1,2,3,7)

Scheme 38. The "head-to-tail" coupling as a new Heck

macrocyclisation reaction. [1391

Macrocycles of various size and structure were generated by

varying the nature of the Heck-macrocyclisation precursors.

An in-depth crystallographic and molecular modelling study

revealed two distinct classes of structures, one of which

resembled a 'barrel' while the other was elongated and [139b] 'staggered' with respect to the arene rings.

A further development to this project was triggered by the

interest and potential of non-racemic macrocycles in

catalysis and molecular recognition. In view of this, a

short and versatile route to a wide range of chiral [ 1401 macrocycles was developed. Natural occurring

enantiopure amino acids were included in the structure of

the alkene precursors for the Heck coupling reaction, and macrocycles derived from the head-to-tail coupling of two 155) (for example compounds 154 and 157) or three (compound 39). units were isolated and characterised (Scheme

91 j

,-10-, COOMe 0 z Nyý No Bn jj: 0

153 156

Pd(OAc)2 (10 mol%), nBU4NCI, NaHC03 DMF (0.05 ", 110 T, 16 h

Bn 0 > MeOC 0 COOMe Bi N

154 Yield = 17% 157 Yield = 25% + j

N,q Bn:2" 100 0,zý 0 NBn

BnN 0

155 Yield = 12%

Scheme 39. The head-to-tail coupling of two or three alkene

units generates "dimeric" 154 and 157 and "trimeric, " 1,5,5 1401 .[

The macrocycles obtained, though, failed to produce appreciable diastereoselectivity and/or enantioselectivity in trial metal-catalysed reactions. This result has been ascribed to the poor coordination properties of this class of N, O-ligands to the metals involved in the catalytic

92 cycle. Moreover, a study of the host properties of these synthetic macrocycles towards organic and metal guests proved unsuccessful. [1411

It was proposed that replacing the oxygen atoms in the

macrocycle structures with more coordinating nitrogen atoms (for example moving from 159 to 158, Figure 29), could

represent a breakthrough towards more effective catalysis and molecular recognition processes.

o 0 instead of H 0

N N

158 159

Figure 29. Designing a new class of macrocycles containing

amide (158) instead of ester moieties (159).

With this modification, better coordination sites between

the metal and the ligand would be distributed all around the inner cavity of the macrocycle, thus enhancing the probability of interaction and/or completely fitting the

required coordination number of a given metal. Free -NH sites included in the macrocycle backbones may also facilitate the formation of hydrogen bonds between the host

and a range of organic and inorganic guests. The planned

synthesis of these novel chiral ligands relied on modification of the precursors already synthesised for the previous study. An analysis of the proposed approach towards the synthesis of possible macrocycles 158 and 161 is presented in Scheme 40.

93 N

ozz NH N

HN 0 NH N ri-`0 158 160 'lý pN

Ilfl- o,163 NH2 N

N NH MeOC)c > HN COOMe NH COOMe 161 162 N

(D' N N N , 163 NH2 N OH 164 165

CHO HNp + OH 166 167

Scheme 40. Retrosynthetic analysis of (S) -prol ine -derived macrocycles 158 and 161.

It was envisaged that alkene acceptors 160 and 162 could be derived from common intermediate 163; this in turn could be obtained by manipulation of compound 165, whose synthesis, [140b] already described by our group, relies on a reductive amination between 4-iodobenzaldehyde 166 and (S) -prolinol

167. A similar route was planned also from valine- containing aminoalcohol 172 towards the synthesis of alkenes 168 and 169 (Scheme 41).

94 H N,, 0"'ýBn NIý rzý "I IC 168 'N NH2 Bn

COOMe 170 H N" N I Bn

169

)ý NH2 N3 * OH N N ::: NC E3n BnBn

170 171 172

CHO OH H2N

166 173

Scheme 41. Retrosynthetic analysis of (S) -valine-derived alkenes 168 and 169.

Once the viability of this methodology had been ascertained, it was planned to synthesise another class of chiral macrocycle employing a nitrogen-containing heterocyclic precursor in order to produce receptors featuring even more potential coordination sites. The activity of these two new families of chiral macrocycles in trial enantioselective catalytic reactions and molecular recognition processes would then become the focus of further investigations.

95 4.2 Synthesis of a novel class of macrocycles with increased an number of nitrogen atoms

4.2.1 Synthesis of the appropriate aldehyde

One of the partners for the reductive amination required in the synthesis of 165 (Scheme 40) and 172 (Scheme 41) is 4- iodobenzaldehyde 166. This was synthesised in two steps from commercially available 4-iodobenzoic acid 174 (Scheme 42). Compound 174 was converted into the corresponding alcohol following a literature procedure. (142 4-Iodobenzyl alcohol 175 was obtained with excellent yield and high 1H 13 purity, and its NMR,, C NMR,, IR, melting point and low resolution mass spectra matched those already reported. [ 1421

COOH BH3. THF (2 eq. ) OH PDC (1.5 eq. ) CHO THF, rt, 16 h1 14, DCM, 0 'C-,, -rt, 14 h 174 175 166

Yield = 98% Yield = 93%

Scheme 42. Synthesis of aldehyde 166 via benzyl alcohol [ 14 21 175.

Treatment of 175 with pyridinium dichromate (PDC) in dry dichloromethane afforded, after filtration, aldehyde 166 as a colourless crystalline solid, which was characterised by the usual means. Its analytical data corresponded to those 11421 reported in the literature. The reliability of ti-iis two step synthesis allowed the production of multi-gram quantities of the desired aldehyde 166.

96 4.2.2 Synthesis of chiral aminoalcohol 165

The study ýof how to introduce a supplementary nitrogen atom into the structure of the alkene precursors started from substrate 165. The presence of a proline ring in the backbone of this compound made it particularly attractive in terms of conformational rigidity, as this was expected to allow a certain degree of control over the intermolecular interactions of the resulting macrocycle.

[140bý Following a procedure already reported by the group, 4- iodobenzaldehyde 166 was subjected to reductive amination with (S)-prolinol 167 (Scheme 43), obtained by reduction of

(S) (See Experimental) 1431 commercially available -proline .[ This two step sequence involves the formation of an iminium ion as an intermediate, which is not isolated, but immediately reduced to the corresponding aminoalcohol by treatment with sodium borohydride. Chiral aminoalcohol 165 was obtained in good yield as pale yellow oil, and its analytical data reproduced those reported in the literature. [140b]

CHO 1) (S)-prolinol 167 (1.5 eq. ), MgS04 DCM, rt, 18 h N 10 2) NaBH4 (2 eq. ) MeOH, 0 'C->rt, 24 h OH 166 165

Yield = 84%

ý140bj Scheme 43. Synthesis of aminoalcohol 165.

97 4.2.3 Introduction of new alkene acceptors containing the (S)-proline unit

Replacement of the oxygen atom into the structure of 165 with a nitrogen to 163 (Scheme 40) atom en -route substrate was first attempted with a Mitsunobu reaction. A slight modification of a literature procedure [ 1441 indeed provided a reliable route to novel azide 164 (Scheme 44).

1) DEAD (1.5 eq. ) N THF, PPh3 0 'C->rt, 10 min.

2) 165 (1 eq. ), rt, 5 min. (1.5 eq. ) N3 3) (PhO)2P(O)N3 (1.5 eq. ) rt, 24 h 164 4) H rt, 1h 20, Yield = 57% Scheme 44. Synthesis of azide 164.

Diethyl azodicarboxylate (DEAD) was added to a stirred solution of triphenylphosphine in THF at low temperature, followed by a THF solution of 165. Diphenyl phosphoryl

azide was then added followed, after 24 h, by distilled

water. After a further hour of stirring, the crude product derived from evaporation of the solvent was purified by chromatography, affording azide 164 as a colourless oil, which was fully characterised. The ease of this procedure

facilitated the synthesis of multi-gram amounts of compound

164 in a reproducible 57% yield.

The 1H NMR spectrum of 164 reveals how effectively the conformational constraint induced by the five-membered ring can reduce the rotational freedom about single bonds. In solution at room temperature, in fact, compound 164 appears as an equimolar mixture of rotamers, each of which exhibits different signals for many of the protons. In particular, the two methylenic protons that were next to the alcoholic group in precursor 165 are shifted upfield, but while the

98 shift is almost 1.5 ppm for one of the rotamers to give a triplet at 2.12 ppm, for the other rotamer the shift is only 0.2 ppm. Two separate signals are detected for the two protons of this rotamer: a doublet of doublets at 3.17 ppm and another doublet of doublets at 3.30 ppm. Calculation of the coupling constants for these two multiplets reveal a geminal coupling (i = 12.4 Hz) and also that the two protons couple differently with the proton of the chiral centre, giving J=4.1 Hz in one case and J=S. 5 Hz in the other.

The IR spectrum of 164 provides e-ýTidence for the introduction of an azide moiety in place of the alcoholic group. The strong band at 3389 cm-1, which in 165 accounted for the hydroxyl group stretching, disappeared and concomitantly a very strong band at 2093 cm-1. typical of (1451 the azide functionality, emerged.

With compound 164 in hand, the reduction of the azide functionality to an amine was addressed. A recent literature procedure that reports the one-pot conversion of azides to the corresponding N-Boc protected secondary amines [ 1461 looked particularly interesting for this purpose. It was envisaged that a protected amine group was desirable as it would eliminate issues of over-reactivity in the following steps of the synthesis. Hence, di-(t- butyl) dicarbonate (BoC20) and Lindlar catalyst were added to a solution of 164 in ethyl acetate, and the reaction vessel was filled with an atmospheric pressure of hydrogen (Scheme 45) The resulting mixture was stirred at room temperature for 18 h, but after filtration of the crude product, unreacted starting material was recovered quantitatively.

99 BOC20 (1.1 eq. ) ND starting material Lindlar catalyst (20% w/w) H2 (1 atm. ), AcOEt, 18 h, rt N3 164

Scheme 45. Attempted one-pot reduction/protection of the [ 14 61 azide moiety.

Since a hydrogen-mediated reduction of the azide functionality to the corresponding amine was not feasible, a more classical approach was attempted. Lithium aluminium hydride (LiAlH4 )was the reagent of choice in the second trial experiment. [ 1471A solution of azide 164 was added to a stirred suspension of LiAlH4 in dry diethyl ether, and the resulting mixture was heated to reflux for 30 min. (Scheme 46).

LiAIH4 (2 eq. ) N N

Et20, 1'1N reflux, 30 min N3 NH2 NH2

164 163 176

Scheme 46. Attempted reduction of 164 to 163 with [ 14 71 LiAlH4-

This short period of time was sufficient to allow complete

conversion of the starting material to another, more polar,

compound (TLC). After work-up and filtration of the

aluminium salts, evaporation of the solvent afforded a 1H clear oil. The NMR spectrum of this material, however, bond revealed that partial cleavage of the carbon-iodine had occurred during the reaction, and that the product 163 obtained was in fact a mixture of the desired compound identical and the iodine-free compound 176. Given their be by polarity, these two compounds could not separated

100 flash column chromatography, and thus a reliable procedure that could produce 163 without any cleavage of the C-I bond was required.

A possible answer was found in a recent report by Hanessian et al. that describes a high yielding conversion of an azido-glycoside into the corresponding amino-glycoside by a

Staudinger reaction in the presence of 4-iodobenzene functionalities. [1481

After a few modifications to this procedure, [ 1481a set of reliable conditions that provided amine 163 in high yield were established. Hence, triphenylphosphine and distilled water were added to a THF solution of azide 164, and the resultinQ mixture was stirred at 50 'C for 20 h (Scheme

47). Observation of the evolution of nitrogen from the reaction flask was considered as a promising sign of the ongoing conversion of the starting material into amine 163.

P Ph3 (2 ), H20 (10 ) eq. eq. N THF, 50 OC,20 h

N3 NH2

164 163

Yield = 78%

Scheme 47. Successful reduction of 164 to 163 via a

Staudinger reaction.

Evaporation of the solvent and flash column chromatography of the crude product afford ed novel amine 163 as a colourless oil in 78% yield. This procedure was readily scaled-up for the production of multi-gram amounts of amine 1H 13 163. It was characterised by NMR, C NMR, IR, low resolution and high resolution mass spectrometry,

101 determination of the optical rotation and elemental analysis.

1H The NMR spectrum of this compound revealed a 1: 2 mixture

of rotamers in solution due to restricted rotation. A

singlet that integrates for 2 protons at 1.44 ppm is

consistent with a successful conversion of the azide moiety

to a primary amine, as is the strong absorption at 3350

cm-1 (NH2 stretching) in the IR spectrum. [ 1451

Amine 163 represents the convergent point in the retrosynthetic analysis of macrocycles 158 and 161

represented in Scheme 40. It was planned to elaborate this primary amine both by acylation and alkylation, to provide

alkene acceptors with different structural features.

The derivatisation of amine 163 began by subjecting it to

acylation reactions. After optimisation of a literature 1491 procedure, [ an appropriate set of conditions was

established. Treatment of 163 with acryloyl chloride and

triethylamine in dry dichloromethane in the presence of 4-

(N, N-dimethyl) amino pyridine (DMAP) afforded, after flash

column chromatography, acrylamide 160 as a colourless solid

in 72% yield (Scheme 48).

acryloyl chloride (1.1 eq. ) N N Et3N (8 eq. ), DMAP (1 mol%) DCM, 0 'C->rt, 16 h 0 NH2 HN

163 160

Yield = 72% Scheme 48. Synthesis of acrylamide 160.

1H 13 Novel compound 160 was characterised by NMR, C NMR, I R, determination of its melting point and optical rotation, low resolution and high resolution mass spectrometry and 102 1H elemental analysis. The NMR spectrum of compound 160

revealed again that in solution a 1: 1 mixture of rotamers is present, and that the reduced conformational freedom

affects the shifts of the protons of the acrylamide moiety.

For example,, proton Hb (Figure 30) would be expected to

give a doublet of doublets for the two different couplings Ha (larger J) Hc (smaller J) with and .

0 HN

Hc Ha Hb 160

Figure 30. The structure of acrylamide 160.

If is assumed that the Hb protons of the two rotamers

behave differently, two doublets of doublets are expected, each integrating for half a proton. What is found, instead,

is that Hb gives a triplet of doublets at 5.54 ppm, with

coupling constants of 9.8 Hz and 2.0 Hz, which integrates for one proton. This can be explained by assuming that the

two expected doublets of doublets partly overlap producing the observed multiplet.

Proton H,,, which also should give two doublets of doublets in a 1: 1 mixture of rotamers, gives what appears to be a doublet of triplets at 6.19 ppm, with coupling constants of

17.0 Hz and 2.0 Hz. This can again be explained by an overlap of the two expected doublets of doublets. Proton H, hand, doublet doublets ,, on the other gives a single of at 6.11 ppm, with coupling constants J 9.8 Hz and J

17.0 Hz, which is consistent with the cis- and trans- coupling observed in the resonances attributed to Hb and

H,. The amide proton (NH) gives a multiplet at 6.56 ppm,

103 consistent with the conversion of the primary amine functionality.

This compound was the first one of the sequence leading from 164 to 160 (Scheme 40) to be subjected to a high- temperature NMR experiment, given the alleged inherent instability to heating of azides (potentially explosive) 1H 13 and primary amines. and C NMR spectra were recorded at

100 'C in deuterated dimethyl sulfoxide (DMSO-CI6) in order to ascertain whether, at that temperature, the two rotamers interconverted. Heating the solution, though, did not result in coalescence since two rotamers were still present in a 1: 1 ratio. In this experiment the higher field (500

MHz rather than 400 MHz) of the spectrometer used to record the spectra revealed the two expected doublets of doublets for protons Haf Hb and H, and a well-resolved set of four doublets for each of the four aromatic protons.

The successful synthesis of alkene 160 had demonstrated that the ester functionality of oxygen-containing precursors like 153 (Scheme 39) could be replaced by potentially more interesting amide-containing precursors by employing a reaction sequence involving a low number of steps. The possibility of replacing the oxygen atom in allylic derivative 156 (Scheme 39) with a nitrogen in order to access another class of alkene precursors was now addressed. Attention therefore turned to the synthesis of

2-carboxymethyl allylamine 162 (Scheme 40).

In 2002 Yadav et al. [ 150ý reported the one-pot conversion of various azides into the corresponding allylamines via an indium-mediated Barbier reaction. This approach was obviously attractive because it would allow direct conversion of 164 into 162.

104 Following the literature procedure, [ 1501 indium and sodium iodide were added to a stirred solution of methyl 2-

(bromomethyl)acrylate in dimethy1formamide (DMF) at room temperature, followed by a solution of azide 164 also in DMF (Scheme 49).

Br OMe N (1.5 eq. ) starting material Nal (1.5 eq. ) N3 In (1.5 eq. ) DMF, rt, 20 h 164

Scheme 49. Attempted one-pot conversion of azide 164 into allylamine 162 via indium-mediated Barbier reaction.

After 20 h, the crude product was subjected to systematic

TLC investigations which revealed that the starting material remained essentially unchanged. Increasing the reaction temperature from room temperature to 55 OC only served to promote side reactions, and therefore the planned one-pot approach to compound 162 was abandoned.

A classical alkylation procedure [ 1511 of amine 163 was then devised and after many attempts a reproducible, though low- yielding, set of conditions was established. The primary amine was dissolved in DMF and potassium carbonate was added (Scheme 50). A substoichiometric solution of 2- bromomethyl methacrylate was added dropwise over a period of 5h at -40 'C, in order to minimise over-alkylation. After 16 hours of stirring at room temperature, the reaction was quenched and the crude product was purified by flash column chromatography, affording novel allylamine 162 in 43% yield as a colourless oil.

105 N

162 COOMe 0 Yield = 43% Br OMe (based on equivalents of bromide) (0.76 eq. ) + No K2CO3 (1 eq. ) NH2 DMF, -40 'C-->rt, 16 h COOMe 163

COOMe

177

Yield = 21 % (based on equivalents of bromide)

Scheme 50. Synthesis of allylamine 162.

A considerable amount of dialkylated compound 177 was also isolated (NMR and MS identification) in 21% yield, which, together with the 43% yield in mono-alkylated 162, accounts for a good conversion of the starting material. Every attempt to improve the yield of this reaction was unsuccessful. When the amount of acrylate used was increased to one equivalent with respect to amine 163, compound 162 was isolated in 16% yield, while the yield of 177 increased to 34%.

1H 13C Allylamine 162 was characterised by NMR, NMR, IR, determination of its optical rotation, low resolution and high resolution mass spectrometry and elemental analysis. 1H Interestingly, the NMR spectrum of 162 did not reveal any restricted rotation, suggesting that in solution this particular derivative is in fact a mixture of fast converting rotamers. The incorporation of the allylic unit is demonstrated by the presence of a doublet at 3.43 ppm

106 (J = 0.7 Hz) which accounts for the two protons next to the secondary nitrogen atom. Moreover, the two protons of the double bond give two separate doublets at 5.70 ppm and 6.22 ppm, with a coupling constant of 1.3 Hz. Finally, the methyl group of the carboxylate unit gives a sharp singlet at 3.75 ppm.

4.2.4 Testing the Heck macrocyclisation on substrate 160

Once two alkene precursors had been synthesised via straightforward modification of substrate 165, everything was in place for assessing the viability of the planned macrocyclisation.

Compound 160 was subjected to the classical Jeffery [ 1521 conditions that had already produced good results [138,139,14 0] within the group. A DMF mixture of alkene 160, palladium acetate, sodium hydrogencarbonate and n-butyl ammonium chloride was heated to 110 'C for 16 h (Scheme

51). Filtration and evaporation of the solvent afforded a brown crude product, which was analysed by TLC. This revealed that the starting material had completely disappeared and that a whole range of compounds had formed.

Careful flash column chromatography led to the isolation of all of them, but only one, which corresponded to the most 1H intense spot on the TLC showed a promising NMR spectrum.

107 N

Pd(OAc)2 (10 M010/0) nBU4NCI (1 eq. ) 0 NH HN HN NaHC03 (2-5 eq. ) DMF, 110 "C, 16 h

N 160 158

Yield = 40% Scheme 51. Heck reaction on substrate 160.

A typical signal for a vinylic benzylic proton at 7.20 ppm was consistent with cyclisation, while the geometry of the double bond was assigned as trans given the high coupling constant (J = 15.6 Hz) between the two protons involved. An encouraging sign of cyclisation was found also in the 13C

NMR spectrum, where a signal at 138.7 ppm was assigned to a vinylic benzylic carbon. Compound 158 was characterised also by IR, determination of its melting point and of its optical rotation, low resolution and high resolution mass spectrometry (FAB/+), which revealed the presence of a 35% ion 485 (M + H+) molecular peak at m1z .

The analytical technique that confirmed the structure of the novel dimer macrocycle 158 was X-ray crystallography, performed on crystals grown by slow evaporation of a dichloromethane: hexane (2: 1) mixture (Figure 31).

108 0(8'A)

/Id op 0(40)

C' /

Figure 31. The molecular structure of macrocycle 158.

The most remarkable feature of this structure is that the asymmetric unit cell is made up of two crystallographically independent molecules of macrocycle held together by a network of hydrogen bonds. A disordered molecule of water

(the 83% occupancy is shown in Figure 31), which is also a good donor/acceptor of hydrogen bonds, is included in the structure of the unit cell, generating an extended 'Ehree- dimensional array. The calculation of the distance between the two proline nitrogen atoms and the distance between the centres of the two double bonds in each macrocycle can give an approximate idea of the dimension of the macrocyclic cavity. These distances are: "upper" N(1) N(18) 10.98 A macrocycle ... 4.28 'A = ... = "lower" N(If) N(18') 11.16 A macrocycle ... 4 48 A .

109 The "lower" macrocycle is roughly C2-symmetric, and the symmetry axes passes through the centre of the ring and almost perpendicularly to the plane of the molecule; the "upper" macrocycle does not posses C2-symmetry but presents "W'-shaped a cavity which could in principle accommodate a small guest (Figure 32).

Figure 32. "Upper"' macrocycle 158 (left) possesses a \"V"-

shaped cavity (right) which could in principle accommodate a small guest.

The fact that hydrogen bonds play such an important role in determining the intermolecular interactions of novel macrocycle 158 was a very promising and much awaited

result. It was in fact anticipated that the same type of interactions could be established with various guests ranging from metals to small organic or inorganic molecules. In addition, the presence of a secondary amide functionality, which can be readily deprotonated by a strong base, is ideal for the formation of covalent nitrogen-metal bonds.

It was not possible to isolate or identify any higher homologues of compound 158 from the crude reaction mixture.

This was in contrast with what had been reported previously for the macrocyclisation of ester group-containing alkenes (Scheme 39) ý14 01 Experiments to . performed provide a

110 reasonable explanation for this result will be discussed in section 4.2.8.

A dilution study has been previously carried out within the group to assess the effect of concentration on the outcome [ 1401 ,of the macrocyclisation. In agreement with results obtained in that study, in the present case and in the following macrocyclisation experiments, no significant difference in yields could be ascribed to small changes of the dilution factor.

4.2.5 The Heck macrocyclisation on substrate 162

The question of whether the nature of the alkene precursor would affect the outcome of the reaction in terms of the number of homologue macrocycles isolated could now be assessed. Accordingly, alkene 162 was subjected to the same coupling conditions that had successfully converted E1521 acrylamide 160 into macrocycle 158 (Scheme 52).

/- \N NýD

ND Pd(OAc)2 (10 MOIO/') MeOOC, I f nBU4NCI(1 eq.) NH HNN NaHC03 (2-5 ) HN eq. COOMe DMF, 110 OC,16 h -COOMe N

162 178

Yield = 16%

Scheme 52. Synthesis of macrocycle 178.

After the reaction had been repeated a few times, it became clear that an aqueous washing of the crude product was essential for good purification of the products by flash column chromatography. Therefore the brown crude product derived from filtration and evaporation of DMF was dissolved in dichloromethane and washed three times with

ill distilled water in order to remove inorganic salts. Flash column chromatography on the product derived from evaporation of the solvent offered macrocycle 178 as a colourless fluffy solid in 16% yield. Its molecular weight was confirmed by low resolution mass spectrometry (FAB/+), which showed 30% ion 573 (M H+) a molecular peak at m1z + -

The structure of this new macrocycle was tentatively proposed to be 178 by analysing its 1H NMR spectrum. In fact, the strong coupling (J = 14.0 Hz) between the proton resonating at 7.48 ppm, which a 1H/13C correlation experiment revealed to be methynic, and a proton at about 5.31 ppm, which in turn belonged to a N-H group, was not consistent with the expected structure 161 (Section 4.1,

Scheme 40). Moreover, COSY, HETCOR and NOESY experiments confirmed the presence of two methylenic groups bound to the benzene ring. These observations support structure 178 which is believed to be the product of an alternative

P-hydride elimination step during the catalytic cycle of the Heck reaction (Scheme 53). COOMe \,,.

H aa compound 178

H PdX b H,,, COOMe / ,. NHb H

MeO( H COOMe

compound 161

Scheme 53. A P-hydride elimination that follows pathway a generates isolated product 178, while pathway b would generate expected 161.

112 Although the geometry of the double bond could not be definitely assigned, the NOESY spectrum seems to suggest a trans- configuration since no cross-peak could be detected for the methynic proton of the double bond and the CH2 bound to the benzene ring (a situation that would probably arise in the case of cis- geometry). A weak cross-peak between the N-H and the same CH2 is consistent with the formulated hypothesis.

Novel macrocycle 178 was fully characterised.

Unfortunately, attempts to grow suitable crystals of 178 for X-ray structural analysis, which would have clarified the molecular structure, met with no success under a wide range of conditions.

Since the yield of dimer macrocycle 178 had been much lower

(16%) than the one obtained in the previous experiment with 158 (40%), it was thought that a reasonable amount of starting material 162 may have been converted into heavier isolable homologues. Unfortunately,, systematic NMR and MS investigations on a large number of products isolated from the crude product mixture did not produce any evidence of the formation of such interesting materials.

4.2.6 Synthesis of amine 170 and introduction of (S)-valine

into the picture

The synthesis of two macrocycles with a higher number of nitrogen atoms and derived from (S)-proline had been successfully accomplished via manipulation of substrate 165 (Scheme 40) Interest lay in finding the . now out whether introduction of a more flexible amino acid like (S)-valine into the structure of the alkene precursors would result in a different outcome to the macrocyclisation. The synthetic strategy planned for the incorporation of (S)-valine was

113 closely related to the one already developed for the introduction of (S)-proline.

Aminoalcohol 172a was synthesised from 4-iodobenzaldehyde 166 and non-racemic chiral aminoalcohol (S) -valinol 173 [140b] (Scheme 54), obtained by reduction of commercially available (S)-valine. [ 1531

1) (S)-valinol 173 (1.5 eq. ), MgS04 CHO OH DCM, rt, 18 hN H 2) NaBH4 (2 eq. ) MeOH, 0 OC-4rt, 24 h 172a 166 Yield = 92%

N"'ý

K2CO3 (1.5 ), BnBr (1.5 ) OH eq. eq. N 18-crown-6 (0.1 eq. ), acetone, rt, 15 hBn

172

Yield = 65% [140b] Scheme 54. Synthesis of 172 via 172a.

Compound 172a was isolated as a pale yellow oil in 92%

yield and its analytical data matched those already

reported by the group. ( 140b1 The secondary amine was then

protected as its benzyl derivative in order to prevent

unwanted side-reactions in the following steps of the synthesis. N-protected aminoalcohol 172 was synthesised

following the procedure developed within the group, [140b] and

was characterised by the usual means.

The conversion of the alcoholic functionality to an azide [ 1441 was accomplished via the Mitsunobu reaction, which produced azide 171 in 87% yield (Scheme 55). It was 1H 13 characterised by NMR, C NMR, IR, determination of its optical rotation, low resolution and high resolution mass spectrometry and elemental analysis.

114 1) DEAD (1.5 eq. ) THF, 0 OC->rt, 10 min. N3 PPh3 N) 2) 172 (1 ), 5 Bn (1.5 eq. ) eq. rt, min. 3) (PhO)2P(O)N3 (1.5 eq. ) rt, 24 h 171 4) H20, rt, 1h Yield = 87% Scheme 55. Synthesis of azide 171.

The reliability of this procedure facilitated the multi- gram synthesis of compound 171. Reduced conformational 1H freedom was evident also in the NMR spectrum of azide 171, which showed a 6: 1 mixture of rotamers. Given the dominance of one of the rotamers, it can be concluded that the more flexible backbone of valine i=oses less conformational constraint compared to that of proline.

Azide 171 was converted into the corresponding primary E14 8j amine via a Staudinger reaction (Scheme 56). The reaction proceeded cleanly to afford 85% yield of novel compound 170, which was characterised by the usual means.

)ý N3 PPh3 (2 eq. ), H20 (1 eq. ) NH2 J: N ýO N Bn THF, 50 OC, 16 h Bn

171 170

Yield = 85% Scheme 56. Reduction of azide 171 to amine 170.

1H No conformational issue could be detected in the NMR spectrum of this compound; a broad singlet at 1.55 ppm, integrating for two protons, confirmed the reduction of the azide to a primary amine.

For the sake of completeness, the reduction of 171 to 170 [ 1471 was attempted also using lithium aluminium hydride, but the issue of concomitant cleavage of the carbon-iodine bond

115 that had arisen previously with compound 164 (see Scheme

46) led to the abandonment of this route. The one-pot conversion of 171 to the corresponding M-Boc-protected [1461 amine (see Scheme 45) also met with no success.

A different procedure to the one used for preparing 160 had to be adopted for the synthesis of acrylamide 168, since application of those conditions (acryloyl chloride, triethylamine, DMAP, Scheme 48) [ 1491 to the present case only afforded negligible amounts of the desired compound.

After a few investigations and optimisation, a protocol employing di-iso-propylethylamine (DIPEA) ý1541 gave an excellent and reproducible yield of 168 (Scheme 57), either on small or large scale.

(I acryloyl chloride (3 eq. ) H NH2 N N '-Zý N I DIPEA (3 eq. ) 6 Bn DCM, 0 'C->rt, 3.5 hBn0

170 168

Yield = 87% Scheme 57. Synthesis of acrylamide 168.

Novel compound 168, obtained as a pale yellow oil, was fully characterised.

Amine 170 was employed also for the synthesis of an alkene precursor containing the methyl methacrylate moiety. Again, the conditions established for the conversion of 163 into 162 (Scheme 50) had to be modified since they did not provide a satisfying yield of required allylamine 169. The one-pot conversion of azide 171 into 169 via indium- [ 1501 mediated Barbier reaction was also attempted in order to check whether, at least in this case, one step could be saved in the planned synthesis; unfortunately, as for

116 substrate 164, no conversion of the starting material was detected (see Scheme 49 for reaction conditions).

Compound 170 was therefore subjected to alkylation by methyl 2-(bromomethyl)acrylate in DMF at -10 OC in the presence of sodium iodide and dry potassium carbonate (Scheme 58) r1511 After hydrolysis . of the reaction mixture, flash column chromatography afforded allylamine 169 as a colourless oil in 41% yield.

Br OMe CN H Jýr NH2 ) N eq. rN OMe Bn K2CO3 (1 eq. ), Nal (10 mol%) Bn 0 18-crown-6 (10 mol%) 170 169 DMF, -10 'C->rt, 16 h Yield = 41% Scheme 58. Synthesis of allylamine 169.

The yield of the reaction could not be improved by employing an excess of acrylate, which instead promoted the formation of a greater amount of dialkylated compound.

Although low yielding, this procedure was reproducible giving a multi-gram scalable route to amine 169, which was characterised by the usual means. In particular, the 1H NMR spectrum shows that the restricted rotation issue has re- emerged, since compound 169 is present in solution as a 3: 1 mixture of rotamers. The two protons on the double bond each gave two sets of doublets, in 3: 1 ratio, with a coupling constant of 1.4 Hz. The methyl group also gave two separate singlets, in the same 3: 1 ratio.

117 4.2.7 The Heck macrocyclisation on substrates 168 and 169

Alkene precursors 168 and 169 were now ready for assessing

the viability and efficacy of the Heck macrocyclisation on

valine-derived compounds. Jeffery macrocyclisation [ 1521 conditions were applied with success in both cases (Scheme 59) Careful flash . column chromatography on the crude product derived from the reaction of acrylamide 168

afforded "dimeric" macrocycle 179 in a respectable 31%

yield. It was characterised by 1H NMR, 13C NMR, I R,,

determination of its melting point and optical rotation,

low resolution and high resolution mass spectrometry and

elemental analysis.

A doublet at 7.33 ppm in the 1H NMR spectrum of 179,

attributed to the vinylic benzylic proton, points to a

successful cyclisation. The geometry of the double bond was

assigned as trans- from the coupling constant (J = 15.6 Hz) between the two vinylic protons.

The structure of macrocycle 179 was confirmed by X-ray

crystallography, performed on crystals grown by slow

evaporation of an ethanol solution (Figure 33). The

macrocycle has crystallographic C2-symmetry about an axis

that passes through the centre of the ring and is The distance N (1) N(1A) perpendicular to the ring plane. ... is 11.35 AO, while the distance between the centres of the double bonds is 4. S7 A.

118 H OMe N NN ---IY Bn Bn 0

168 169

Pd(OAc)2 (10 mol%), nBU4NCI (1 eq. ) NaHC03 (2.5 eq. ), DMF, 110 OC,16 h

N N BD, n Bn HN HN

MeOOC NH NH COOMe Bn Bn N N

179 180

Yield = 31 % Yield = 25%

Scheme 59. Heck reaction on substrates 168 and 169.

Figure 33. The molecular structure of macrocycle 179.

As for the cyclisation of substrates 160 and 162, in spite

of very careful purification procedures, no appreciable

sign of any heavier homologue of 179 could be detected. It

119 was concluded that, as in the previous reactions, the rest of the starting material had been converted into an intractable mixture of polymers and oligomers.

Compound 180 was isolated as a fluffy colourless solid in 25% yield from the reaction carried out on acrylate 169. 1H The NMR of this compound showed analogous features to that of macrocycle 178, which was rationalised to have formed via an alternative P-hydride elimination pathway

(Scheme 53) Thus it was concluded that in this case, too, the double bond had formed in a position next to the expected one, which is consistent with the presence of a strong vicinal coupling (J 14 Hz) between the methynic proton and the NH. Compound 180 was characterised by the usual means but in spite of the many solvent mixtures tried for that purpose, no suitable crystals could be obtained for crystallographic structural analysis. Finally, as in the previous cases, it was concluded that the macrocyclisation had not produced appreciable amounts of any homologues of 180 since nothing but decomposition products could be isolated by careful flash column chromatography of the crude product mixture.

120 4.2.8 An experimental assessment for the selective

formation of "dimers" during the macrocyclisation step

None of the Heck macrocyclisation reactions carried out so

far had produced heavier "oligomers" of "dimers" 158,178"

179 and 180. This result came as a surprise since in the

previous studies on ester-containing macrocycles the

isolation and characterisation of "trimer" adducts had

proven possible. [ 140)

[ 1551 Very recently Moreno-Maftas et al. reported the

isolation and characterisation of stable palladium

complexes of polyolefinic macrocycles. They were obtained

by heating under reflux a source of Pd(O), usually bis(dibenzylideneacetone)palladium(O) [Pd(dba) 21 or tetrakis(triphenylphosphine)palladium(O) [Pd(PPh3 ) 41 r with the appropriate macrocycle in a variety of solvents,

including dimethy1formamide and THF. These complexes, which

are stable to air and to chromatographic conditions,

feature coordination of the metal to the double bonds

embedded in the structure of the synthetic macrocycles.

Experimental evidence suggested that palladium(O) could

exert a templating effect on the assembly process, [ 1561 and

therefore the possibility that a palladium-templated

selective formation of "dimeric" macrocycles was taking

place during the Heck cyclisation step was explored. This might explain why only a single "size"' of macrocycles was being generated, and an experimental assay was set up to test this hypothesis.

Macrocycle 158 was chosen to carry out these experiments since its crystalline nature might be preserved in a palladium(O) complex, allowing easy isolation and (1571 characterisation. Following the literature procedure,

121 compound 158 was heated under reflux for 15 h with an excess of Pd (dba) in THF (Scheme 60, A) 2 -

Pd(dba)2 (5 eq. ) unreacted p 0. starting A N material recovered THF, reflux, 15 h

00,1 Z:ýrj NH HN 0 Pd(PPh3)4 (7 eq. ) Im unreacted starting B material recovered THF, reflux, 40 h 158

Scheme 60. Studies of Pd-templating effect in the macrocyclisation reaction on substrate 158.

Disappointingly, systematic TLC investigation of the crude reaction product did not produce any evidence of the formation of a possible palladium-complex. The same experiment was repeated with another source of 157 palladium(O), namely Pd(PPh3) 4r using a longer reaction time (B), but unfortunately also in this case no conversion of the starting material was observed.

This brief study led to the conclusion that, even if a palladium-templating effect is responsible for the selective formation of "dimeric" macrocycles during the

Heck cross-coupling, a stoichiometric Pd(O)/158 complex is not formed under the conditions examined.

122 4.3 Synthesis of a novel class of pyrrole- containing macrocycles

4.3.1 Background to the introduction of pyrroles

The synthesis of macrocycles containing four nitrogen atoms

had been successfully achieved employing standard chemistry

in a reasonably short number of steps. Some of the chiral

receptors obtained had started to display very interesting

features in terms of intermolecular interactions and

crystallinity, which represented a promising background for

their future applications.

It was envisaged that a slight modification to the

structure of these compounds could open the way to a still

greater enhancement of their coordination properties. it

was planned to achieve this by the introduction of

supplementary nitrogen atoms into their backbone, without

elongating or entirely modifying the efficient synthetic

route developed so far. One of the possible ways of

achieving this goal would be to identify a heteroaromatic

building block on which all the transformations described

so far could be carried out.

Pyrrole was chosen from many possible candidates.

Introduction of this nitrogen-containing heterocycle into

the design of chiral macrocycles was anticipated to give

access to very versatile and powerful receptors. The anion-

binding properties of pyrrole are in fact well known, and

in recent years many useful applications of pyrrole- [ 1581 containing macrocycles in supramolecular chemistry and E159] host-guest recognition processes have been reported.

The synthesis of pyrrole-containing chiral macrocycles was planned from a pyrrole scaffold that contained an iodine 123 atom and an aldehyde functional group, the two essential elements for taking the established synthesis forward. If this type of building block could be easily obtained from

commercial sources, or via straightforward modification of

commercial compounds, then the development of a facile

synthesis of this new family of macrocycles would rely only

on the successful implementation of the sequence developed

for the previous class of compounds.

Given the crystallinity and the appreciably higher stability of macrocycles 158 and 179, which are

respectively derived from the head-to-tail coupling of acrylamides 160 and 168, it was planned to synthesise only

amide-containing alkene precursors in order to test the

viability of the procedure. Depending on the result of this first screening, modification of the newly obtained

macrocycles could be employed to maximise their performance

in any given context.

124 4.3.2 Synthesis of the appropriate aldehyde

Commercially available pyrrole 2-carbaldehyde 181 was chosen as an amenable substrate for developing the planned synthesis. Introduction of an iodine atom on the aromatic ring via electrophilic substitution is well documented in [ 1601 the literature, and the regioselectivity of the reaction is expected to be in favour of the formation of the 4-substituted isomer.

Treatment of a carbon tetrachloride solution of 181 with

[bis(trifluoroacetoxy)iodo]benzene and iodine offered, after work-up and careful flash column chromatography, compound 182 as a colourless crystalline solid in 54% yield (Scheme 61) E1611 4-Iodo-lH-pyrrole-2-carbaldehyde 182 . was characterised by the usual means and its analytical data [1601 matched with those reported in the literature.

FýýCHO (CF3COO)2lPh (1 eq. ) W CHO N 12(1 eq. ), CC14, rt, 18 h HH 181 182

Yield = 54% [1601 Scheme 61. Synthesis of compound 182.

The anticipated substitution pattern on the aromatic ring 1H was confirmed by the NMR spectrum of 182 which revealed a coupling constant between proton 3 and 5 (See General experimental for numbering) of 1.5 Hz, typical for a meta- coupling in pyrroles. Given the known propensity of pyrrole derivatives to undergo oxidation reactions in the presence of light and air, all such compounds were stored under nitrogen in the dark, and used immediately whenever possible.

125 Compound 182 was subjected to reductive amination with proline, affording a very good yield of the corresponding aminoalcohol. Unfortunately, the Mitsunobu reaction that should have converted the alcohol group into the corresponding azide did not produce the desired product. An

NMR investigation seemed to suggest that the free N-H of the pyrrole may be responsible for undesired side-reactions during this step, and therefore it was decided that protection of the nitrogen was needed.

The choice of the protecting group fell on benzyl since its removal from pyrroles under hydrogenolysis or acidolysis conditions had already been reported. [ 1621 Following a [ 1633 literature procedure, compound 181 was added carefully to a stirred suspension of sodium hydride in DMF at 0 OC

(Scheme 62). The anion was allowed to form over a period of

30 min and then benzyl bromide was added. A TLC check after 50 min showed that the starting material had been completely converted into a less polar compound. After quenching, flash column chromatography of the crude product afforded M-protected pyrrole 183 in 97% yield as a pale pink oil.

F1 NaH (1.1 eq. ), BnBr (1 eq. ) O'CHO \' "" CH0 0- N DMF, 0 OC->rt, 80 N HI min. Esn 181 183

Yield = 97% [162,1631 Scheme 62. Synthesis of AT-protected pyrrole 183.

Compound 183 was characterised by the usual means and its [1621 data matched with those already reported.

The introduction of an iodine atom on the pyrrole ring was nprfnrmed employing the same conditions previously used for

126 E1611 the preparation of 182. Compound 184 was isolated as a colourless crystalline solid by very careful flash column chromatography (Scheme 63), necessary to achieve complete separation from other regioisomers of very similar polarity.

(CF3COO)2'Ph (1 eq. ) I/N,-AN'ý-CHO 0- Wý'CHO 12(1 eq. ), CC14, rt, 18 h Bn Bn 183 184

Yield = 62% Scheme 63. Synthesis of compound 184.

Novel compound 184 was fully characterised and the 1,4- relationship of the two substituents was again confirmed by a typical meta-coupling constant between protons 3 and 5 (J 1.5 Hz) The this two = . reliability of step procedure facilitated the production of multi-gram amounts of compound 184.

4.3.3 Synthesis of a proline-derived alkene precursor

The reductive amination of pyrrole-derivative 184 with (S)- prolinol 167 was carried out under the conditions used previously. The intermediate iminium ion was not isolated but immediately reduced to the corresponding aminoalcohol with sodium borohydride (Scheme 64). Novel compound 185 was isolated in 70% yield as a clear oil, and was characterised by the usual means.

127 1) (S)-prolinol 167 (1.5 eq. ), MgS04 bN"ýz DCM, rt, 18 h 7 N -CHO N 2) NaBH4 (2 ) eq. 1 OH Bn MeOIH, 0 OC--->rt,24 h BBn

184 185

Yield = 70% Scheme 64. Synthesis of aminoalcohol 185.

[ 1441 A slight modification to the conditions previously developed for the synthesis of 164 and 171 led to the successful replacement of the alcohol with an azide group via a Mitsunobu reaction (Scheme 65).

1) DEAD (2 eq. ) THF, 0 OC->rt, 10 ýN PPh3 min / N

2) 185 (1 eq. ), rt, 5 min. N3 (2 eq. ) 3) (PhO)2P(O)N3 (2 eq. ) Bn 24 h rt, 186 4) H20, rt, 1h Yield = 93% Scheme 65. Synthesis of azide 186.

Flash column chromatography of the crude product afforded 93% yield of novel azide 186 as a clear oil, which was fully characterised. This procedure proved suitable for the synthesis of multi-gram amounts of 186.

It is noteworthy that pure compound 186 appears as a mixture of two well separated rotamers on TLC using hexane/ethyl acetate 7: 3 as solvent mixture (see

Experimental); these two compounds have both been isolated 1H and characterised, and their NMR and 13C NMR spectra in

CDC13 are completely superimposable. Hence, in subsequent experiments, they were collected together as a single compound, which exhibited the same NMR spectra as the two separated rotamers.

128 [ 1481 A Staudinger reaction on substrate 186 afforded a satisfactory 63% yield of novel primary amine 187, which was obtained as a clear oil after flash column chromatography (Scheme 66) and fully characterised.

PPh3 (2 eq. ), H20 (10 eq. ) N N N THF, 50 OC, 20 h Ný I N3 I NH2 Bn t3n 186 187

Yield = 63% Scheme 66. Reduction of azide 186 to amine 187.

In the NMR spectra of amine 187 two rotamers are present in a 1: 1 ratio, exhibiting distinct signals for almost each proton and each carbon atom.

Acylation of 187, necessary for the introduction of the alkene moiety required for the Heck coupling reaction, proved to be the most challenging step in the whole sequence. Despite trying many reaction conditions, only 27% yield of compound 188 could be obtained at best employing triethylamine and DMAP in dichloromethane (Scheme 67). A slightly higher yield (30%) was obtained when the reaction was performed on a smaller scale (0.80 g rather than 2.0 g).

acryloyl chloride (3 eq. ) N N Ný Et3N (8 eq. ), DMAP (1 mol%) Ný NH2 I NH Esn DCM, 0 OC->rt, 16 h Bn 187 188 0

Yield = 27% Scheme 67. Synthesis of acrylamide 188.

129 Nevertheless, this procedure gave multi-gram amounts of novel alkene 188, which was fully characterised. As already found for compound 186, two well separated and isolable rotamers were detected by TLC (ethyl acetate), but they displayed identical NMR spectra and were collected together as a single compound for further manipulation.

4.3.4 Synthesis of a valine-derived alkene precursor

Once the feasibility of introducing a pyrrole scaffold into

the structure of a proline-derived alkene precursor had been established, the same sequence of reactions was used

to synthesise a valine-containing substrate. Aldehyde 184 was reacted with (S)-valinol 173 in the presence of

MgS04 (Scheme 68) The imine anhydrous . resulting was not isolated but immediately reduced to the corresponding [1401 secondary amine by sodium borohydride.

1) (S)-valinol 173 (1.5 eq. ), MgS04 h ýN\ýCHO DCM, rt, 48 H N -"'0 H 2) NaBH4 (2 ) I eq. tin MeOH, 0 OC-ýrt, 18 h Bn 184 189

Yield = 98% Scheme 68. Synthesis of alkene 189.

Flash column chromatography afforded novel secondary amine

189 in excellent yield as a pale yellow oil. It was

characterised by the usual means and the reliability of this two step sequence provided access to multi-gram amounts of 189.

Protection of the secondary nitrogen atom was necessary in order to prevent unwanted side-reactions in the following steps of the synthesis. The choice naturally fell on a benzyl protecting group, since its cleavage would provide

130 concomitant deprotection of the pyrrole nitrogen. Hence

secondary amine 189 was treated with one equivalent of benzyi bromide in the presence of activated potassium carbonate and 18-crown-6 in dry (Scheme 69) [140b) acetone .

K2CO3 (1.5 ), BnBr (1.5 ) H eq. eq. Bn N 0. N N 18-crown-6 (0.1 eq. ), acetone, rt, 72 h N OH Bn I Bn 1-1ý 189 190

Yield = 67% Scheme 69. Synthesis of 190.

A longer reaction time was required in this case (See

Scheme 54 for comparison) since the starting material did

not convert completely within 15 h. and it is of note that

even after 72 hours some starting material remained unchanged. Novel compound 190 was isolated as a clear oil

in a respectable 67% yield after flash column

chromatography. The unreacted starting material was recovered in excellent purity and reused in future runs.

Fully protected amine 190 was characterised by the usual means, and although two rotamers were clearly visible on

the TLC (hexane/ethyl acetate/triethylamine 5: 5: 0.5), only

one species was detected in solution during NMR

experiments. In particular it is of note that the two different types of benzylic protons (those attached to the alkyl amine and those attached to the pyrrole nitrogen) exhibit very different shifts in the 1H NMR spectrum.

Whilst the former give two doublets which are far apart from each other (more than I ppm of difference) with a coupling constant of ý. l Hz, the latter give two quite close doublets (less that 0.1 ppm of difference) with aJ of 16.0 Hz.

131 The alcohol functionality of 190 was converted into the ý1443 corresponding 191 azide 1 which was afterwards reduced [ 14 81 to the primary amine 192 (Scheme 70) .

1) DEAD (2 eq. ) TH F, 0 10 PPh3 OC->rt, min Bn NN N 2) 190 (1 eq. ), rt, 5 min. (2 eq. ) 3) (PhO)2P(O)N3 (2 eq. ) Bn rt, 24h 191 4) H20, rt, 1h Yield = 95%

h3 H20 PP (2 eq. ), (10 eq. ) Bn N ýNI-12 THF, 50 OC,16 h Bn 1-1ý 192

Yield = 92%

Scheme 70. Synthesis of amine 192 via azide 191.

Novel compound 191 was isolated in 95% yield as a clear oil

after a Mitsunobu reaction, and was fully characterised by the usual means. Compound 192, isolated as a clear oil in

92% yield, was also fully characterised. Compounds 191 and 192 both exhibited restricted rotation in their 1H NMR

spectra.

Acylation of the primary amine 192 was attempted employing

the same conditions that had successfully provided 168 (See Scheme 57) [1541 but acrylamide F unfortunately no trace of the desired product was obtained despite complete

reaction of the starting material (Scheme 71, A). A totally different approach, relying on a mixed-anhydride procedure employing 2-ethoxy-l-ethoxycarbonyl-1,2-dihydroquinoline [ 1641 (EEDQ) as a condensing agent was then attempted, given that direct acylation of amine 187 (Scheme 67) had also proven rather troublesome. Acrylic acid was added to a stirred solution of EEDQ in THF at room temperature,, and

132 the mixed anhydride to form 3h (B) was allowed over .A solution of amine 192 was then added, but systematic TLC investigation showed no sign of conversion of the starting material even after 48 hours.

acryloyl chloride (3 eq. ) decomposition products DIPEA (3 eq. ) DCM, 0 'C-4rt, 3h Bn N N NH2 Bn acrylic acid (1 eq. ) 192 starting material B EEDQ (1 eq. ) THF, rt, 48 h

Scheme 71. Attempted acylation of amine 192.

In another attempt, amine 192 was reacted with acryloyl chloride in the presence of triethylamine and DMAP in dry dichloromethane (Scheme 72). [ 1491 Flash column chromatography afforded, to our delight, desired acrylamide

193 in 50% yield as a colourless solid. Though not very high-yielding, this sequence led to the production of multi-gram amounts of novel alkene 193, which was characterised by the usual means.

Bn (3 ) Bn N acryloyl chloride eq. N NH2 NN Et3N (8 ), DMAP (1 mol%) IH tin eq. Esn DCM, O'C->rt, 18 h 192 193

Yield = 50%

Scheme 72. Successful acylation of amine 192 to 193.

133 4.3.5 The Heck macrocyclisation on substrates 188 and 193

The investigation of the feasibility of a head-to-tail coupling reaction of pyrrole-containing substrates 188 and 193 began with literature conditions developed by Fukuyama [ 165 et al. for Heck reactions between 2-iodoindoles and methyl acrylates. A completely new set of conditions, which may be more suitable for electron-rich heteroaromatic precursors, was thus used for the palladium-catalysed cyclisation step.

A mixture of alkene 193, palladium acetate,, tris (o-tolyl) phosphine and trietl 'iylamine in anhydrous acetonitrile was heated under reflux for 18 h under an atmosphere of dry [ 1651 nitrogen (Scheme 73). Unfortunately, a TLC investigation of the crude reaction product revealed that a negligible amount of starting material had reacted.

0 Pd(OAc)2 (10 Bn M010/0) N no reaction "ýN'ký' Nýý Et3N (1.1 eq. ), P(O-tO03 IH Bn CH3CN, reflux, 18 h

193

Scheme 73. Attempted cyclisation of substrate 193 with [1651 Fukuyama's conditions.

In view of this disappointing result, it was decided not to proceed with an optimisation of these conditions but rather to assess the applicability of classical Jeffery conditions [ 1521 to this specific substrate. The same reaction was thus attempted employing sodium bicarbonate as base, tetra-n-butyl ammonium chloride and palladium acetate in DMF (Scheme 74). After 16 h the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The crude product obtained needed to be washed with water in order to dissolve the inorganic salts that 134 would otherwise interfere with the purification procedure.

Flash column chromatography afforded eventually novel macrocycle 194 in 35% yield as a fluffy colourless solid, which was fully characterised by the usual means.

Pd(OAC)2 (10 MOl 0m NýH 0 N nBU4NCI (1 eq. ) Bn Bn 'ý E3nN N NBn ' Bn Ný N N IH NaHC03 (2.5 eq. ) Bn DMF, 110 OC,16 h HN'

193 194 0

Yield = 35% Scheme 74. Synthesis of macrocycle 194.

For the first time in the lH NMR spectrum of a macrocycle formed in this study, locked conformations gave rise to the duplication of proton resonances. For example, the benzylic protons attached to the nitrogen of the pyrrole ring give two sets of two doublets, the ratio between the two sets being 4: 1. Each doublet exhibits a coupling constant of

15.5 Hz, slightly smaller than the one found for the same protons of the starting material (i = 16.0 Hz). The vinylic benzylic proton gives the expected doublet at 7.51 ppm; the geometry of the double bond is confirmed as trans- given the high value of the coupling constant between the two protons involved (J = 15.3 Hz). Duplicate signals for the 13 two rotamers were seen also in the C NMR spectrum.

The low resolution mass spectrum of compound 194 confirmed its molecular weight. Unfortunately, in spite of attempts based on many solvent mixtures, no suitable crystals could be obtained for crystallographic structural analysis.

In view of the successful outcome of the head-to-tail coupling on substrate 193 employing the usual conditions, 135 the same experiment was tried on alkene 188. The reaction was carried out following the procedure already described [ 1521 (Scheme 75) In order to avoid interference from the inorganic salts during the purification step, the filtered reaction mixture was dissolved in dichloromethane and washed with water. Flash column chromatography of the crude product afforded "dimeric" macrocycle 195 in 39% yield as a fluffy colourless solid.

0: N, Pd(OAc)2 (10 MO'O/') ýT 'Bn NH N nBU4NCI (1 eq. ) HN Bn\ N N0 I NH NaHC03 (2.5 ) Bn eq. DMF, 110 OC,16 h N 0 188 195

Yield = 39% Scheme 75. Synthesis of macrocycle 195.

Novel compound 195 has been characterised by the usual means. It is noteworthy that it tends to go a light pink

colour even in the solid state, and gives a pink solution when dissolved in deuterated chloroform.

A very slow rate of interconversion of rotamers could be the possible cause of the very broad peaks exhibited by macrocycle 195 in its 1H NMR spectrum. The alkyl region seems to be the most affected by the broadening since only broad peaks are detected for the protons of the proline backbone. Nevertheless, a doublet at 7.43 ppm with a coupling constant of 15.2 Hz indicates that the macrocyclisation had proceeded to give the expected trans- double bond. The low resolution mass spectrum confirms the molecular weight of the newly generated macrocycle, for which unfortunately no crystallographic confirmation could be obtained.

136 4.3.6 Attempts to remove the benzyl protecting group from macrocycles 194 and 195

The choice of a benzyl protecting group both for the secondary alkyl amine of substrate 194 and the pyrrole nitrogen of 194 and 195 was dictated by an anticipated ease of removal. In fact literature methods exist for the deprotection of M-benzyl-protected pyrroles either via hydrogenolysis or acidolysis procedures. [1621

Performing a one-pot deprotection of both kinds of benzyl group in 194 would give access to a system which contained four secondary nitrogen atoms. It is reasonable to assume that such a fully deprotected macrocycle would exhibit a high level of activity in host-guest chemistry, molecular recognition processes and ultimately in metal-catalysed asymmetric reactions. A similar behaviour could be predicted for the product derived from the removal of the benzyl groups from macrocycle 195, which would feature four

N-H's and two tertiary nitrogen atoms.

Both macrocycles were therefore subjected to palladium- catalysed hydrogenolysis following a literature procedure. [ 1621 Unfortunately, using heterogeneous hydrogenation conditions (10% Pd/C) and a pressure either of 100 or of 120 psi for a long reaction time, it was not possible to achieve any conversion of both macrocycles (Scheme 76) Filtration of the crude products on a short pad of celite led to the recovery of unreacted starting materials 194 and 195.

137 --Z N Bn N, HN H2 (100 Psi) 0 0 Bn 01- ureacted starting material Bn Pd/C (10% w/w) NH N Bnrl AcOH, rt, 24 h N

194

0ý, H2 (120 psi) Bn NH 0.- unreacted starting material HN Bn\ Pd/C (10% w/w) N0 AcOH, rt, 48 h

N 195

Scheme 76. Attempted removal of the benzyl protecting groups from substrates 194 and 195 via hydrogenolysis.

The reason for such a disappointing result was ascribed to a poisoning of the palladium on charcoal catalyst by the many nitrogen atoms present in both macrocycles 194 and 195.

A deprotection procedure that did not rely on the use of a metal was thus needed, and an answer to this problem was sought by carrying out an acid-mediated cleavage of the benzyl groups. [ 1621 In two separate experiments, macrocycles

194 and 195 were dissolved in trifluoroacetic acid in the presence of a catalytic amount of sulfuric acid (Scheme

77). An excess of methoxybenzene (anisole), which was intended to act as a trap for the benzyl cation, were added and the resulting mixture was heated under reflux for 30 min. During the course of the reaction, the mixture turned intense red which was interpreted as a promising sign of ongoing conversion.

138 Indeed, both substrates reacted completely under the

conditions employed; unfortunately, TLC investigations on

the crude products showed that the reactions had not proceeded cleanly, producing a range of difficult-to- identify compounds.

'ýý N Bn2ý X N anisole (6 eq. ) -Bn complex mixture Bn, H2SO4 (cat. ) of products NHN Bn CF3COOH, reflux, 30 min. N

194

N anisole (3 eq. ) complex mixture H2SO4 (cat. ) of products Bn NH CF3COOH, reflux, 30 min. HN Bn\ N0

N 195

Scheme 77. Attempted acid-mediated removal of the benzyl

protecting groups from substrates 194 and 195.

On just one occasion, a very small amount of a red-coloured

compound, whose mass spectrum showed the molecular peak of

a completely deprotected species,, was isolated from the

reaction of substrate 195.

Though not conclusive, these results suggest that, even if an acid-mediated removal of the benzyl groups was feasible, these very harsh and unforgiving conditions militate against clean conversion and high yields of the desired products.

139 4.4 Application of the synthetic macrocycles:

host-guest chemistry

4.4.1 Introduction

Host-guest chemistry, the branch of science which is concerned with the selective molecular interactions between a receptor and a substrate, has become the subject of increasing interest within the scientific community over the last twenty years. Vital biochemical processes such as molecular transport, genetic information processing and protein assembly involve molecular recognition and complexation as an essential action. Thus the design and development of synthetic systems that can help the elucidation and understanding of such phenomena has become [1661 a rapidly growing field of chemistry.

According to the Kitaigorodski model, [ 167 of the two molecules involved in the association event, the "guest" is identified as the molecule presenting the convex surface while the "host" is the molecule presenting a more concave aspect. In common applications the host is a large molecule that features a sizeable, central hole or cavity capable of binding the guest (a relatively small charged or neutral molecule) by encapsulating it into a cleft or pocket.

In the field of host-guest chemistry, two principles have been found to be of special importance for the successful design of strongly binding host molecules: 1) the principle of stereo-electronic complementarity between host and guest and 2) the principle of preorganization of a binding site prior to complexation. The former essentially represents a modern formulation of the lock-and-key principle introduced by Emil Fisher, [ 1681 while the latter states that the is preorganization of a host prior to complexation an 140 essential factor controlling the association strength.

Therefore if a host is not "ready for its guest",

reorganization must occur upon complexation. This

reorganization can cost part of the free binding energy

(See Section 3.6.1); if the energy needed to reorganize the

binding site is larger than the free binding energy then no binding will occur.

Hydrogen bonding arrays provide suitable forces for the

specific complexation of small molecules by synthetic

receptors (e. g. macrocycles) in organic solvents. For

example, macrocycles 196,197 and 198 have been carefully

designed to contain several hydrogen bond donors and

acceptors all around the ring in a position to potentially interact (Figure 34) [ 1691 with complementary substrates .

0 H OYH I ,- o y) N

196 R= 4-NO2C6H4 197 198

Figure 34. Macrocycle 196 effectively binds to p- [1691 nitrophenol while 197 and 198 do not.

NMR investigations of the interaction of 196 with p-

nitrophenol revealed that hydrogen bonding recognition

occurs involving the NH and CO groups on the aliphatic bridge (Ka,,, 102 M-1) but the nitrogen. ýý2.3X , not pyridine Interestingly, receptors 197 and 198 show only weak binding

to p-nitrophenol presumably because of the twisted

conformation that 197 can adopt, and because of the rigid p-xylene spacer in 198 which prevents the two amide groups 141 in the bridge from binding effectively to the phenolic hydroxyl group.

Another important association factor in the complexation of organic guests by appropriate hosts is n-n stacking between aromatic rings with opposite electronic features (one electron-rich and the other electron-poor), which can involve face-to-face or edge-to-face interactions. (166d] The cationic chiral cyclophane 199 was studied as a host for chiral and racemic n-donor molecules (Figure 35) [117f]

H N NN0 H00 0 NH HO NH OH NH3 HO)ý +

(±)-DOPA N N

199

Figure 35. Cationic macrocycle 199 binds enantioselectively to (R)-DOPA. [ 1177EI

Titration experiments by NMR were performed with several different pharmaceutically interesting guest molecules including P-blockers and amino acid derivatives. An (R)I(S) enantioselectivity ratio of 13±5 was found with DOPA, which 1H is a strongly ri-donating cationic guest, and NOESY NMR spectra confirmed that (R)-DOPA binds inside the cavity of the host.

142 4.4.2 Investigation of the host properties of the synthetic macrocycles

All the macrocycles synthesised in the course of this study feature a significant number of nitrogen atoms which are potential interaction sites with organic guests. Macrocycles 158 and 179 contain two amide functionalities which can act as hydrogen bond donors (N-H) and acceptors

(0-H) and two slightly electron-poor benzene rings that can in principle establish n-n interactions with electron-rich aromatic rings embedded in the structure of an appropriate guest (Figure 36) Macrocycles 178 and 180, on the other hand, contain two secondary nitrogen atoms (hydrogen bond donors) which are also potential binding sites for molecular recognition. Macrocycles 194 and 195, apart from two amide groups, contain two pyrrole moieties which not only represent electron-rich aromatic rings but can also act as hydrogen bond donors through their N-Hs. However, given that the deprotection of the pyrrole nitrogen was unsuccessful under a range of conditions, it was decided not to investigate the host properties of these highly promising systems, whose potential may ultimately be realised with the choice of a more easily removable protecting group.

Macrocyles 158,179 and 178 were employed in the NMR investigation. Equimolar amounts of the macrocyclic host and the guest candidate were mixed in 500 pl of CDC13 and a

1H NMR spectrum (300 MHz) was recorded. If the spectrum showed any significant changes in terms of chemical shifts and multiplicities of the host and/or the guest, which would be the sign of an appreciable degree of interaction, the binding would then be further investigated by accurate

H NMR titration in order to calculate the binding constant 36, 3.6.1) [ 1141 Kass (See Scheme section .

143 zýZ lý N 1- N N p Bn HN MeOOC 1 " 0H fN jF "5, NH 0 NH 0HN0 NH B nri COOMe N "'." N N 158 179 178

MeOO pN

ýý ýNB N 0 "Bin NH Bn NH Bn Bn HN Bn\ BnN % HN No NBn N ýý HN N --i Meoot 180 194 195

Figure 36. The structure of the synthetic macrocycles obtained in this study.

range of small molecules exhibiting structural symmetry and functional complementarity to the hosts were chosen as potential guest candidates.

lH Since the NMR spectra of equimolar mixtures of macrocycle 179 and each of the five organic guests showed no host-guest interactions, it was concluded that the anticipated hydrogen bonding and/or ri-ri stacking did not occur (Table 1). Macrocycle 158 was screened against benzoquinone and 4-amino phenol, but again no appreciable interaction was detected.

144 0 NH2 OH 0

Macrocycle N (N D

OH OH 0 guest NH2

179 x x x x x

158 x x

178 x x

Table 1. Macrocycles 179,158 and 178 showed no appreciable binding to a range of small organic guests (x = no binding detected).

Macrocycle 178 was also screened towards 4-amino phenol and hydroquinone in the hope that the presence of a different nitrogen-containing functionality (a secondary amine instead of a secondary amide) would change the complexation properties of the receptor. Unfortunately, though, no significant changes in terms of chemical shifts and multiplicities of the host and the guests were detected in the 1H NMR spectrum, which suggested very poor or nonexistent interaction.

Although the results of this first screening were disappointing, it is envisaged that the successful synthesis of pyrrole-containing macrocycles with available

N-Hs could represent a breakthrough in enhancing the complexation properties of this new class of macrocycle.

145 4.5 Application of the synthetic macrocycles:

asyrmnetric catalysis

4.5.1 Introduction

Given the potential represented by amino acid-containing macrocycles as ligands in asymmetric catalysis (Section

3.3), the possibility of applying the synthetic macrocycles

obtained in this study to a metal- catalys ed asymmetric

transformation appeared stimulating and promising. The 1701 investigation was triggered by a report [ on the use of

chiral bis-pyridino-18-crown-6/rare earth metal triflates

complexes in the catalytic asymmetric Mukalyama aldol 1711 reaction [ in aqueous media (Scheme 78). Lanthanide trifluoromethanesulfonates [lanthanide triflates, Ln(OTf)31

have recently received much attention in the catalysis area

NN00- 200

0 0_ (24 4ýý', -, M01%) OH 0 0 QSiMe3 RE(OTf)3 (20 AH+ mol%) Ph Ph Ph Ph H20/EtOH = 1/9,0 OC llýýý

up to 85% d.e. 82% e. e. Yields = 49-95%

Scheme 78. The catalytic asymmetric Mukaiyama aldol E"70ý reaction with a chiral macrocyclic ligand 200.

given their strong Lewis acidities and unique 1723 properties. [ Their intrinsic water tolerance has led to the development of Lewis-acid catalysed reactions in aqueous media. The great advantage of these reactions, apart from the use of the cheapest and "greenest" solvent, 146 is the avoidance of the tedious and money wasting procedures to remove water f rom solvents,, substrates and catalysts. (1731

Although many chiral lanthanide complexes had been synthesised, characterised and used in asymmetric [ 17 catalysis, 41 Kobayashi's report represents the f irst catalytic asymmetric aldol reactions using Ln(OTf) 3 in aqueous media. The most important feature in designing a

chiral ligand for Ln(OTf) 3 for reactions in aqueous media is its binding properties to the lanthanide cations. A

ligand with strong coordinating ability reduces the Lewis

acidity of the metal and thus often produces lower yields

of the desired catalytic product. On the other hand, weaker binding ability can result in significant quantities of

solvent-coordinated metal cations which are able to

,catalyse the achiral reaction.

[ 1701 For the reaction shown in Scheme 78, it has been shown

that both the diastereoselectivity and the

enantioselectivity decreased with decreasing Rare Earth

(RE) atomic radius: the best results were obtained with Is Ce (OTf) 3 and Pr (OTf) 3, and practically zero e. e. were obtained with Sc(OTf)3 and Yb(OTf)3. The reactions were

carried out in mixed water/ethanol, and good

diastereoselectivities and enantioselectivities were

obtained only in the presence of water. The X-ray crystal

structure of the complex of crown ether 200 with Pr(OTf)3,

which showed that the Pr cation was located almost at the

centre of the macrocycle, led to the formulation of a

transition state model which could explain the absolute in configuration of the favoured enantiomer of the product (Figure 37, A) [170bI Given the the asymmetric aldol reaction . fact that some macrocycles containing amide and amine

functionalities (the same contained in the macrocycles

147 synthesised in this study) have also been shown to form stable complexes lanthanide (B) [1751 it with cations " Was envisaged that the inspiring work described above would be

an excellent assay for the ligand behaviour of the synthetic systems depicted in Figure 36.

R Me3SiO-ý R 3+ R 1 11ý-0 H-N H-- 0H N-R N HCH3 Ný -ýH3C Y-H "" 1- r, ------0---- / \ý - 0----0- -pr, --c N\ý. l', N H0 l' ý- H N- R-N H0 CH3 N-H R A B

Figure 37. Proposed transition state for the Pr(OTf)3-

cataiysed asymmetric aldol reaction (A) [170b3 and lanthanide complexes of amine / amide containing macrocycles (B). [1751

4.5.2 Testing the synthetic macrocycles as chiral ligands

in the RE (OTf) 3-catalysed Mukaiyama aldol reaction

In order to screen the performance of the synthetic

macrocycles as ligands in the chosen assay, the reactivity

of the system in the absence of the chiral ligand needed to

be assessed. The reported results [ 1701 proved very easy to

reproduce and the only divergence from the literature

procedure was the use of a THF/water mixture instead of EtOH/water, due to the poor solubility of the macrocycles

in alcoholic media. Praseodymium triflate, which had been

shown to produce some of the best e. e. fs in the reported work, [ 1701 was used as catalyst. Z-Silyl enol ether 201 was

synthesised according to a literature procedure and its [ 1761 analytical data matched those reported (Scheme 79).

This enol ether was then used in the "blank" reaction together with benzaldehyde 202; hydroxyketone 203 was

148 isolated in excellent purity and yield, and its analytical data [ 170 matched those reported. The s_vnlanti ratio was calculated from the integration of the two benzylic

resonances (5.00 ppm for anti, 5.24 ppm for syn). [' 7Oj

1) LDA (1.1 eq. ), THF, -78 'C, 1h OSiMe3

Ph 2) Me3S'C' (1.1 eq. ), THF, 'C, 20 h ---ý h -78 ýP 201 Yield = 57%

0 OH 0 OSiMe3 Pr(OTf)3 (20 mol%) Ph H "'A PKýýPh Ph H20/EtOH = 1/9 0 "C, 18 h 202 201 203

(1.5 eq. ) Yield = 91 % d. e. 17%

[ 17 6 Scheme 79. Synthesis of enol ether precursor 201 and [1701 the "background" Mukayiama aldol reaction.

The first macrocycle to be screened as a potential ligand

was proline derived compound 158, which was subjected to

the same reaction conditions as those reported (Scheme

80) [170 1 from the discussed f apart already change of solvent system. The low yield and practically unchanged diastereoselectivity achieved (Table 2, entry 1) were

considered a sign of efficient and irreversible coordination of the ligand to the metal, and this inference was confirmed by the determination of the e. e. of the product, which proved to be zero (chiral HPLC determination). Consistent results were obtained with valine derived macrocycles 180 (entry 2) and 179 (entry 3), both of which gave very low yields of racemic product along with practically unchanged diastereoselectivity. Macrocycle

178, on the other hand, showed an even more efficient encapsulation of Pr since no trace of the product could be detected under the standard reaction conditions (entry 4).

149 Macrocycle (24 OH 0 0 OSiMe3 mol%) AH+ Pr(OTf)3 Im Ph Ph Ph --'ý Ph H20/EtOH = 1/9 0 OC, 18 h 202 201 203

eq. )

Scheme 80. Screening of the chiral macrocycle in the

Pr(OTf)3-catalysed Mukalyama aldol reaction (see Table 2).

Pyrrole derived macrocycles 194 and 195 were also tested for ligand activity in the assay. The valine-containing macrocycle 194 behaved like the parent benzene-containing analogues 179-180, affording a slightly higher yield (41% instead of 27% and 31%, respectively), similar d. e. (15% instead 11% 12%) (entry 5) of and and yet again zero e. e. . Proline derived system 195 proved more efficient in irreversibly binding to the metal since no product formation could be detected when this macrocycle was used as ligand (entry 6).

150 Entry Macrocycle Pr (OTf )3 Ligand Yield synl e. e.

used as (mo 1 %) MM anti M

ligand (d. e. %)

r 1 "r, 20 24 48 16 0

158

MeO0C

NBn 2 BnN 20 24 31 12 0

,c HN

me00c

180

rN J_ý B,n ýc- HN 0

0 NH ýI B. 3NJ: 20 24 27 11 0

179

LNH ýN HN 4 20 24 coome

178

N NH N, Bn Bn Bn HN ' 5 NB N 20 24 41 15 0 0 194

PNH

Bn 20 24 c) N

195

151 Entry Macrocycle Pr(OTf)3 Ligand Yield synl e. e. used as (Mol %) M M anti (%) ligand (d. e. %)

7 12 24

158

Table 2 (continued). Screening of the chiral macrocycles in the RE-catalysed Mukaiyama aldol reaction.

These results gave a tentative picture of the role that the chiral macrocycles were playing during the catalytic cycle.

It was reasoned that a significant percentage of the metal was being strongly held by the ligand and therefore was unable to take part in the catalytic pathway, whereas the remaining "free" metal could still catalyse the racemic formation of the product. This hypothesis was strengthened by the result obtained in the last run, where macrocycle 158 was used in a 2/1 ratio to the metal (entry ý): in this case no product was detected, thus confirming that with this ligand/metal stoichiometry the macrocycle completely removed the Lewis acid from the catalytic cycle.

152 4.5.3 Assessment of the nature of the interaction between

the ligand and the metal

In light of the results obtained during the catalytic screening, the question regarding the nature of the interaction between the metal and the macrocycles needed to be addressed. Proline derived compound 158 was chosen for a complexation experiment with Pr(OTf)3 due to its crystalline nature, which would hopefully be maintained upon complexation with a metal. Unfortunately, X-ray quality material could not be obtained from crystallisation of the solid isolated after refluxing 158 with Pr(OTf)3 in ethanol, which is in agreement with the reported low quality of the crystals obtained from pyridine-containing [170b] macrocycle 200 and Pr(OTf)3- The complexation

experiment was then modified to involve heating an ethanol

solution of macrocycle 158 and Pr(N03)3 (Scheme 81), which

also had proven capable of catalysing the asymmetric

Mukaiyama aldol reaction when used together with Kobayashi"s 200 (Scheme 78) [170b The macrocycle . solution obtained was allowed to stand at 5 OC under ethanol vapour

to give single-crystal material whose structure was determined by X-ray diffraction (Figure 38).

Xp N

I Pr(N03)3o6H20 (1.5 eq. ) 0: "r NH (C3oH38N402)2[Pr(NO3)61(NO3) 93H20 HN EtOH/H20 (100/1) 80 OC until dissolution 204 then 5 OC

N Yield = 63% 158

Scheme 81. Synthesis of complex 204.

153 0(5W,'

0(8')

0(251 If

Figure 38. The molecular structure of praseodymium complex 204.

The asymmetric unit contains a Pr (N03) 6 trianion sandwiched between two unique macrocyclic dications. The praseodymium

hexanitrate trianion is involved in two hydrogen bonds with

the "upper" macrocycle and two with the "lower" macrocycle.

In particular it is of note that the nitrate oxygen involved in the hydrogen bonds is the one directly bound to

the Pr cation [0(46), 0(49), 0(56) and 0 (4 3) ]. In both

macrocycles the nitrogen atoms of the proline rings have

been protonated during the complexation react-ion, which

results in one of the amide oxygens in each macrocycle

[0(25) and 0(25')] being involved in an internal hydrogen

bond with this protonated nitrogen [N(18) and N(18')]. This

is the main cause for the change of relative orientation of

the two carbonyl oxygen atoms within each macrocycle if

compared with the structure of compound 158 (See Figure 31,

section 4.2.2). For each macrocycle, the other protonated nitrogen [N(1) and N(1')] is instead involved in a hydrogen

154 bond to the nitrate oxygen, leaving the remaining amide oxygens [0(8) and 0(8')] uncoordinated.

The reason for the formation of "sandwich" complex 204 instead of a host-guest complex where the metal is

accommodated in the cavity of the macrocycle has been

tentatively ascribed to the high thermodynamic stability of

the Pr (N03) 6 trianion. This crystalline species is

presumably the first to precipitate during the

crystallisation process, driving the organization of the

remaining species present in solution (e. g. macrocycle 158

and water) around itself and the formation of the observed

sandwich complex.

Although this result does not give any indication of the type of interactions involving 158 and Pr during the

attempted asymmetric aldol reaction described above (which

was carried out using a different source of metal), it is

nonetheless interesting insomuch as it reinforces the idea

that hydrogen bonding is the main force responsible for the

intermolecular interactions of the synthetic macrocycles

obtained in this study.

155 4.6 Summary and outlook

A versatile synthesis of two new classes of non-racemic macrocycles has been developed employing standard chemistry

to achieve highly functionalised and diverse systems (Sections 4 4.3). The facile .2 and synthetic route developed for benzene-containing macrocycles 158,178,179

and 180 was successfully adapted to the synthesis of pyrrole-containing systems 194 and 195, designed to maximise the potential of these receptors towards a range (See Chapter 3) The difficulties of applications . many encountered in attempts to remove the benzyl group from the

pyrrole nitrogen suggest that the use of an easier to

remove protecting group is required. This minor

modification to the synthetic strategy developed in this

study would allow the synthesis of highly functionalised

systems containing up to six "free"' nitrogen atoms, whose

potential can be exploited in many different areas.

The structures of macrocycles 158 and 179 were elucidated

by X-ray diffraction (Sections 4.2.4 and 4.2.7). In

particular it was found that hydrogen bonds play an

important role in determining the intermolecular interactions between two independent molecules of macrocycle 158 in the solid state. This result was

considered a promising requisite for further applications

of these new classes of macrocycles in host-guest chemistry and asymmetric catalysis. Unfortunately, though, preliminary NMR host-guest complexation studies did not produce any evidence for interaction between some of the synthetic macrocycles and a range of small organic molecule (Section 4 2) .4 . .

Assay of these macrocycles as ligands in the Pr(OTf)3- catalysed Mukaiyama aldol reaction produced very low yields 156 of a racemic product (Section 4.5.2). This result was tentatively attributed to strong interaction between the ligand and the metal during the catalytic cycle. To assess the nature of this interaction some complexation reactions were carried out. Although it was not possible to obtain a complex with Pr (OTf) 3. the species used as Lewis acid in the catalytic assay, macrocycle 158 was shown to form a

"sandwich"-like complex with Pr (N03) 31 in which the praseodymium hexanitrate trianion and two macrocyclic dications are held together by hydrogen bonds.

These results suggest that an exploration of the interactions of the synthetic macrocycles with other

inorganic anions (e. g. phosphates, halides, nitrates,

carbonates) or organic anions (e. g. carboxylates) may be a

very promising area.

157 Chapter 5

Experimental

158 5.1 General experimental

All reactions and manipulations involving organometallic compounds were performed under an inert atmosphere of dry nitrogen, using standard vacuum line and Schlenk tube (177a] techniques. Reactions and operations involving

(arene)tricarbonylchromium(O) complexes were protected from light. THF was distilled from sodium benzophenone ketyl.

Dichloromethane was distilled from calcium hydride. Acetone was distilled from activated potassium carbonate and stored over 3A0 molecular sieves. Triethylamine was distilled from

calcium hydride and stored over 3A molecular sieves. The

concentration of nBuLi was determined by titration against [177bI diphenylacetic acid in THF. All remaining chemicals

were used as received from commercial sources.

Flash column chromatography was performed using Merck

silica gel 60 (230-400 mesh) Analytical TLC was carried

out on Merck 60 F245 aluminium backed silica gel plates

using UV light (254 nm) as visualizing agent and/or

vanillin or potassium permanganate and heat as developing

agents.

Optical rotations were recorded on a Perkin Elmer 343 polarimeter using a1 dm path length. Concentrations (given in dL-1) temperatures are indicated g , and solvents used for each case.

Melting points were recorded in open capillaries on a Btichi

510 melting point apparatus, and are uncorrected.

TR snectra were recorded on a Perkin Elmer 1600 FT-IR KBr spectrometer,, neat (unless otherwise stated) using plates.

159 NMR spectra were recorded at room temperature on a BrUker

AC 300F. AM 360,, DRX 400, AM 500 or DRX 500 instrument at room temperature unless otherwise stated. Chemical shifts are reported in ppm relative to the residual undeuterated solvent as an internal reference. The following abbreviations are used to define the multiplicities: s=

singlet, d= doublet, t= triplet, q= quartet, m= multiplet, dd = doublet of doublets, bs = broad singlet, dt

= doublet of triplets, td = triplet of doublets. The carbons have been assigned with the aid of DEPT and 1H/13C

correlation (HETCOR) experiments wherever necessary. For

the sake of clarity in the assignment of the NMR spectra,,

the carbons of the paracyclophane products in Chapter 2 are

numbered as shown in Figure 39.

13 12 16 17 11 15 12 10 11 14 15 16 14 13 87 2S 9 8 Zý 777 10 69 934 4556 Cr(CO)3 Cr(CO)3

Figure 39. Numbering for the interpretation of the NMR

spectra of compounds in Chapter 2.

The carbons of the arene ring of the aldehydes through to

the macrocyclic products in Chapter 4 are numbered as shown in Figure 40.

22 143 33

66 5 ff\1W

Figure 40. Numbering for the arene rings in Chapter 4.

160 The arene rings are indicated as shown in Figure 41

depending on their substitution pattern.

Ar Ph Arcr(CO)3 HetAr N Cr(CU)3

Figure 41. Abbreviations used for aromatic rings throughout the manuscript.

The symbol ""Ar" has been used whenever it was not possible

to unambiguously assign a specific NMR signal to a substituted (Ar) or to an unsubstituted (Ph) arene ring.

Mass spectra were recorded on JEOL AX 505W and Kratos MS890MS spectrometers at King's College London and Micromass Platform II and Micromass AutoSpec-Q at Imperial College London. Elemental analyses were performed by the

University of North London microanalytical service.

Analytical HPLC was performed using a Unicam Crystal 200

pump,, a Unicam Spectra 100 UV-Vis detector and a 25 cm x 0.46 cm Chiralcel AD and AS columns purchased from Daicel Chemical Industries Ltd.

The order of experiments of Chapter 4 has been chosen in order to first show the synthesis of the building blocks for the synthesis of alkene precursors 160,162,168 and

169, then the synthesis of alkene precursors 188 and 193 and to ultimately illustrate a convergent synthesis.

161 5.2 Experimental of Chapter 2

Tricarbonyl([2.2]paracyclophane)chromium(O) 38 (391

I Cr(CO)3

A suspension of hexacarbonylchromium(O) (2.11 g, 9.60 mmol)

and [2.21paracyclophane (2.00 g, 9.60 mmol) in dry di-n-

butyl ether (57 mL) and dry THF (5.5 mL) was thoroughly

saturated with nitrogen, before being heated to 135 'C and

maintained under a slight nitrogen overpressure (ca. 50

mbar). After 48 h the deep yellow reaction mixture was

allowed to cool to room temperature and the solvent was

removed in vacuo. Crystallization of the crude yellow solid

from nitrogen saturated DCM/hexane afforded 38 (2.63 g,

80%) as yellow crystals which were protected from light

upon storage. Rf = 0.24 (Si02; hexane/DCM 5: 5); m. p. (dec. [391 p. ) 184-186 'C [lit. M. P. (dec. p. ) 188 'C]; IR (DCM):

19 50 [Cr (C=O) 1887 [Cr (C=O) 1H NMR (360 -Vma,, = 31 f 31 CM-1; MHz, CDC13) : 2.79-2.83 (m, 4H; ArCH2CH2Arcr(CO)3), 3.20-3.25 (m, 4H; ArCH2CH2ArCr(CO)3), 4.67 (s, 4H; Arcr(CO)3H), 6.81 (s, 13 4H; ArH) ppm; C NMR (90 MHz, CDC13) : 33.9 (ArCH2CH2Arcr(CO)3) 35.5 (ArCH2CH2Arcr(CO)3) 92.7 (HCArcr(CO)3) , , r 121.0 (CH2CArCr(CO)3) 133.9 (H CAr) 140.1 (CH2CAr) ppm; MS f r (EI) : m1z M: 344 (16) [M'] 288 (22) [M+ - 2COI 260 3COI 208 (15) [M+ Cr (CO) 104 (50) [M+ (100) [M+ - 31 r - I; HRMS (EI) for CjqHj6Cr03: Cr (CO) 3- CH2-C6H4-CH2r : calcd found 344.0514 [M+1 344.0505, -

162 N, NI-Bis[(R)-(+)-l-phenylethyl]-1,2-ethanediimine 71[421

A mixture of glyoxal (8.9 mL, 40% w/w in water, 78.0 mmol),

(R)-(+)-l-methylbenzylamine (20.6 mL, 160.0 mmol), formic acid (0.50 mL) and anhydrous MgS04 (40 g) in DCM (150 mL) was stirred for 20 min at room temperature. The suspension was filtered over celite and the residue washed with DCM

(50 mL). The filtrate was evaporated under reduced pressure

and the remaining brown oil was dissolved in hexane (150 mL), dried over anhydrous MgS04 for 3 h, filtered and

concentrated in vacuo to afford 71 (19.0 g, 92%) as an

orange oil. Rf = 0.28 (Si02; hexane/diethyl ether 9: 1);

25 in 1667 (C=N) 10ý1D +200 (c 0.02 DCM) IR: vmc, 1H cm-1; NMR (360 MHz, CDC13) 1.50 (d, J=6.6 Hz; 6H;

4.4 1 (q, H 2 H; PhC H (CH3) N) 6.9 7-7.2 9 (m, CH3) J=6.6 z, , 13C 1OH; PhH) 7.97 (s, 2H; N=CH) ppm; NMR (90 MHz, CDC13) :

6 =: 23.9 (CH3) 69.5 (PhCH (CH3) N) 127.6 (CPhH) 129.3 (CPhH) (CPhH) 14 8.0 (CPhCH) 16 1.2 (N=CH) ppm; MS 0,129.8 , (%) 265 (5) [M H+1 120 (3) [C6H5CH (CH3) N+] (FAB/+) : m1z : + r r 105 (100) C6H5CHN+) ; HRMS (FAB/+) calcd for C18H21N2: 265.1705, found 265.1702 [M + H+] .

163 (S, S) 2-Diphenyl-N, -1,, N' -bis- [ (R) - (+) -1-phenylethyl] -ethane- ý431 1r2 -dicamine 72

Ph Ph

NH HN-b'ý

Phenyl magnesium bromide (48.0 mL, 3M in diethyl ether,

144.0 mmol) was added via a syringe pump at -78 "C to a vigorously stirred solution of 71 (8.50 g, 32.0 mmol) in

dry diethyl ether (100 mL) over a period of 1 h. A white

precipitate formed immediately, and the mixture was allowed

to warm to room temperature over a period of 8h and then

stirred for further 2 h. The mixture was quenched with a

saturated aqueous solution of ammonium chloride (80 mL),

the organic layer separated and the aqueous layer extracted

with ethyl acetate (3 x 100 mL). The combined organic

layers were dried over anhydrous MgS04 and the solvent was

removed in vacuo. Purification of the remaining viscous

brown oil by flash column chromatography (Si02;

hexane/diethyl ether 9.5: 0.5) gave a pale yellow solid

which was crystallised from hexane/dichloromethane to

afford 72 (2.7 g, 20%) as a colourless crystalline solid.

Rf 0.21 (Si02; hexane/DCM 3. b: 6. b); m. p. i2U-J-212- -ýý

[431 25 0.0203 in (lit. M. p. 119-122 0c) ; [a] D = +208 (c

CHC13) (lit 431 [W 28 +205, c=0.7 in CHC13) IR (DCM) : -[ D 1; 1H 1.27 (d, vmax = 3317 (NH) cm- NMR (360 MHz, CDC13) : 6H; CH3) 2 (bs, 2H; NH) 3.3 8 (s, 2H; J=6.7 Hz, .26 , NHCHPh) 3.4 4 (q, J=6.7 Hz, 2H; PhCHCH3) 6.92-7 (m, , , .29 13 CDC13) 25.7 (CH3) 55.4 20H; PhH) PPM; C NMR (90 MHz, :6= f (NHCH(Ph)CH),. 66.1 (PhCH(CH3)N), 126.9 (CPhH)j 127.0 (CPhH),

127.1 (CPhH)f 128.2 (CPhH),, 128.3 (CPhH),, 128.7 (CPhH)f 142.0 (FAB/+) (%) 421 (58) [M + and 146.0 (CPhCH) ppm; MS : m1z :

164 H+l 210 (96) [M+/21 , ; HRMS (FAB/+) calcd for C30H33N2: 421.2644, found 421.2637 [M + H+] .

113 [ (R) -Di -1 -phenylethyl 4 (S) 5 (S) -diphenylimidazolidi ne 74

Ph ýPh

A solution of 72 (0.700 g, 1.62 mmol) in THF (15 mL) was

added dropwise to a stirred solution of formic acid (13.1

mL) and formaldehyde (13.1 mL, 37% w/w in water) in water

(15 mL) at 0 OC. The mixture was refluxed for 14 h, cooled

down to room temperature and quenched with aqueous NaOH 50%

in a water-ice bath. The aqueous layer was extracted with

diethyl ether (3 x 150 mL) and the combined organic layers dried MgS04 Evaporation the were over anhydrous . of solvent under reduced pressure afforded 74 (0.68 g, 94%) as a

colourless crystalline solid. Rf 0.52 (Si02; OC; 25 hexane/diethyl ether 9: 1); mp 135-138 [Cý] D =+ 40.1 (c

= 0.105 in DCM); IR (DCM): "Omax 2924,2854,1459,1377, 1H 1113 cm-1; NMR (360 MHz, CDC13) 5=1.04 (d, J=6.9 Hz,

6H; CH3)f 3.53 (s,. 2H; NCH2N), 3.68 (s, 2H; NHCH(Ph)CH),

3.73 (q, J=6.9 Hz, 2H; PhCHCH3) 07-7 23 (m, 20H; PhH) ,7 . . 13C NMR (90 MHz CDC13) 22.9 (CH3) 61.5 ppm; . :6 r (NHCH (Ph) CH) '70.9 (NCH2N) 75 (PhCH (CH3) N) 127 (CPhH) f .9 , .2 I 12 7.3 (CPhH) 12 8.0 (CPhH) 12 8.3 (CPhH) 12 8.4 (CPhH) 12 8.5 f , r f (CPhH) 14 2.6 14 3.6 (CPhCH) ppm; MS (E I) : m1z (%) :432 f and (32) [M+] HRMS (EI) : calcd for C31H32N2: 432.2565, found

432.2557 [M+] ; elemental analysis calcd (%) f or C3, H32N2

(432.25) C 86-11f H 7.41,, N 6.48; found: C 85.90, H 7.60,

N 6.42.

165 Tricarbonyl(4-methyl[2.2]paracyclophane)chromium(O) 70

Cr(CO)3

Procedure involving TMEDA as additive:

nBuLi (2.75 mL, 1.60 M in hexane, 4.41 mmol) and TMEDA

(0.66 mL, 4.41 mmol) were added dropwise to a stirred

solution of 38 (0.300 0.87 mmol) in dry THF (20 mL) at - 'C. 78 The solution was allowed to reach -40 'C. After 3 h, methyl iodide (1.10 mL. 17.4 mmol) was added in one portion

to the resulting deep red solution and stirring was continued for 3h before nitrogen saturated methanol (10

mL) was added at -78 'C and the solvent removed in vacuo. Purification of the yellow residue by flash column chromatography (Si02; hexane/DCM 5: 5) afforded 70 (0.245 g,

78%) as a yellow solid which was protected from light upon

storage. Rf = 0.24 (Si02; hexane/DCM 5: 5); m. p. (dec. p. )

194-196 'C; IR (DCM) 1947 [Cr(C'-ý ý0)3]r 1883 [Cr(C=0)31

1H (3 60 1.9 6 (s, 3H; CH3) 2.53- cm-1; NMR MHz. CDC13) ,

3.15 (m, 8 H; ArCH2CH2Arcr (CO)3 and ArCH2CH2Arcr (CO)3) 4.28 (d, J 1.6 Hz, 1H; Arcr (dd, J=1.6,6.8 Hz, 1H; = (CO)3H5) ,4 .48 Arcr 4.64 (d,, J=6.8 H 1H; Arcr 6.6 1 (dd, J (co) 3H'7) z,, (CO)3H8) f = 7.9,1.7 Hz, 1H; ArH), 6.73 (dd, J=7.9,1.7 Hz, IH; ArH) 6.8 0 (dd, J=7.9,1.7 Hz, 1H; ArH) 6.8 8 (dd, J= , , 7.9,1.7 Hz, 1H; ArH) ppm; 13C NMR (90 MHz, CDC13) :6= 20.5

(CH3), 31.9,33.6,34.2 and 35.3 (ArCH2CH2Arcr (CO)3 and ArCH2CH2Arcr(CO)3) 90.6 (HCArcr(CO)3) 95.2 (HCArcr(CO)3) 95.9 r Y f (HCArCr(CO)3) 119.0 (CH2CArCr(CO)3) 129.7 (H CAr) 133.4 (H CAr) r 1 r f 134 (HCAr) 134 (HCAr) 140.2 (CH2CAr) PPM; MS (EI) : MIZ .0 .4 r 166 (%) 358 (17) [M+1 302 (20) [M+ 2C01,274 : , - (100) [M+ - 3C01 259 (20) [M+ 3CO CH31 222 (5) [M+ (CO) ; , - - , - Cr 31 HRMS (EI) : calcd f C20Hj8Cr03: 358 0661, found 358.0665 Or . [M+] ; elemental analys is calcd (%) for C20Hj8Cr03 (358.06) :C 66.98, H 5.02; found: C 67.12, H 4.93.

Procedure involving (-) -sparteine as additive:

nBuLi (2.75 mL, 1.60 M in hexane, 4.41 mmol) and (-)- sparteine (1.00 mL, 4.41 mmol) were added dropwise to a stirred solution of 38 (0.300 g, 0.87 mmol) in dry THF (20 'C. 'C. mL) at -78 The solution was allowed to reach -40

After 6 h, methyl iodide (1.10 mL, 17.40 =ol) was added in one portion to the resulting deep red solution and stirring was continued for 14 h before nitrogen saturated methanol

(10 mL) was added and the solvent removed in vacuo.

Purification of the yellow residue by flash column chromatography (Si02; hexane/DCM 5: 5) afforded 70 (0.35 g,

25 0.0105 in 99%) as a yellow solid. [a] D =0 (c = DCM).

Procedure involving no additive:

nBuLi (1.38 mL, 1.60 M in hexane, 2.21 mmol) was added dropwise to a stirred solution of 38 (0.150 g, 0.44 mmol) 'C. in dry THF (10 mL) at -78 The solution was allowed to reach -40 'C. After 6 h, methyl iodide (0.54 mL, 8.80 mmol) was added in one portion to the resulting deep red solution and stirring was continued for 14 h before nitrogen OC saturated methanol (10 mL) was added at -ý8 and the solvent removed in vacuo. Purification of the yellow residue by flash column chromatography (Si02; hexane/dichloromethane 5: 5) afforded 0.19 g of an inseparable mixture of 70 and of the starting material 38 in 83: 17 ratio.

167 Tricarbonyl[4-(phenylhydroxymethyl)[2.2]paracyclophane] chromium(O) 76 and 77

5ý11 OH HO

Ph Ph Cr(, CO)3 Cr(CO)3

76 and 77

Procedure involving TMEDA as additive:

nBuLi (4.15 mL, 1.60 M in hexane, 6.63 mmol) and TMEDA

(0.99 mL, 6.63 mmol) were added dropwise to a stirred solution of 38 (0.457 g, 1.33 mmol) in dry THF (40 mL) at -

78 'C. The solution was allowed to reach -40 'C. After 6 h, benzaldehyde (2.70 mL, 26.5 =ol) was added in one portion to the resulting deep red solution and stirring was continued for 18 h at -78 'C before nitrogen saturated methanol (15 mL) was added and the solvent removed in vacuo. Purification of the yellow residue by flash column chromatography (Si02; hexane/diethyl ether 10: 0 to 6: 4) afforded 76 (0.30 g, 50%) as a yellow fluffy solid and 77

(0.29 g, 49%) as a yellow crystalline solid. Both of them were protected from light upon storage. Data for 76: Rf =

0.33 (Si02; hexane/diethyl ether 6: 4); m. p. 56-58 'C; IR

(DCM) (OH) 19 51[Cr (C=0) 1866 [Cr (C=0) : -vý, =3563 , 31 r 31 2.30 (bs, lH; OH) 2.57 cm-i ;1H NMR (4 00 MHz, CDC13) = , (M, 2H; 2 (bs, lH; ArCH2CHHArcr (CO)3) 2.72-2.79 ArCH2CHHArcr(C0)3) 3.02-3.10 (m, 2H; ArCH2CH2Arcr(C0)3) 3.21- , , 3.23 (m 2H; ArCH2CH2Arcr(co)3) 3.41 (bs, lH; ' t ArCH2CHHArcr(C0)3) 43 (bs, lH; Arcr(co)3H) 65-4 76 (m, 2H; ,4 . ,4 . . Arcr 5.58 (bs, IH; CHPh) 6.44-6.82 (m, 4H; ArH) (CO)3H) , , , 13 7.33-7.65 (m. 5H; PhH) PPM; C NMR (100 MHz, CDC13) :8 1-ýý

168 31.8,32.8,34 34.8 .6 and (Ar CH2CH2Arcr (CO) 3 and ( CArCr ArCH2CH2Arcr(CO)3) r 74 (CHPh) 92.8 (CO) 93.8 .1 , 3H) r ( cArCr(CO)3H) CArcr (CH2CArcr(CO)3) 94 (CO) 117.0 f .9( 3H) f f 127.0 ( CphH) 128.4 ( CPhH) 128 CPhH) 132.6 CArH) 132.8 , .7( r r (CArH) 132.9 CArH) 133 CArH) 139.4 14 0.7 CAr , , .6 , and (CH2 CPhCH) (C-E-: and ,234.9 0) ppm; MS (E I) : M/z (%) : 450 (55) [M+1 366 (15) (CO) [M+ - 3COI 314 (17) [M+ - Cr 31 HRMS C26H22CrO4: (EI) calcd for 450.0923, found 450.0936 [M+] ; elemental analysis calcd (%) for C26H22CrO4 (4 50.0 9) C 69.32, H 4.89; found: C 69.40, H 5.00.

(Si02; Data for 77: Rf = 0.19 hexane/diethyl ether 6: 4); m. p. 17 0- 17 2 'C (DCM) (OH) 19 46[Cr (Cz-rO) ;IR :=3390 f 31 r 1H 1874 [Cr(Cý0)3J cm-'; NMR (400 MHz CDC13) :8=2.05 (d, i=6.8 Hz, IH; OH) 9-2.4 4 (m, lli; ArCH2CHHArcr ,2 .3 (co) 3) r 2.60-2 63 (M, lH; ArCH2CHHArCr 2.70-2.72 (M, IH; . (CO)3) r ArCH2CHHArCr(CO)3) 98-3 02 (m, 2H; ArCH2CH2ArCr(CO)3) 3.14- ,2 . . , 3.22 (m 2H; ArCH2CH2Arcr 3.46-3.58 (m lH; ' (CO)3) r , ArCH2CHHArcr (d, J 1.4Hz1H; Arcr 4.45 (CO)3) ,4.12 =: (CO)3H5) (d, J=6.8 H 1 H; Arcr (dd, J=6.8,1.4 H z, (CO)3H8) ,4.71 Z, IH; Arcr(C0)3H7) 5- 50 (dr J=6.8 Hz. lH; CHPh) 6.36-6.80 , (m, 4H; ArH), 7.32-7.55 (m, SH; PhH) PPM; 13C NMR (100 MHz

CDC13): 8= 31.5,32.7,34.0 and 34.5 (ArCH2CH2ArCr(CO)3 and

ArCH2CH2ArCr(CO)3) 73.0 (CHPh) 92.7 ( C7ArCr 93.8 1 (CO)3H) f (C8ArCr 95.6 (C5ArCr 116.5 (CH2CArcr(co)3) 127.3 (CO)3H) r (CO)3H) r r (CPhH) 128.8 (CPhH) 128.9 (CPhH) 130.5 (CArH) 132.7 r f r (CArH) 133.2 (CArH) 133 (CArH) 13 9.3 13 9.6 (CH2CAr f .4 and and CPhCH), 234.6 (C=-0) ppm; MS (EI): mlz (%): 450 (10) [M+] 366 (50) [M"- 3C0) 314 (26) [M+ Cr (CO) HRMS , - , - 31 ; + (EI) : calcd for C26H22Cr04: 450.0923, found 450.0942 [M 1; elemental analysis calcd Mf or C26H22Cr04 (450.09): C

69.32f H 4.89; found: C 69.40, H 4.89.

169 Procedure involving (-) -sparteine as additive:

nBuLi (0.92 mL. 1.60 M in hexane, 1.45 mmol) and (-)-

sparteine (0.33 mL. 1.45 mmol) were added dropwise to a

stirred solution of 38 (0.100 gf 0.29 mmol) in dry THF (15 OC. ')C. mL) at -78 The solution was allowed to reach -40

After 4.5 h. benzaldehyde (0.59 mL, 5.80 mmol) was added in

one portion to the resulting deep red solution and stirring OC was continued for 14 h at -40 before nitrogen saturated 'C methanol (20 mL) was added at -78 and the solvent

removed in vacuo. Purification of the yellow residue by

flash column chromatography (Si02; hexane/diethyl ether

10: 0 to 6: 4) afforded 76 (0.064 g, 49%) as a yellow fluffy

solid and 77 (0.063 gf 48%) as a yellow crystalline solid.

Both of them were protected from light upon storage.

(531 2,11-Dithia[3.3]paracyclophane 78

An equimolar mixture of 1,4-benzenedimethanethiol 80 (0.700

g, 4.11 mmol) and a, al-dibromo-p-xylene 81 (1.08 g, 4.11

mmol) in ethanol (140 mL) was added dropwise at room

temperature to a stirred solution of KOH (0.460 g, 8.21

mmol) in ethanol (420 mL) over a period of 6 h. The

solution was stirred at room temperature for 14 h and the

solvent was removed in vacuo to afford a white solid which layer was dissolved in DCM (400 mL). The organic was washed MgS04- with water (3 x 80 mL) and dried over anhydrous

After evaporation of the solvent under reduced pressure, from the crude product was crystallised toluene to afford 170 78 (0.78 70%) gf as a colourless crystalline solid. Rf = 0.40 (Si02; hexane/diethyl ether 9.5: 0.5); m. p. 238-240 'C (lit. [53] M. P. 236-238 'C) ; IR (DCM) : -vma., = 2924f 2854f 1460,1377 1; 1H cm- NMR (360 MHz, CDC13) :6=3.74 (s, 8H;

ArCH2S) 6.7 9 (s,, 8H; 13 , ArH) PPM; C NMR (90 MHz, CDC13) :6 38 (ArCH2S) 129.9 (CphH) 135.9 (CPhCH2) .7 . r PPM; MS (EI) : m1z (%) :272 (10 0) [M+1 167 (15) [M+ CH2-C6H4-CH2] 136 (25) - f [M+/2] ; HRMS (EI) calcd for C16H16S2: 272.0693, f ound 272.0694 [W] .

2,11-Dioxo-2,11-dithia[3.3]paracyclophane 82

os so

2,11-Dithia[3.3]paracyclophane 78 (0.300 g, 1.10 mmol) was dissolved in acetic acid (50 mL) and CHC13 (15 mL) and the stirring solution was cooled to 10 'C. Hydrogen peroxide

(0.25 mL, 27.5% w/w in water, 2.20 mmol) was added dropwise and the solution was allowed to reach room temperature.

Stirring was continued for 40 h then aqueous NaOH 50% (50 mL) was added at 0 OC. The aqueous layer was extracted with

CHC13 (3 x 100 mL) and the combined organic layers were dried over anhydrous MgS04- Evaporation of the solvent under reduced pressure afforded 82 (0.289 g, 86%) as a colourless solid. Rf = 0.14 (Si02; acetone); m. p. 245-248

'C; 1150 (S-,:::::::: 1; 1H (360 MHz, IR (Nuiol): Vmax -:-- O) cm- NMR

CDC13,2: 1 mixture of diastereomers): 6=4.04 (d, J= 13.7

Hz,, 2.8H; ArCHHSO), 4.06 (d, J= 13. ý Hz, 1.2H; ArCHHSO),

4.43 (dr J= 13.7 Hz, 2.8H; ArCHHSO), 4.50 (d, J= 13.7 Hz, 13 1.2H; ArCHHSO), 6.97-7.01 (m, 8H; ArH) PPM; C NMR (90

171 MHz, CDC13, mixture of diastereomers) :6= 60 (ArCH2SO) .6 . 61.5 (ArCH2SO) 130.5 (CArCH2) 130 (CArH) 130 (CArH) , f .6 , .9 f NH 131.6 (CArH) 32 (CArH) MS (CI 3) : MIZ ,1 .4 ppm; f M: 32 2 NH4+1 (75) [M 305 (45) NH3) : + , [M + H-'] ; HRMS (CI, calcd for C16H1-702S2: 305.0670, found 305.0670 [M + H+1 ; elemental analysis calcd (%) for C16H1602S2 (304.06): C 63.12,, H 5.31; found: C 63.21, H 5.25.

2,2,11,11-Tetraoxo-2,11-dithia[3.3]paracyclophane 83 [521

02S S02

2,11-Dithia[3.3]paracyclophane 78 (0.390 q, 1.43 mmol) was

dissolved in chloroform (60 mL) and the stirring solution

was cooled to 0 OC. m-Chlo rope roxyben zo ic acid (1.37 g,

71.5 % w/w in water, 5.72 mmol) was added in one portion,

the solution was allowed to warm to room temperature and

stirring was continued for 48 h. The solid precipitated

during this lapse of time was collected by filtration and washed several times with chloroform, affording 83 (0.337 (521 g, 70%) as a colourless solid. M. p. 310-312 'C (lit. M. 1H p. >250 OC) ; IR (Nujol) : Vrnax 1113 (O=S=O) cm-1; NMR

(360 MHz, CF3COOD) 36 (s, 8H; S02CH2Ar) 07 (s, 8H; :6=4 . ,7 . 13 63.4 (S02CH2Ar) ArH) ppm; C NMR (90 MHz, CF3COOD) :6= , 130.0 (CArCH2) 132.6 (CArH) MS (EI) M: 336 (12) r ppm; : In1Z [M+] 208 (75) [M+ - 2SO21 104 (100) [M+ - 2SO2 - CH2-C6H4-

CH21 HRMS (EI) calcd for C16H1604S2: 336.049OF found

336.0502 [M+I.

172 Tricarbonyl(2,11-dithia[3.3]paracyclophane)chromium(O) 84 and bis-tricarbonyl(2,11-dithia[3.3]paracyclophane)chromium(O) [541 85

Cr(CO)3

Cr(CU)3 Cr(UO)3

84 85

A suspension of hexacarbonylchromium(O) (0.530 g, 2.42 mmol) and 2,11-dithia[3.3]paracyclophane 78 (0.600 g, 2.20 mmol) in dry di-n-butyl ether (60 mL) and dry THF (6 mL) was thoroughly saturated with nitrogen, before being heated

to 145 'C and maintained under a slight nitrogen

overpressure (ca. 50 mbar). After 18 h the deep yellow

reaction mixture was allowed to cool to room temperature

and the solvent was removed in vacuo. Purification of the

crude product by flash column chromatography (Si02; hexane/diethyl ether 10: 0 to 5: 5) afforded 84 (0.648 g,

72%) as a yellow crystalline solid and 85 (0.132 g, 11%) as a yellow crystalline solid. Both were protected from light upon storage. Data for 84: Rf = 0.34 (Si02; hexane/diethyl [541 ether 6: 4); m. p. (dec. p. ) 170-172 'C (lit. M. P. 170-

0)31 171 'C) IR (DCM) -vmx 1961 [Cr (C-=0) 31 f 1874 [Cr(C-= cm-1 1H NMR (300 MHzf CDC13): 3.36 Sf 4H; ArCH2SCH2ArCr(CO)3) 3.81 (s, 4H; ArCH2SCH2Arcr(CO)3), 4.93 (sf 13 Arcr(CO)3H) 4H; C NMR (75 MHz, 4H; , 7.04 (S' ArH) ppm; (ArCH2SCH2ArCr(CO)3) CDC13) : 36.8 1 37.9 (ArCH2SCH2ArCr(CO)3) r

CArcr CArcr (CO) 3) 13: 0.2 (HCAr) 136.7 92.6 (H (CO) 3)r 108.4 (CH2 r r (CH2 CAr) 233.6 (C-=O) MS (EI) MIZ M: 408 (5) [M+1 , ppM; : , 2COI 324 (30) [M+ 3COI 272 (100) [M+ 352 (3) [M+ - , - f -

173 Cr (CO) 31 ; HRMS (EI): calcd for C, 407 9946, found gH, 6Cro3S2: . 407 9954 [M+] . .

Data for 85: Rf 0.10 = (Si02; hexane/diethyl ether 6: 4) ; m.

p. (dec. p. 220-222 OC; IR (DCM) Vmax 1961 [Cr(C- : ý0) 31 t 1856 [Cr (C2--0) 1H 31 cm-'; NMR (400 MHz, DMSO-d6) : 3.68 (s, 8 H; SC 13 H2ArCr (CO)3) 5.67 (s, 8H; HCArCr(C0)3) PPM; C NMR (7 5

MHz, DMSO-d6) 35.6 (SCH2Arcr(co)3) 95.7 (HCArCr 112.2 r (CO)3) r (CH2CArCr(C0)3) 234 (C=-0) MS (EI) (%) , .8 ppm; mlz : 544 (10) [M+] 4 60 (3) [M+ 3C0] 408 (10) [M+ Cr (CO) 324 (100) - , 31 , [M+ Cr (CO) 372 (22) [M+ 2Cr (CO) 3 -3C01 , - 31 ; HRMS (EI) : calcd for 'C22H16Cr206S2: 543.9199, found 543.9216 [M+] .

Tricarbonyl(2-thia-10-thiomethyl[3.2]paracyclophane)

chromium(O) 87

CH3 s ,,, Cr(CO)3

Procedure involving diamine 89

nBuLi (0.98 mL, 2.50 M in hexane, 2.45 mmol) was added dropwise to a stirred solution of Aý, N2-dibenzylethane-1,2- diamine 89 (0.29 mL, 1.22 mmol) in dry THF (10 mL) at -78 'C. The solution was allowed to reach room temperature and to stir for 10 min, then it was re-cooled back to -78 OC. A pre-cooled solution of complex 84 (O. SOO g, 1.22 mmol) in dry THF (25 mL) was added dropwise via a cannula, the resulting solution was allowed to reach room temperature and to stir further. After 3 h, methyl iodide (1.50 mL, ias added in one portion at room temperature to

174 the resulting deep orange solution and stirring was continued for 18 h before nitrogen saturated methanol (10 mL) was added and the solvent removed in vacuo.

Purification of the yellow residue by flash column

chromatography (Si02; hexane/DCM 10: 0 to 5: 5) afforded 87

(0.100 g, 21%) as a yellow solid which was protected from

light upon storage. Rf = 0.41 (Si02; hexane/DCM 4: 6); m. p.

162-164 'C; IR (DCM): '0max = 1957 [Cr(C-0)31,1871 [Cr(C-=0)31 1H cm-1; NMR (500 MHz, CDC13) 2.16 (s, 3H; CH3), 2.23

(dd, J= 13.7,6.2 Hz1H; ArCHHCHArcr (CO)3) 3.2 4 (dd, J= 13.7,9.8 H 1 H; ArCHHCHArcr 3.4 1 (d, J 14 Hz, z, (CO)3) , .5 1H; ArCH2SCHHArcr(CO)3) 3.45 (d, 1 14.5 Hz, 1H; r ArCH2SCHHArCr(CO)3) 3.87 (d, 1 15.3 Hz, 1H; r 3.94 (d, 1 15.3 Hz, 1H; ArCHHSCH2Arcr(CO)3) f ArCHHSCH2Arcr (dd, J=9.8,6.2 H 1 H; ArCH2CH (CO)3) ,427 z, 6.7,1.5 Hz, 1H; Ar-lr(CO)3H) 4.64 Arcr (CO)3) 4.57 (dd, 1 , (dd, J=6.7,1 Hz 1H; Arcr (dd, J=6.7,1 .5 (CO)3H) r4.85 .5 1H; ArCr H) 89 (dd, 1 6.7,1.5 Hz, 1H; Hz, (CO)3 ,4 . 13 ArCr(CO)3H) 6.74-7.29 (m, 4 H; H CAr) PPM; C NMR (125 MHz,

16.0 (CH3) 36.5,36.8 37.6 CDC13) :8- r and (SCH3) Arcr(CO)3) (ArCH2SCH2ArCr(CO)3,, ArCH2SCH2ArCr(CO)3 and ArCH2CH i 51.1 (CHSCH3) 90.7 (HCArcr(CO)3) 90-9 (HCArcr(CO)3) 91.8 , f r (HCArCr(CO)3) 93.6 (H CArCr(CO)3) 111.8 and 112.9 (SCH2CArCr 3 r 1 (CO) 129.8 (HCAr) 130.2 (HCAr) 131.3 (HCAr) and CH2CHCArCr(CO)3) r f r , 133.1 (HCAr) 138 139.0 (SCH2CAr and CHCH2CAr) 233 f .3 and .9 366 (20) [M+ (C=-O) ppm; MS (EI) m1z (%) : 422 (17) [M'] -

2CO] 338 (80) [M' 3COI 286 (86) [M' Cr (CO) 31 HRMS , - , 422 0102, f 422 0115 [M +I; (EI) : calcd f or C2oHl8CrO3S2: . ound . (422.01) C elemental analysis calcd Mf or C20Hj8CrO3S2 56.87f H 4.26; found: C 57.18, H 4.10.

175 Procedure involving chiral diamine 72

nBuLi (0.22 mL, 2.50 M in hexane, 0.54 mmol) was added dropwise to a stirred solution of (S, S)-1,2-diphenyl-AT, AT'- bis-[(R)-(+)-l-phenylethyll-ethane-1,2-diamine 72 (0.113 g, 0.27 in OC. mmol) dry THF (5 mL) at -78 The solution was allowed to reach room temperature and to stir for 10 min, it OC. then was re-cooled back to -78 A pre-cooled solution of heat-gun dried lithium chloride (0.010 g, 0.25 mmol) in dry THF (5 mL) was added in one portion via a cannula followed by a solution of complex 84 (0.100 g, 0.25 mmol) in dry THF (7 mL). After 3.5 h, methyl iodide (0.30 mL, 4.9 'C mmol) was added in one portion at -78 to the resulting deep orange solution and stirring was continued for 16 h before nitrogen saturated methanol (10 mL) was added and the solvent removed in vacuo. Purification of the yellow residue by flash column chromatography (Si02; hexane/dichloromethane 10: 0 to 5: 5) afforded 87 (0.072 g,

70%) as a yellow solid which was protected from light upon storage. The enantiomeric excess was determined by HPLC analysis (Daicel Chiralpack AS, hexane/iPrOH = 92/8, flow rate = 0.6 mL/min, 330 nm); first eluted enantiomer: tR

49.65 min, second eluted enantiomer: tR = 61.00 min: 0% ee.

176 2,5,8,17,20,23-Hexaoxa[9.9]paracyclophane go [ 631

ý_o OJ

A solution of diethylene glycol 91 (5.0 mL, 52.7 mmol) in

toluene (350 mL) was stirred at 60 'C for Ih with tBuOK

(12.4 g, 110.0 mmol) under dry nitrogen atmosphere.

Subsequently the nearly homogeneous solution was cooled to

room temperature and a solution of a, a'-dibromo-p-xylene

92 (13.9 g, 52.7 mmol) in toluene (120 mL) was added in one

portion. The resulting mixture was heated at 60 OC for 4h

and then cooled down to room temperature. The precipitate

formed was filtered, the filtrate was concentrated to a

small volume and the yellow oil residue was dissolved in

chloroform. Purification of the crude product by flash

column chromatography (Si02; hexane/diethyl ether 8: 2 to

5: 5 then acetone) afforded 90 (4.6 g, 21%) as a yellow

viscous oil. Rf = 0.57 (Si02; acetone) IR vmax 3479f 2861,2360,1716,1453,1421,1351,1120,1103,853,810

1; 1H cm- NMR (360 MHz, CDC13) :6=3.41-3.65 (m, 16H; 13C OCH2CH20), 4.48 (s. 8H; ArCH20), 7.23 (sr 8H; ArH) PPM;

69.8 (OCH2CH20) 7 1.1 (OCH2CH20) NMR (90 MHz, CDC13) :6= f 73.4 (ArCH20) 128.2 (CArH) 138 (CArCH20) MS (CI , .0 PPM; F NH3) : inlz (%) 434 (100) [M + NH4+1,417 (5) [M+] ; HRMS (CIr for C24H36NO6: 434.2543, found 434 2549 [M + NH3) : calcd . NH4+1 -

177 5.3 Experimental of Chapter 4

5.3.1 Experimental of Section 4.2 towards the synthesis of alkenes 160,162,168 and 169

(4-Iodophenyl)methanol 175 ý1423

175

To a solution of 4-iodobenzoic acid 174 (25.0 g, 100.0 mmol) in dry THF (200 mL) a 1.0 M solution of BH3-THF complex (200 mL) was added via a cannula over 20 min at room temperature under an inert atmosphere of nitrogen. The reaction mixture was left stirring at room temperature for

16 h and was then quenched with a2 A7 HC1 solution (500 mL). The organic product was extracted with dichloromethane

(2 x 500 mL), washed with saturated sodium hydrogencarbonate (2 x 400 mL), brine (2 x 300 mL), dried over anhydrous MgS04 and concentrated in vacuo to afford 175 (23.1 98%) Rf 0.21 (Si02; as a colourless solid g, . = [1421 hexane/diethyl ether 6: 4) ; m. p. 65-67 'C (, it. M. P. 1; IH 61-66 'C) ; IR (nujol) : 'Vmax = 3280 (OH) cm- NMR (3 00

MHz, CDC13) 46 (bs, IH; ArCH20H) 4.59 (S' 2H; :6=2 . , ArCH20H) 7.07 (d, J=8.1 Hz, 2H; ArH2,6) 7.67 (d, J=8.1

13 (75 CDC13) 63 Hz. 2H; ArH3,5) ppm; C NMR MHz, :6= -6 (ArCH20H), 92.1 (CArI)f 127.9 (CAr2,6H)F 136.7 (CAr3,5H)f 139.5

252 (9) [M NH4+1 (CArCH20H) ppm; MS (CI, NH3) MIO M + f

234 (100) [M+] ; HRMS (CIf NH3) : calcd for C-7H710: 233.9541, found 233.9553 [M+I.

178 4-Iodobenzaldehyde 166 [ 14 21

CHO

166

To a stirred suspension of pyridinium dichromate (25.8 g, 68.7 mmol) in dry DCM (150 mL), a solution of 175 (10.7 g,

45.8 mmol) in dry DCM (100 mL) was added via a cannula over

10 min at 0 'C under an inert atmosphere of nitrogen. The resulting mixture was allowed to reach room temperature and stirred for 14 h. Diethyl ether (250 mL) was added and the reaction mixture was filtered through a pad of celite (6 cm) over silica gel (10 cm) The filtrate was concentrated in vacuo to yield 166 as a colourless solid (9.9 g, 93%).

(Si02; Rf = 0.58 hexane/diethyl ether 6: 4) ; m. p. 72-74 'C [1423 (, it. M. p. 71-73 'C) ; IR (nujol) 'ý)max 1705 (C=O) cm-1; 1H NMR (300 MHz, CDC13) :8=7.60 (d,, J 8.1 Hz, 2H; ArH2,6) 7.92 (d, J=8.1 Hz, 2H; ArH3,5) 97 (s, 1H; CHO) , ,9- 13 CDC13): (CAII) ppm; C NMR (75 MHz,. 6= 103.4 1 131.2

(CAr2,6H),, 135.9 (CArCHO)f 138.8 (CAr3,5H),, 191.8 (CHO) ppm; MS

(CI, NH3) : MIZ (%) : 250 (4) [M + NH4+1 232 (100) [M+] ; HRMS

(CI, NH3): calcd for C7H5IO: 231.9385, found 231.9383 ýM+I-

General procedure for the reduction of aminoacids

To a suspension of LiAlH4 (7.30 g, 192.0 mmol) in dry THF

(150 mL) at 0 'C was carefully added the appropriate (128 The aminoacid (S) -proline or (S) -valine mmol) . mixture into 125 was refluxed for 16 h and after cooling was poured layer (7.5 mL of diethyl ether. To the ether water mL) was (7.5 added slowly, followed by 15% aqueous NaOH mL) and filtered the water (22.5 mL). The solution was and

179 precipitate was washed with diethyl ether. The organic

layers were combined and dried over anhydrous MgS04-

(S)-Prolinol 167 [1431

OH 167

Evaporation of the solvent afforded (S)-prolinol 167 (12.3

g, 95%) as a light yellow oil which was protected from

[ 20 light upon storage. (X] D +29.0 (c = 0.98 in C6H5CH3) [1431 20 (lit [ U- +31.0, in C6H5CH3) IR: 2914 . D = c=1 V,, a,. = 1H (NH and OH) cm-1; NMR (300 MHz, CDC13) : = 1.12-1.85 (m,

4H; NCHCH2CH2 NCHCH2CH2) 2.32-2.99 (m, 2H; NH OH) and and , 13 3.04-3.67 (m, 5H; NHCH2CH2. CH20H and NCH) PPM; C NMR (7 5

MHz,, CDC13) 25.9 (NCHCH2CH2) 27 NCHCH2 CH2) 4 6.6 :6= , .8( (NCH2CH2) 60.3 (NCHCH2) 64.9 (CH20H) ppm; MS (CI NH3) :

NH3) m1z (%) : 102 (100) [M + H+] ; HRMS (CI,, calcd for C5H12NO: 102.0919, found 102.0914 [M + H+1 .

[ 15 31 (S)-Valinol 173

OH H2N,ý

173

Evaporation of the solvent afforded (S)-valinol 173 (12.8 IOQD 20 (c 9.21 in g, 97%) as a light yellow oil. +20.0 = [1531 20 (lit 1 (1- 1D = 11.53 in CH3CH20H); CH3CH20H) . +17.0, c -1; 1H NMR (300 MHz, IR: -Vmax = 2501-3304 (NH and OH) cm 6H; 1.48-1.57 CDC13) :6=0.86 (d, J= 6.7 Hz, CH3CHCH3),

180 (m, 1H; CH3CHCH3) 9-2.55 (m, 1H; NCHCH2) 68 (bs, 3H; ,2 .4 ,2 . NH2 and OH) 3.23-3 30 (m, 1H; . CHHOH) 3.56-3.61 (m, 1H; 13 CHHOH) PPM; C NMR (7 5 MHz, CDC13) := 18.4 (CH3CHCH3) . 19.3 (CH3CHCH3) 31.1 (CH3CHCH3) 58 (NCHCH2) 64 (CH20H) , , .4 , .5 ppm; MS (CI, NH3) : MIZ (0-0) : 104 (100) [M + H+] ; HRMS (CI,,

NH3) : calcd for C5H14NO: 104.1075, found 104.1072 [M + H+l .

General procedure for reductive amination with 4-iodobenzaldehyde 166

To a solution of aldehyde 166 (60.0 mmol) in dry DCM (100 mL), the appropriate amino alcohol (S)-valinol 173 or (S)- prolinol 167 (90.0 mmol) and anhydrous magnesium sulfate

(6.00 g) were added. The mixture was stirred under a slight over pressure of nitrogen at room temperature for 18 h. The reaction mixture was then transferred upon filtration to another flask, the solution was concentrated in vacuo and the resulting residue was dissolved in dry methanol (100 mL) and cooled to 0 'C. Sodium borohydride (4.54 g, 120.0 mmol) was added cautiously and, when the addition was complete, the resulting mixture was allowed to reach room temperature and stirred for 24 h. The reaction mixture was quenched with distilled water (100 mL) and extracted with ethyl acetate (3 x 200 mL). The combined extracts were washed with brine (50 mL), dried over anhydrous MgS04 and concentrated in vacuo.

181 ((S)-I-(4-Iodobenzyl)pyrrolidin-2-yl)methanol 165 [140bi

1-ýI OH 165

Purification of the crude product by flash column chromatography (Si02; hexane/acetone 10: 0 to 2: 1) afforded 165 (11.5 84%) Rf 0.18 (Si02; as a pale yellow oil g, . == 20 hexane/acetone 8: 2); MD -36.5 (c 1.92 in DCM)

(lit. [140b] 1a1D 20 6, in DCM) IR: 3389 = -37 . c3 vmax = 1H (OH) cm-1; NMR (300 MHz, CDC13) :8=1.59-1.72 (m, 2H;

NCHCH2CH2) 1.74-1.96 (m, 2H; NCHCH2CH2) 2.16-2.25 (m, 1H; . , NCHCH2) 2.67 (bs, 1H; CH20H) 2.89 (m 2H; NCH2CH2CH2) , , . 3.2 5 (d, J 13.2 Hz, 1H; NCHRAr) 3.4 0 (d, J= 10.5 Hz, , IH; CHHOH) 3.5 9 (dd, J=2.5,10.5 Hz, 1H; CHHOH) 3.8 7 , , (d, J 13.2 Hz1H; NCHHAr) 7.0 2 (d, J=7.5 Hz, 2H; , ArH2,6) 7 68 (d, J=7 Hz, 2H; ArH3,5) 13C NMR (7 5 . .5 PPM; MHz, 23.5 (NCHCH2CH2) 27 (NCHCH2 CH2) CDC13) :6= , .7 r54.5 (NCH2CH2) 58.1 (ArCH2N) 62.1 (CH20H) 64 (N CH) 92.4 . , , .4 , (CArI) 130 (CAr2,6H) 137 (CAr3,5H) 139.1 (CArCH2) PPM; MS r .7 , .4 f 318 (100) [M H+] 192 (17) [M (CI, NH3) : InIZ : + , -I+H + H+] ; HRMS (CI NH3) calcd f or C12H17INO: 318.0354, f ound

318.0351 [M + H+].

182 (S)-2-(4-Iodobenzylamino)-3-methylbutan-l-ol 172a [140b]

I OH N'I H

172a

Purification of the crude product by flash column chromatography (Si02; hexane/ethyl acetate /triethylamine

7: 3: 0.5 to 6: 4: 0.5) afforded 172a as a pale yellow oil

(12.6 92%) Rf 0.16 (Si02; hexane/ethyl 9f . 20 acetate/triethylamine 5: 5: 0.5); [CC] D = +8.8 (c = 1.25 in

DCM) (, it [140b] I(XI 20 +11.8f in DCM) IR: . D = c=6 ; vmax = 1H 2957-3353 cm-1 (NH and OH) ; NMR (400 MHz, CDC13) :6=

0.87 (d, J=6.9 Hz, 3H; CH3CHCH3) 0.93 (d, J=6.9 Hz,

3H; CH3CHCH3) 1.78-1.88 (m, 1H; CH3CHCH3) 2.37-2.41 (m, , f 1H; NHCH) 3.34 (dd, J=7.0,10.6 Hz, 1H; CHHOH) 3.58 , , (ddf 10.6 Hz, IH; CHHOH) 3.66 (d, J= 13.2 Hz, J=4.1r , 1H; ArCHHNH) 3.7 3 (d, J= 13.2 Hz, 1H; ArCHHNH) 7.05 (d, , , J=8 Hz, 2H; ArH2,6) 7 60 (d, J=8 Hz, 2H; ArH3,5) .2 . .2 13C NMR (100 MHz,, CDC13) 18 (CH3CH CH3) 19 PPM; :6= .4 r -5 (CH3CHCH3) 28.7 (CH3CHCH3) 50.8 (Ar CH2NH) 60.5 (CH20H) , r 63.8 (NHCH) 92.4 (CArI) 130.1 (CAr2,6H) 137.5 (CAr3,5H) . , , 140.2 (CArCH2) PPM; MS (CI, NH3) M/Z (%) 320 (100) [M +

H+1 194 (25) [M H+] ; HRMS (CI. NH3) calcd f or , -I+H+ C12H19INO: 320.0511, found 320.0514 [M + H+]

183 (S)-2-(N-ý(4-Iodobenzyl)-N-benzylamino)-3-methylbutan-l-ol

172 [140b]

0H N ýPh

172

Benzyl bromide (4-2 mL, 35.4 mmol) was added in one portion

at room temperature to a stirred mixture of aminoalcohol 172a (7.52 23.6 K2CO3 (4.88 35.4 18- g, mmol) , g, mmol) and crown-6 (0.624 g, 2.36 mmol) in dry acetone (100 mL). The

resulting mixture was stirred at room temperature for 15 h

then the solvent was removed in vacuo. Purification of the

crude product by flash column chromatography (Si02;

hexane/ethyl acetate 10: 0 to 8: 2) afforded 172 as a clear

(6.28 65%) Rf 0.19 (Si02; hexane/ethyl oil g, . acetate 20 (C 1.63 in DCM) (lit. [140b] 8: 2); 1(1-] D -7.4

[a] 20 6, in DCM) IR: 3437 (OH) cm-1; D = -12 . c=0.7 ; Vmax =

1H NMR (4 00 MHz, CDC13) :8=0-89 (d, J 6.7 Hz, 3H;

CH3CHCH3) 1.13 (d, J=6.7 Hz, 3H; CH3CHCH3) 2.01-2.08 (m, , , 1 H; CH3CHCH3) 2.4 7-2.5 2 (m, 1 H; NHCH) 2.8 9 (b I H; OH) . , s, , 3.47 (dd, i=9.5f 10.5 Hz, 1H; CHHOH) 3.58 (m, 1H;

CHHOH) 3.65 (d, J 13.5 Hz, IH; ArChHN) 3.72 (d, J= , 13.5 Hz, 1H; ArCHHN), 3.79 (d, J 13.5 Hz,. 1H; ArCHHN),

13.5 1H; ArCHHN) 7.00 (d, J8.0 Hz, 2H; 3.83 (d, J= Hz, , ArH2,6) 7.2 5-7.3 4 (m,, 5H; NCH2PhH),, 7.61 (dr J=8.0 Hz, , 13C 620.2 (CH3) 2H; ArH3,5) PPM; NMR (100 MHz,. CDC13) f

22.7 (CH3), 27.6 (CH3CHCH3). 53.9 and 54.2 (NCH2Ar and

NCH2Ph) 59.3 (CH20H)f 64.9 (NCH), 92.5 (CAJ) 127.3 , f (NCH2CArH) 128.5 (NCH2CArH) 129.2 (NCH2CArH) 131.1 F f F ( CAr2,6H) 13 7.4( CAr3,5H) 139.6 and 139.7 (CArCH2 and CPhCH2) r F (%) 410 (100) [M H+1 378 (22) [M+ ppm; MS (CI,, NH3) : MIZ : + , (18) [M H+] HRMS (CIF NH3): calcd - CH20H] 284 -I+H+ ; found 410.0984 [M + H+] for C19H25INO: 410.0981, . 184 (S)-l-(4-Iodobenzyl)-2-(azidomethyl)pyrrolidine 164

164

DEAD (7-2 mL, 45.8 mmol) was added dropwise over a period

of 5 min to a stirred solution of triphenylphosphine (12.0

g, 45.8 mmol) in dry THF (60 mL) at 0 'C under an inert

atmosphere of nitrogen. The resulting solution was allowed

to reach room temperature and stirred for 10 min. A

solution of aminoalcohol 165 (9.69 g, 30.6 mmol) in THF (60

mL) was added quickly via a cannula, followed after 5 min

by diphenyl phosphorylazide (9.9 mL, 45.8 mmol). The

resulting mixture was stirred at room temperature for 24 hr

then distilled water (3.4 ml) was added and the stirring

was continued for a further hour. The solvent was removed

in vacuo and purification of the crude product by flash

column chromatography (Si02; hexane/ethyl acetate 10: 0 to 6: 4) 164 (5.96 57%) Rf afforded as a colourless oil g, . = 20 0.58 (Si02; hexane/acetone 8: 2); [a]D -_ 12.3 (c = 0.57 in 1H DCM) IR: 'Vmax = 2093 (N3) CM-1; NMR (400 MHz, CDC13,1: 1

mixture of rotamers): = 1.35-1.44 (m. 0.5 H; NCHCHHCH2)f 1.52-1.60 (m, 0.5 H; NCHCH2CHH), 1.69-1.81 (m, 2H; 1-5

NCHCH2CH2 and 0.5 NCHCHHCH2), 1.89-1.99 (m, 1H; NCHCHHCH2)i 2.12 (trJ=9.5 Hz, 1H; CHHN3) 2.17-2.24 (m, 1H; , 2.5 6-2.5 8 (m, 0.5H; NCHHCH2CH2) 2.7 4 8 (mf NCHHCH2CH2) , -2.7 (m, 0.5H; NCHHCH2CH2) 3.18 (dd, J 1H; NCHCH2) 2.92-2.96 , =: 4. lf 12 Hz,, 0.5H; CHHN3) 3.29 (dd, J=5.5,12 Hz, .4 , .4 0.5H; CHHN3) 3 (d, J 13.3 Hz, 0.5H; NCHHAr) 3.4 5 (s, .36 , 13.3 Hz,, 0.5H; NCHHAr) 7.05-7 10 1H; NCHRAr) 3.9 6 (d, J , . 13 (m, 2H; ArH2,6) 62-7 64 (m. 2H; ArH3,5) PPM; C NMR (10 0 ,7 . .

MHz, CDC13,, mixture of rotamers): 6= 23.1 and 23.2

185 (NCHCH2CH2) 28 and 29.4 (NCHCH2CH2) 52 9,54 5ý , .8 . .4 and .4 (CH2N3) , 52 and 54 (NCH2CH2) 57 1 and 63.3 (NCHCH2) .9 .4 . 58.7 and 62.2 (ArCH2N) 92.2 (CArI) 130.6 1 and 130.9 ( CAr2,6H) 13 7.3 CAr3,5H) 13 7.7 NH3) f r (CArCH2) PPM; MS (CI, : m1z (%) : 343 (100) [M + H+] 315 (10) [M N21 286 , - , (15) [M+ CH2N31 - 217 (58) [M -I+H+ H+] ; HRMS (CI, NH3) : calcd for C12H16IN4: 343.0419,. found 343.0407 [M + H+] ; elemental analysis calcd (%) f or C12H15IN4 (342 03) C 42 12, H4 42,, . . . N 16.37; found: C 42.27F H 4.30f N 16.56.

(S)-N-(4-Iodobenzyl)-l-azido-N-benzyl-3-methylbutan-2-amine

171

N3 N

171

DEAD (3.5 mL, 22.4 mmol) was added dropwise over a period

of 5 minutes to a stirred solution of triphenylphosphine

(5.88 g, 22.4 mmol) in dry THF (60 mL) at 0 'C under an

inert atmosphere of nitrogen. The resulting solution was

allowed to reach room temperature and stirred for 10 min. A

solution of aminoalcohol 172 (6.12 g, 15.0 mmol) in THF (60

mL) was added quickly via a cannula, followed after 5 min

by diphenyl phosphorylazide (4.8 mL, 22.4 mL). The

resulting mixture was stirred at room temperature for 24 hf

then distilled water (2.0 mL) was added and the stirring

was continued for a further hour. The solvent was removed

in vacuo and purification of the crude product by flash

column chromatography (Si02; hexane/ethyl acetate 1: 0 to

8 : 2) af f orded 171 as a colourless oil (S. 65 g, 87%) Rf =

2) 20 (c 0.73 (Si02; hexane/ethyl acetate 8 : ;[ (X D _ -26.7 = 1; 1H 0.59 in DCM) ; IR: Vmax = 2094 (N3) CM- NMR (400 MHz,

CDC13r 6: 1 mixture of rotamers) :8=0.7 6,, 0.8 8,, 0.8 9 and

186 1.01 (d x 4, J=6.6 Hz, 6H; CH3CHCH3) 1.68-1.73 , and 1.91- 1.9 9 (m 2,1H; x CH3CHCH3) 2 6-2.4 0 (m, 1H; CH2NCHCH2) .3 , 3.44-3.56 (m, 4H; CH2N3 and NCH2Ar) 3.80 (d, J= 14.0 Hz, 1H; ArCHHN) 3.8 4 (d, J= 14.0 Hz 1H; ArCHHN) 7.13 (d, , , , J =8.1 Hz, 2H; ArH2,6) 7.23-7.37 (m,. 5H; NCH2PhH) 7.63 (d, , J=8.1 Hz, 2H; ArH3,5) 13 PPM; C NMR (100 MHz,, CDC13,, mixture 6= of rotamers): 17.4f 19.9,20.2 and 21.1 (CH3CHCH3 4) x , 28.3 (CH3CHCH3). 49.3 (CH2N3)f 53.9 and 54.4 (ArCH2N and PhCH2N) 62.5 (CH2NCHCH2) 92.1 ( CAJ )f 127.0 (NCH2CPhH) , f 128.3 (NCH2CPhH) (NCH2CPhH) 130.8 (CAr2,6H) 137.3 1,128.9 r f (CAr3,5H) 13 9.5 and 13 9.6 (CA, CH2 and CPhCH2) MS (CI , PPM; f NH3) : MIZ (%) :435 (10 0) [M + H+] 407 (30) [M+ N21 378 , - , (22) [M+ CH2N31 309 (85) [M I+H+ H+1 281 (60) [M - r , - N2 -I+H+ H+] ; HRMS (CI NH3) : calcd for CjqH241N4: 435.1046, found 435.1046 [M + H+] ; elemental analysis calcd (%) for C19H23IN4 (434.10) C 52.54f H 5.34f N 12.90; found:

C 52.58f H 5.38f N 12.98.

((S)-I-(4-Iodobenzyl)pyrrolidin-2-yl)methanamine 163

NH2

163

Triphenylphosphine (9.05 g, 34.5 mmol) and distilled water

(3.1 mL, 172.0 mmol) were added in one portion to a stirred solution of azide 164 (5.90 g, 17.3 mmol) in THF (50 mL) at

room temperature. The resulting solution was heated up to

50 'C and stirred for 20 h. The solvent was removed in vacuo and purification of the crude product by flash column chromatography (Si02; ethyl acetate and then methanol/triethylamine 10: 0.5) afforded 163 as a colourless oil (4.25 g,, 78%). Rf = 0.49 (Si02; methanol/triethylamine

187 20 10: 0.5) ; [(X] D -26.7 (c = 0.56 in DCM) IR: 10max = 3350 1H (NH2) cm-1; NMR (400 MHz, CDC13r 1: 2 mixture of rotamers) :6=1.02-1.09 (m, 0.7H; NCHCHHCH2) 1.44 (s, 2H; , CH2NH2) 1.47-1.56 (m" 1H; NCHCH2CHH) 1.61-1.67 (m, 2 , , H; NCHCHHCH2 and NCHCH2CHH), 1.76-1.89 (m, 1H; 0.3 NCHCHHCH2 and 0.7 CHHNH2). 1.90-2.10 (m, 0.7H; NCHHCH2), 2.11-2.16

(m,, 0.3H; NCHHCH2CH2),, 2.52-2.54 (m. 1H; 0.3 NCHCH2 and 0.7 NCHHCH2) 2 65-2 74 (m. 1.3H; 1 CHHNH2 0.3 NChHCH2) , . . and . 2.80-2.89 (m, 1H; 0.7 NCHCH2 and 0.3 CHHNH2), 3.20 (d, J= 13.5 Hz, 0.3H; NCHHAr), 3.36 (d, J= 13.5 Hz, 0.7H;

NC.HHAr) 3.41 (d, J= 13.5 Hz, 0.7H; NCHHAr) 3.88 (d, J , , 13.5 Hz, 0.3H; NCHHAr) 7.03 (d, J=8.0 2H; , Hz ArH2,6) 13 7.59 (d, J=8.0 Hz, 2H; ArH3,5) PPM; C NMR (100 MHz,,

CDC13, 6= 23.0 23.6 (NCHCH2CH2) mixture of rotamers) and . 27 33.9 (NCHCH2CH2) 44 (CH2NH2), 47 (NCHCH2) .9 and .1 .9 . 53.5 54.5 (NCH2CH2) 58.4 62.5 (ArCH2N) 62.4 and , and , (CH2NH2). 92.2 (CAJ) 130.6 131.0 (CAr2,6H) 137 and .2 and 138 (CA 13 9.7 (CArCH2N) MS (CI NH3) , .3 r3,5H) f ppm; MIZ 0) 317 (100) [M H+] 191 (25) [M H+] HRMS (C I + f -I+H+ ; NH3) calcd for C12H18IN2: 317.0515, found 317.0508 [M + H+] elemental analysis calcd (%) for C12H17IN2 (316.04) C

45.58f H 3.42f N 8.86; found: C 45-64, H 5.41f N 8.80.

188 (S) -N2- (4-Iodobenzyl) -R2-benzyl-3-methylbutane-1,2-diamine 170

CNH2

ý, Ph

170

Triphenylphosphine (7.03 g, 26.8 mmol) and distilled water

(2.4 mL, 133.9 mmol) were added in one portion to a stirred

solution of azide 171 (5.82 gr 13.4 mmol) in THF (40 mL) at

room temperature. The resulting solution was heated up to

50 'C and stirred for 16 h. The solvent was removed in

vacuo and purification of the crude product by flash column

chromatography (Si02; hexane/ethyl acetate/triethylamine

7: 3: 0.5 to 0: 10: 0.5) afforded 170 as a colourless oil (4.65

g, 85%). Rf 0.19 (Si02; ethyl acetate/triethylamine

20 1.25 in 3400 10: 0.5); (X] D -16.8 (c = DCM) ; IR: Vinax = 1H (NH2) cm-1; NMR (400 MHz, CDC13) :6= 0-90 (d, J=6.8 1-01 (d, Hz, 3H; CH3CHCH3) 1.55 Hz, 3H; CH3CHCH3) J=6.8 , (bs, 2H; NH2) 2.02 (m, 1H; CH3CHCH3) 2.26 (m, 1H; , , CH2NCHCH2) 2.71 (m, 2 H; CH2NH2) 3.5 9-3.7 8 (m, 4 H; ArCH2N , 7.04 (d, J=8.0 Hz, 2H; Ar-H2,6) 7 23-7.32 (m,, and PhCH2N) . 13 SH; NCH2PhH) 7 60 (d, J=8.0 Hz,. 2H; ArH3,5) PPM; C NMR . 20.1 (CH3CHCH3) 22 (CH3CHCH3) 27 (100 MHz, CDC13) :6= , .4 , .4 (CH3CHCH3) 39.5 (CH2NH2) 53.9 54 (ArCH2N PhCH2N) . and .4 and , 92.1 (CArI) 126.9 (NCH2CPhH) 128.1 (NCH2CPhH) 128.3 r f f (NCH2CPhH) 130.9 (CAr2,6H) 137.2 CAr3,5H) 140.0 and 140.1 r r r [M (CA, CH2 and CPhCH2) PPM; MS (CI, NH3) MIZ (%) : 409 (100)

H+] 378 (30) [M+ CH2NH21 283 (98) [M H+] ; + , - , -I+H+ 409-1139 HRMS (CI,. NH3) : calcd for C19H261N2: 409.1141, found for C19H25IN2 [M + H+] ; elemental analysis calcd (%)

(408.11) C 55.89F H 6.17,, N 6.86; found: C 55.69, H 6.10,

N 6.75.

189 N-(((S)-I-(4-Iodobenzyl)pyrrolidin-2-yl)methyl)acrylamide

160

HN 0

160

Triethylamine (5.8 mL, 41.4 mmol) and DMAP (0.0065 g, 0.05 mmol) were added in one portion to a stirred solution of amine 163 (1.67 g, 5.3 mmol) in dry DCM (40 mL) at room temperature. The resulting solution was cooled down to 0 'C and a solution of acryloyl chloride (0.48 mL, 5.9 mmol) in dry DCM (20 mL) was added dropwise over a period of 40 min.

The reaction mixture was allowed to reach room temperature and stirred for 16 h. Distilled water (50 mL) was added and the mixture was stirred for a further 1 h, then the two layers were separated and the aqueous layer was extracted with DCM (3 x 200 mL). The combined organic extracts were dried over anhydrous MgS04 and the solvent was removed in vacuo. Purification of the crude product by flash column chromatography (Si02; hexane/ethyl acetate/triethylamine

6: 4: 0.5 to 3: 7: 0.5) afforded 160 as a colourless solid

(1.40 72%) Rf 0.37 (Si02; /triethylamine g, . = ethyl acetate 20 10: 0.5) ; m. p. 118-120 'C; [ (X]D = -25.8 (c = 0.89 in DCM); 1H IR (DCM) 1545 (C=C) 1654 (C=O) 3266 (N-H) Vinax ý--- , , Cm-1;

NMR (400 MHz, CDC13r 1: 1 mixture of rotamers) 6=1.47-

1.59 (m, 3.5H; 2 NCHCH2CHH and 1.5 NCHCHHCH2) 1-79-1.8 5

(m. 0.5H; NCHCHHCH2), 2.09-2.15 (m, 0.5H; CHHNHCO), 2.23

(m,, 1.5H; NCH2CH2CH2), 2.45 (m, 0.5H; NCH2CH2CH2), 2.66 (m,

0.5H; NCHCH2), 2.84 (m, 0.5H; C.HHNHCO) 3.10-3.16 (m, 0.5H;

CHHNHCO), 3.19 (d, J= 13.0 Hz, 0.5H; ArCHHN), 3.31 (d, J=

13.5 Hz, 0.5H; ArCHHN), 3.36 (d, J= 13.5 Hz, 0.5H;

ArCHHN), 3.50-3.56 (m,, 0.5H,, CHHNHCO),, 3.83 (d,, J 13.0

190 Hz, 0.5H; ArCHHN) 4.04 (bs, 0.5H, NCHCH2) S. 54 (td, , . J= 9.8,2 Hz, 1H; COCH=CHH, 6.10 (dd, .0 cis) , J=9.8,17.0 Hz, 1H; COCH=CH2) 6.19 (dt, J= 17.0, 2.0 Hz, 1H; COCH=CHH,, trans) 6.56 (m, 1H; 6.97-6.99 , NHCO),. (m, 2H; ArH2,6) lH . 7.53-7.56 (m. 2H; ArH3,5) ppm; NMR (500 MHz,

DMSO-d6,100'C, 1: 1 mixture of rotamers): 6= 1.23-1.30 (m,

0.5H; NCHCHHCH2). 1.47-1.59 (m, 1H; 0.5 NCHCHHCH2 and 0.5 NCHCH2Ch'H), 1.60-1.69 (m, 1.5H; NCHCH2CHH), 1.72-1.77 (m,

0.5H; NCHCHHCH2). 1.81-1.88 (m, 0.5H; NCHCHHCH2). 1.97 (dd,

i=8 8,10.6 Hz 0.5H; CHHNHCO) 2.08 (tdF 10.6f 3.1 . . , J =: H 1H; NCHHCH2CH2) 2.22 (dd,, J= 17.0, 8.0 0. SH; z,. , Hz, CHHNHCO), 2.55-2. S8 (mr 1H; NCHHCH2CH2) 2.68-2.74 (mr , 0.5H; NCHCH2) 2.80-2.84 (m, 0- SH; CHHNHCO) 3.08-3.13 (m, , , 0.5H; CHHNHCO) 1.35 (d, J= 13.5 Hz, 0. SH; ArCHHN) 3.4 4 , (s, 1H; ArCHHN) 3.81-3.8 6 (m, 0- SH; NCHCH2) 3.93 (d, J= , , 13.5 Hz, 0.5H; ArCHHN) 5.50-5.54 (2 dd, J= 10.3,1.9f 2.1 , Hz, 1H; NHCOCH=CHH, 6.03-6.08 (2 dd, J= 17 1,1.9, cis) , . 2.1 1 6.2 0-6.2 8 (2 dd,, J= 17.1, H z, H; NHCOCH=:CHHf t ran s) f 10.3 1H; 7.10 (d, 1H; ArH2,6) Hz, NHCOCH=CH2) J=8.0 Hz . , 1H; 7.50-7.53 (m, 1H; NHCO) 7.13 (d, J 8.0 Hz,, ArH2,6) f 7.62 (dr J8.0 Hz 1H; ArH3,5) 7.65 (d, J=8.0 Hz 1H; . . ArH3,5) ý)PM; 13C NMR (100 MHz,, CDC13) :6= 22.2 and 22.5 (NCHCH2 CH2) 2 9.0 (NCH CH2CH2) (CH2NHCO) ,28.0 and ,40.7 r45-1 (NCHCH2) 53.1 (NCH2CH2CH2) 54 (CH2NHCO) 57 (ArCH2N and . .0 r .7 62.0 92.1 (CAJ) 125.7 NCH2CH2CH2), (NCHCH2 and ArCH2N) , , (COCH=CH2) 130.4 130.6 (CAr2,6H) 130.8 and 131.0 f and F (COCH=CH2) 137.0 (CAr3,5H) 138.7 (CArCH2) 164 r 1,137 .6 and f .4 13C and 165.6 (NHCOCH=CH2) PPM; NMR (125 MHzr DMSO-d6r 21.8 22 (NCHCH2CH2) 100"C, mixture of rotamers) :6= and .8 r 29.1 and 29.2 (NCHCH2CH2),, 41.6 (CH2NHCO), 45.2 (NCHCH2)f 52.2 (NCH2CH2CH2) 52.9 (CH2NHCO) 56.9 (ArCH2N) 57 , , , .4 (CH2NHCO) 60 (ArCH2N) 62.2 (NCHCH2) 91.1 and 91.4 , -8 . CAr2,6H) (CArl) 123.6 (COCH= CH2) 13 0.2 and 13 0.3 ( 131.7 . f f (COCH=CH2) 136.2 136.3 (CAr3,5H) 137.9 and 139.3 r and f

191 ( CArCH2) 163.5 and 164.4 (NHCOCH==CH2) PPM; MS (CI, NH3) : (%) 371 (100) [M m1z + H+1 302 (5) [M - NHCOCHCH2 +H+ H+1 245 (80) [M NH3) - I+H+ H+] ; HRMS (CI,, calcd for C15H20IN20: 37 1.0 62 0, found 371.0603 [M + H+] elemental

analysis calcd (%) for C15H, gIN20 (3ý0.05) C 48.66,, H 5.17, N 7.57; f C 48 57f H 5.13f ound: . N 7.52.

Methyl 2-((((S)-l-(4-iodobenzyl)pyrrolidin-2-yl)methyl

amino)methyl)acrylate 162

'I,N

-COOMe

162

A solution of 2- (bromomethyl) acrylate (0.11 mL, 0.92 mmol)

in DMF (20 mL) was added dropwise over a period of 5h to a

stirred solution of amine 163 (0.379 g, 1.2 mmol) in DMF

(30 mL) at -40 'C in the presence Of K2CO3 (0.166 g, 1.2 mmol). The resulting solution was allowed to reach room temperature and to stir for 16 h, then the solvent was removed in vacuo. The crude was quenched with water (100 mL) and the aqueous layer was extracted with diethyl ether

(3 x 100 mL). The combined extracts were dried over anhydrous MgS04 and the solvent was removed in vacuo.

Purification of the crude product by flash column chromatography (Si02; hexane/ethyl acetate/triethylamine

10: 0: 0.5 to 7: 3: 0.5) afforded 162 as a colourless oil

(0.214 43%) Rf 0.17 (Si02; hexane/ethyl 9" . 20 acetate/triethylamine 7: 3: 0.5); IOCID = -20.4 (c = 0.39 in 1720 (C=: O), 1639 (C=C) 1; 1H NMR (400 DCM); IR: vmax --:-- cm- (m. 1H; NCHCHHCH2) 1.47-1.57 MHz,, CDC13) :6=1.17-1.24 . (m,, 1H; NCHCH2CHH) 1.60 (bs 1H; NH) 1.62-1.69 (m, 1H; , . , 192 NCHCH2Ch-H) 1.77-1.80 (m, 1H; NCHCHHCH2) 1.90-1.93 (m, 1H;

NCHCHHNH) 2.04-2.07 (m, 1H; NCHHCH2) 2 55-2.57 (m, 1H; . NCHHCH2) 2.61-2.69 (m, 1H; NCHCH2) 2.74-2.77 (m, 1H; , , NCHCHHNH) 3.4 2 (s, 2H; ArCHHN) 3.4 3 (d, J=0.7 2H; , , Hz, NHCH2C=CH2) 3.7 5 (s, 3H; COOCH3) 5.7 0 (d, J=1.3 1H; , , Hz, C=CHH trans COOCH3) 6.22 (d, J=1.3 Hz, 1H; C=CHH, , cis COOCH3) 7.04 (d, J 8.3Hz, 2H; ArH2,6) 7.60 (d, J= 8.3

Hz, 2H; ArH3,5) PPM; 13C NMR (100 MHz,, CDC13) :6= 23.5 (NCHCH2CH2) 30.8 (NCHCH2CH2) 47.6 (NHCH2C=CH2) 51.8 . (COOCH3) 53.3 (NCHCH2) 53.7 (NCH2CH2) 59.4 (NCHCH2NH) , , . 62.6 (ArCH2N) 92.2 (CArI) 125.8 (C=: CH2) 13 0.9( CAr2 , r , 6H) f 137.2 (CAr3,5H) 138 2 138 (CA, CH2 C=CH2) 167 . and .8 and f .1 415 (100) [M H+] 317 (COOCH3) PPM; MS (CI,, NH3) : InIZ (%) : + f (25) [M - CH2C (==CH2)COOMe +H+ H+] 289 (30) [M -I+ H+ H+] ; HRMS (CI, NH3) : calcd for C17H24IN202: 415.0882, f ound 415.0881 [M + H+]; elemental analysis calcd (%) for C17H23IN202 (414.08): C 49.29r H 5.60f N 6.76; found: C

49.29f H 5.76f N 6.74.

N-((S)-2-(N-(4-iodobenzyl)-N-benzylamino)-3-methylbutyl)

acrylamide 168

168

in Acryloyl chloride (0.16 mL, 1.9 mmol) was added slowly 170 (0.261 g, one portion to a stirred solution of amine in DIPEA 0.64 mmol) in dry DCM (15 mL) the presence of 'C. was (0.33 mL. 1.9 mmol) at 0 The resulting solution for 3.5 h. allowed to reach room temperature and stirred in of the The solvent was removed vacuo and purification flash (Si02; crude product by column chromatography 193 hexane/ethyl acetate/triethylamine 8: 2: 0.5 to 6: 4: 0.5) afforded 168 as a pale (0.257 87%) Rf yellow oil g, . = 0.24 (Si02; hexane/ethyl acetate/triethylamine 7: 3: 0.5);

[U] 20 (c 1.85 in DCM) IR: 15-50 (C=: C) D = -54 .1 = ; Vmax ý= r 1655 (C=O) 3289 (N-H) 1H NMR (400 , cm-1; MHz, CDC13) :6= 0.94 (d, J 6.6 Hz, 3H; CH3CHCH3) 05 (d, J=6.6 Hz, .1- 3H; CH3CHCH3) 2.04 (m 1H; CH3CHCH3) 2.41 (m 1H; , . CH2NCHCH2) 3.14-3.19 (m, 1H; CHHNHCO) 3.47-3.53 (m,, 1H; , CHHNHCO) 3.5 6 (d, J= 13.5 Hz 1H; ArCHHN) 3.62 (d,, J , 13.5 Hz, 1H; ArCHHN) 3.7 3 (d, J= 13.4 Hz, 2H; ArCH2N) , 5.58 (d, J= 10.1 Hz 1H; NHCOCH=CHH, 5.92 (dd, J . cis) , 17.0,10.1 Hz, 2H; NHCOCH=CH2 NHCO) 6.15 (d, J= 17.0 and , Hz, 1H; NHCOCH=CHH, trans) 6.94 (df J=8.0 Hz ArH2,6) , , , 7.17-7 31 (m, SH; NCH2PhH) 59 (d, J=8.0,, 2H; ArH3,5) . ,7 . 13 (100 CDC13) 20.1 (CH3CHCH3) 22 PPM; C NMR MHz, :6= , .3 (CH3CH CH3) (CH3 CHCH3) (CH2NHCO) 5 3.2 and 5 3.8 ,28.0 ,37.5 (Ar CH2N PhCH2N) 62.7 (NCHCH2) 92.3 (CAJ) 125.7 and , . 127.1 (NCH2CPhH) 128 (NCH2CPhH) 128.9 (COCH=CH2) 1 .4 137.3 (CAr3,5H) (NCH2CPhH) 130.9 (CAr2,6H and COCH=CH2) r 13 9.9 (CArCH2 CPhCH2) 165.1 (NHCOCH=CH2) MS (CI and f PPM; r 337 NH3) : 1n/Z (%) : 463 (100) [M + H+] 371 (5) [M+ - CH2Ph]

(25) [M I+H+ H+] ; HRMS (CI,, NH3) calcd for C22H28IN20:

4 63.12 46f ound 4 63.12 41 [M + H+1 elemental analysis calcd

(%) for C22H27IN20 (462.12) :C 57.15f H 5.89f N 6.06; found:

C 57.26f H 5.91f N 6.09.

194 Methyl 2-(((S)-2-(N-(4-iodobenzyl)-N-benzylamino)-3- methylbutylamino)methyl)acrylate 169

H N OMe N 0 Ph

169

NaI (0.017 g, 0.11 mmol), K2CO3 (0-153 g, 1.11 mmol) and

18-crown-6 (0.029 g, 0.11 mmol) were added in one portion to a stirred solution of amine 170 (0.454 g, 1.11 mmol) in

DMF (100 mL) at room temperature. The resulting mixture was

cooled down to -10 0C and a solution of 2-

(bromomethyl) acryl ate (0.13 mL, 1.11 mmol) in DMF (30 mL) was added dropwise over a period of 1 h. The reaction mixture was allowed to reach room temperature and to stir

for 16 h, then the solvent was removed in vacuo. The crude was quenched with water (100 mL) and the aqueous layer was extracted with diethyl ether (3 x 100 mL). The combined extracts were dried over anhydrous MgS04 and the solvent was removed in vacuo. Purification of the crude product by

flash column chromatography (Si02; hexane/ethyl acetate

10: 0 to 5: 5) afforded 169 as a colourless oil (0.228 g, 20 41%). Rf 0.11 (Si02; hexane/ethyl acetate 7: 3); 10ý]D =_ 1722 (C=O) 1633 (C=C) 28.5 (C 1.19 in DCM) ; IR: Vinax , cm- 1; 1H NMR (400 MHz,, CDC13,3: 1 mixture of rotamers) :6= 0.75H; CH3CHCH3) (d, J=6.7 H z, 0.83 (d, J=6.7 Hz. .0-91 0.75H; CH3CHCH3) 2.25 H; CH3CHCH3) 0.95 (d, J=6.7 Hz, . CH3CHCH3) 1.72 (bs, 1H; NH) 1.02 (d, J 6.7 Hz, 2.25 H; . , 1.98-2.07 (m, 0 75H; 1.81-1.84 0.25H; CH3CHCH3) . . CH3CHCH3) 2.4 6-2.52 (m, 1H; CH2NCHCH2) 2.5 9 (dd, J=3.6,

12.1 Hz, 1H; NCHCHHNH), 2.70 (dd, J 8.8,12.1 Hz, 1H;

NCHCHHNH), 3.28 (df J= 15.1 Hz, IH; ArCHHN), 3.34 (d, J=

15.1 Hz. 1H; ArCHHN), 3.54-3.76 (m, 4H; ArCH2N and 195 NHCH2C=CH2) 3.72 (S' 0.75H; COOCH3) 3.78 (S' , , 2.25H; COOC.H3) 5.66 (d, J=1.4 Hz, 0.75H; C=CHH, trans COOCH3) , r 5 85 (d, J=1.4 Hz, 0.25H; C=CHH, trans COOCH3) 6.25 (bs . f . 0.75H; C=CHH COOCH3) 6.29 (bs, 0.25H; cis , C=CHH, cis COOCH3) 03 (d, J=8 Hz, 2H; ArH2,6) 7 20-7 35 (m, 5H; ,7 . .2 . . NCH2PhH) 7 59 (d, J=8 Hz 2H; ArH3,5) 13 . .2 , PPM; C NMR (100 MHz, CDC13, mixture of rotamers) :6 == 20.1,20.6 and 22.3 (CH3CHCH3) 27-7 and 2 9.7 (CH3CHCH3) 4 6.9,4 7 47 .7 and .9 (NCHCH2NH) 50.2 (ArCH2N), 51.6 51.7 (COOCH3) 52.5, and f 54 and 54.4 (Ar CH2N NHCH2C=CH2) 59.9 63.0 .0 and , and (NCHCH2) 91.7 and 92.0 (CArI) 125.2 127.1 (C=CH2) . r and r 126.6 and 126.8 (NCH2CPhH) 128 and 128 (NCH2CPhH) 128 .0 .1 , .7 and 128 (NCH2CPhH) 130 and 130.9 (CAr2,6H) 136 .8 , .7 , .9 and 137 (CAr3,5H) 138.6,140.0,140.1 140.3 (CArCH2r .I , and CPhCH2 C=CH2) 166 167.2 (COOCH3) MS (CI, NH3) and r .9 and PPM; : MIZ (%) :507 (10 0) [M+ H+ ], 409 (3 0) [M- CH2C (=CH2) COOMe +H+

H+1 381 (40) [M H+] 289 (45) [M CH2C6H5 -I+H+ , -I- + H+] HRMS (CI, NH3) for C24H32IN202: 507 1509f found : calcd . 507.1516 [M + H+]; elemental analysis calcd M for C24H31IN202 (506.14): C 56.92, H 6.17r N 5.53; found: C

56.84F H 6.09f N 5.60.

196 5.3.2 Experimental of Section 4.3 towards the synthesis of alkenes 188 and 193

4-Iodo-IH-pyrrole-2-carbaldehyde 182 E1601

Ný'CHO H 182

[Bis (trif luoroacetoxy) iodo] benzene (5.79 g, 13.5 mmol) and iodine (3.42 g, 13.5 mmol) were added in one portion to a stirred solution of pyrrole 2-carbaldehyde 181 (2.46 g,

25.9 mmol) in CC14 (50 mL) at room temperature under an inert atmosphere of nitrogen. The resulting mixture was

stirred for 18 h. The reaction was quenched with a 0.1 M solution of Na2S203 (100 mL) and extracted with diethyl ether (3 x 100 mL) The combined extracts were dried over anhydrous MgS04 and concentrated in vacuo. Purification of the crude product by flash column chromatography (Si02; hexane/ethyl acetate 10: 0 to 8.5: 1.5) afforded 182 as a (3.09 54%) Rf 0.51 colourless crystalline solid g, . = 6: 4); 120-122 'C (, it [1601 (Si02; hexane/ethyl acetate m. p. . 1; 1H 00 M. P. 120 'C) ; IR (DCM) : 'Vmax = 1678 (C=O) cm- NMR (3

MHz, CDC13): 6=7.10 (d, J=1.5 Hz, 1H; HetArH3), 7.21

1H; HetArH5) 9.4 9 (s JH; CHO) 10.2 0 (bs (d, J=1.5 Hz , . r . 13 6= 63.0 (CHetArI) 1H; NH) PPM; C NMR (7 5 MHz, CDC13) t 134.1 (CHetArCHO) 127.6 and 131.2 ( CHetAr3H and CHetAr5H) 1 178.7 (CHO) MS (CI, NH3) M: 239 (45) [M + NH4+1 ppm; : -MIZ f [M NH4+1 96 (77) [M 222 (83) [M + H+1 113 (100) -I+ t -I for 221.9416f +H+ H+] ; HRMS (CI, NH3) calcd C5H51NO: (M H+j found 221.9422 + .

197 1-Benzyl-IH-pyrrole-2-carbaldehyde 183 [1621

F ýCHO N ) Ph

183

Pyrrole 2-carbaldehyde 181 (5.00 g, 52.6 mmol) was added cautiously in one portion to a stirred suspension of sodium hydride (60% in mineral oil) (2.31 g, 57.8 mmol), previously washed three times with hexane, in dry DMF (40 mL) at 0 'C under an inert atmosphere of nitrogen. The resulting mixture was allowed to reach room temperature,, stirred for 30 min and then recooled back to 0 'C. A solution of benzyl bromide (6.3 mL, 52.6 mmol) in dry DMF

(20 mL) was added dropwise over a period of 5 min. The resulting solution was stirred at 0 'C for 50 min, then it was allowed to reach room temperature and stirred for 30 min. The reaction mixture was quenched with distilled water (50 DCM (3 250 The mL) and extracted with x mL) . combined extracts were dried over anhydrous MgS04 and concentrated in vacuo. Purification of the crude product by flash column chromatography (Si02; hexane/ethyl acetate 1: 0 to

9: 1) afforded 183 as a pale pink oil (9.5 g, 97%) Rf =

0.41 (Si02; hexane/ethyl acetate 8 : 2) ; IR: Vmax :ýý 1660 (C=O)

(s, 2H; NCH2Ph) cm-1 ;1H NMR (300 MHz, CDC13) :6=5.58 , 6.28 Hz, 1H; HetArH4) 6.99 (df J=3.5 Hz, 2H; (d, J=3.5 , (m, 5H; NCH2PhH) 9.57 (s HetArH3 and HetArHs) 7.14-7.35 , f 13 (7 5 MHz,. CDC13) (NCH2Ph) 1 H; CHO) PPM; C NMR :6= -51 -9 110.2 ( CHetAr4H) 124.9 ( CHetArH) 127.3 (CPhH) 127 (CPhH) f r f .7 128.7 (CPhH) 131.5 (CHetArH) 137.6 (CPhCH2N) 179.6 (CHO) f f f 186 (100) ppm; MS (CI, NH3) : InIZ (%) : 203 (75) [M + NH4+1

[M H+] 156 (10) [M+ CHO] ; HRMS (CI,, NH3) calcd for + f - found 186.0918 [M + H+] C12H12NO: 186.0918, .

198 I-Benzyl-4-iodo-lH-pyrrole-2-carbaldehyde 184

NýýCHO ) Ph 184

[Bis (trifluoroacetoxy) iodo] benzene (22.5 g, 52.4 mmol) and iodine (12.3 ýg, 52.4 mmol) were added in one portion to a stirred solution of 183 (19.4 g, 104.8 mmol) in CC14 (100 mL) at room temperature under an inert atmosphere of nitrogen. The resulting mixture was stirred for 18 h. The reaction was quenched with a 0.1 M solution of Na2S203 (200 diethyl (3 300 The mL) and extracted with ether x mL) . combined extracts were dried over anhydrous MgS04 and concentrated in vacuo. Purification of the crude product by

(Si02; flash column chromatography hexane/ethyl acetate 10: 0 to 7: 3) afforded 184 as a colourless crystalline solid (20.2 62%) Rf 0.47 (Si02; hexane/ethyl 8: 2); g, . = acetate 1H m. p. 79-81 'C; IR (DCM) : -vmx = 1664 (C=O) cm-1; NMR (400

MHz, CDC13) :6 == 5.53 (S' 2H; NCH2Ph), 6.98 (bs, 1H; HetArH3) 04 (d, J=1.5 Hz 1H; HetArH5) 7 13-7.35 (m, ,7 . . . 13 5H; NCH2PhH) 9.51 (s. 1H; CHO) C NMR (100 MHz, , ppm; CDC13) :6= 52 1 (NCH2Ph) 61.1 (CHetArI) 127.5 (NCH2CPhH) , r r 128.1 (NCH2CPhH) 128.8 (NCH2CPhH) 130.7 (CHetAr5H) 135.3 f r f (CHetAr3H) 133 13 6.7 (CHetArCHO CPhCH2) 17 8 (CHO) r .2 and and r .7 NH3) : MIZ 329 (95) [M NH4+1 312 (85) [M ppm; MS (CI, M: + , H+] 203 (100) [M NH4+1 186 (100) [M H+] ; + , -I+ -I+H+ ( CI NH3) f HRMS IF calcd for C12H11INO: 311.9885, ound

311.9881 [M + H+] elemental analysis calcd (%) for

C12HjoINO (310.98) :C 46.33, H 3.24f N 4.50; found: C 46-24, H 3.25, N4 46. F .

199 ((S)-l-((l-Benzyl-4-iodo-lH-pyrrol-2-yl)methyl)pyrrolidin-

2-yl)methanol 185

N N ) OH Ph 185

A solution of (S)-prolinol 167 (4.87 g, 48.2 mmol) in dry

DCM (30 mL) was added in one portion at room temperature to

a stirred solution of aldehyde 184 (10.0 g, 32.1 mmol) in

dry DCM (60 mL) in the presence of anhydrous MgS04 (3.21 g,

26.7 mmol). The mixture was stirred under a slight over

pressure of nitrogen at room temperature for 18 h. The

reaction mixture was then transferred upon filtration to

another flask, the solution was concentrated in vacuo and

the resulting residue was dissolved in dry methanol (60 mL)

and cooled to 0 'C. Sodium borohydride (2.43 g, 64.3 mmol) was added cautiously and, when the addition was complete,

the resulting mixture was allowed to reach room temperature and stirred for 24 h. The reaction mixture was quenched with distilled water (100 mL) and extracted with diethyl ether (3 x 300 mL). The combined extracts were dried over anhydrous MgS04 and concentrated in vacuo. Purification of the crude product by flash column chromatography (Si02; hexane/ethyl acetate 10: 0 to 0: 10) afforded 185 as a clear oil (8.88 g, 70%). Rf = 0.16 (Si02; hexane/ethyl acetate

1: 1) [a] 20 (c 0.47 in DCM) IR: 3422 (OH) ; D = -4 .2 = ; Vmax = 1H cm-1 ; NMR (400 MHz, CDC13) :6=1.51-1.61 (m, 1H;

NCHCHHCH2). 1.63-1.77 (m, 2H; NCHCHHCH2 and NCHCH2CHH) , 1.84-1.94 (m, IH; NCHCH2CHH) 12 (bs, 1H; OH) 20-2.29 ,2 . ,2 . 2.5 9-2 62 1H; NCHCH2) 2.91-2.95 1H; NCHHCH2CH2) . , 13.7 1H; 1H; NCh`HCH2CH2) 3.29 (d,, J Hz,, NCHHHetAr) , 3.31-3.34 (m, 1H; CHHOH) 3.4 6 (dd, J= 10.8,3.4 Hz, 1H;

CHHOH) 3.72 (d, J= 13.7 Hz 1H; NCHHHetAr) 5.15 (s, 2H; , , , 200 NCH2Ph) 6.17 (d, J 1.5 Hz IH; HetArH3) 6.7 0 (d, , , , i= 1.5 Hz, 1H; HetArHs) 7.00-7.34 (m, 5H; NCH2PhH) ppm; 13c (100 NMR MH z,. CDC13) :6 23.9 (NCHCH2CH2) 28.2

(NCHCH2CH2) 50.3 (NCH2HetAr) 50.8 (NCH2Ph) , 55.2 (NCH2CH2CH2) 58.8 (CHetArI) 62.9 (CH20H) 64.9 (NCHCH2) , , 117.0 ( CHetAr3H) 126.6 (NCH2CPhH) 127.4 CHetAr5H) 128.0 r F (NCH2CPhH) 129.2 (NCH2CphH) 138.2 143.9 (CHetArCH2N F r and and

CPhCH2) PPM; MS (CI, NH3): InIZ M: 397 (100) [M + H+] 271 , (10) [M -I+H+ H+] ; HRMS (CIF NH3) : calcd for C17H22IN20:

397.0777, found 397 0771 [M + H+] . elemental analysis calcd (%) for C17H21IN20 (396.07) :C 51.53, H 5.34, N 7.07; found:

C 51.58F H 5.33f N 7.00.

(S)-2-((l-Benzyl-4-iodo-lH-pyrrol-2-yl)methylamino)-3-

methylbutan-l-ol 189

b/\ H N ýN "ý5'ýOH

Ph 189

A solution of (S)-valinol 173 (3.08 g, 29.9 mmol) in dry

DCM (40 mL) was added in one portion at room temperature to a stirred solution of aldehyde 184 (6.20 g, 20.0 mmol) in

dry DCM (60 mL) in the presence of anhydrous MgS04 (1-99 gr

16.6 mmol). The mixture was stirred under a slight over

pressure of nitrogen at room temperature for 48 h. 'The

reaction mixture was then transferred upon filtration to

another flask, the solution was concentrated in vacuo and

the resulting residue was dissolved in dry methanol (60 mL)

and cooled to 0 'C. Sodium borohydride (1.51 gr 39.9 mmol) was added cautiously and, when the addition was complete, the resulting mixture was allowed to reach room temperature and stirred for 18 h. The reaction mixture was quenched

201 with distilled water (100 mL) and extracted with diethyl ether (3 x 300 mL) The combined extracts were dried over anhydrous MgS04 and concentrated in vacuo. Purification of the crude product by flash column chromatography (Si02; hexane/ethyl acetate /triethylamine 8: 2: 0.5 to 5: 5: 0.5) f 189 (7 98%) Rf 0.27 af orded as a pale yellow oil .79g, . = 20 (Si02; hexane/ethyl acetate/triethylamine 5: 5: 0.5); (XID =

+4 (c 3.88 in DCM) IR: 2956-3410 (NH and OH) cm- .6 = ; '0max = 1; 1H NMR (400 MHz, CDC13) :6=0.85 (d, J=6.9 Hz, 3H;

CH3CHCH3) 90 (d, J=6.9 Hz, 3H; CH3CHCH3) 1.65-1.82 (m, ,0- f 1H; CH3CHCH3) 2.3 6-2.4 1 (m, 1H; NHCH) 2.64 (bs, 1H; OH or . , NH), 3.27-3.33 (m, 1H; CHHOH), 3.53-3.56 (m, 1H; CHHOH),

3.58 (d, J= 13.4 Hz, 1H; NCHHHetAr) 3.68 (d, J= 13.4 Hz,

1H; NCHHHetAr) 5.15 (s, 2H; NCH2Ph) 6.19 (d, J=1.7 Hz, , 1H; HetArH3) 6.7 0 (d, J 1.7 Hz, 1H; HetArH5) 03-7 35 , =:= ,7 . . 13 (m,, 5H; NCH2PhH) PPM; C NMR (100 MHz, CDC13) :8= 18.3

(CH3CHCH3) 19.2 (CH3CHCH3) 28.6 (CH3CHCH3), 43.2 . 50.5 (NCH2Ph) 58.2 (CHetArI) 60.6 (CH20H)r (NCH2HetAr) , 63 (NCHCH2) 115 (CHetAr3H) 126 (CPhH) 126.9 (CHetAr5H) .8 .7 f .4 1 r 127.7 (CPhH) 128.9 (CPhH) 133.4 and 137 (CHetArCH2N and 1 , .7 [M H+] 296 CPhCH2) PPM; MS (CI, NH3) : IýIIZ (%) : 399 (100) + , (CH3) CH20H) (15) M-I+H+ H+ ]; (100) M+ - NH (CH 2) r273 found HRMS (CIf NH3): calcd for C17H241N20: 399.0933, for 399.0929 [M + H+]; elemental analysis calcd (%) C C17H23IN20 (398.09): C 51.27, H 5.82, N 7.03; found:

51.37, H 5.76F N 7.02.

202 (S) -2- (N-Benzyl-N- ((l-benzyl-4-iodo-IH-pyrrol-2-yl)methyl) amino)-3-methylbutan-l-ol 190

Ph r

N -ý N70H ,

Ph 190

Benzyl bromide (1.4 mL, 11.6 mmol) was added in one portion

at room temperature to a stirred mixture of aminoalcohol 189 (3.08 7.7 K2CO3 (1.60 11.6 18- g, mmol) , g, mmol) and crown-6 (0.204 g, 0.77 mmol) in dry acetone (60 mL). The

resulting mixture was stirred at room temperature for 72 h

then the solvent was removed in vacuo. Purification of the

crude product by flash column chromatography (Si02;

hexane/ethyl acetate/triethylamine 10: 0: 0.5 to 7: 3: 0.5) 190 (2.53 67%) Rf (mixture afforded as a clear oil g, . of rotamers) = 0.70 (one rotamer) and 0.66 (one rotamer)

(Si02; hexane/ethyl acetate/triethylamine 5: 5: 0.5);

20 (c in CH2C12) ; IR: Vmax 3440 (OH) cm- D = _11 .9 =0.42 1H NMR (400 MHz, CDCi3) :5=0.88 (d, J 6.7 Hz, 3H;

CH3CHCH3) 1.07 (d, J=6.7 Hz, 3H; CH3CHCH3) 1.96-2 05 (m,, . . . 1H; CH3CHCH3) 2 (d, J=7.1 Hz IH; HetArCH2NCHHPh) .54 . , OH) 4-3.51 (m,, IH; CHHOH) 2.58-2.67 (m, 2H; NCHCH2 and ,3 .4 . 3.63-3.67 (m, 2H; 3.57 (d,, J := 13.1 Hz,, 1H; NCHHHetAr) 3.83 (df J= 13.1 Hz, 1H; CHHOH and HetArCH2NCHHPh) . NCHHHetAr),. 4.74 (d, J= 16.0 Hz, 1H; NCHHPh), 4.82 (df J=

16.0 Hz 1H; NCHHPh) 6.18 (d,, J=1.6 Hz 1H; HetArH3) , , . . 6.63-6.64 (m 2H; 6.62 (d, i=1.6 Hz, IH; HetArH5) . f 13C (100 MHz, NCH2PhH), 7 18-7 37 (m, 8H; NCH2PhH) PPM; NMR . . (CH3CHCH3) 27 (CH3CHCH3) 45.8 CDC13) :6= 20.1 and 22.6 .1 , (NCH2Ph) (HetArCH2N) and 4 6.2 (HetArCH2NCH2Ph) ,50-0 ,53.8 , 64.4 (N CHCH2) 118 CHetAr3H) 58.2 CHetArI ) 59.3( CH20H) -1 1, -, 126.9 (NCH2CPhH) 127.1 (CHetAr5H) 127.3r 126.3 (NCH2CPhH) , 203 127 128.6 129.4 CPhH)f .4f and (NCH2 131.3,137.4 and 139.6 ( CHetArCH2N and CPhCH2) PPM; MS (CI,, NH3) : MIZ (%) : 489 (100) [M + H+] 457 (10) [M+ CH20H] 363 , - (10) [M -I+H+ H+] ; NH3): HRMS (CI,, calcd for C24H30IN20: 489.1403f found 489.1416 [M + H+]; elemental analysis calcd (%) for C24H29IN20 (488.13): C 59.02,, H 5.98, N 5.74; found: c 58.93f H 5.84f N 5.68.

2-(((S)-2-(Azidomethyl)pyrrolidin-1-yl)methyl)-l-benzyl-4-

iodo-lH-pyrrole 186

br N N N3 Ph"'i 186

DEAD (6.2 mL, 39.3 mmol) was added dropwise over a period of 5 min to a stirred solution of triphenylphosphine (10.3 g, 39.3 mmol) in dry THF (60 mL) at 0 OC under an inert atmosphere of nitrogen. The resulting solution was allowed to reach room temperature and stirred for 10 min. A solution of aminoalcohol 185 (7.80 g, 19.7 mmol) in THF (50 mL) was added quickly via a cannula, followed after 5 min by diphenyl phosphorylazide (8.5 mL, 39.3 mmol). The resulting mixture was stirred at room temperature for 24 hr then distilled water (3.5 mL) was added and the stirring was continued for a further hour. The solvent was removed in vacuo and purification of the crude product by flash column chromatography (Si02; hexane/ethyl acetate 10: 0 to

50: 5 0) afforded 186 as a clear oil (7.68 g, 93%) Rf

(mixture of rotamers) = 0.62 (one rotamer) and 0.45 (one 20 rotamer) (Si02; hexane/ethyl acetate 7: 3); [ (X D = -14.4 (c 1; 1H = 1.32 in DCM) ; IR: -vmax = 2091 (N3) CM- NMR (400 MHz,

(m,, 2H; NCHCHHCH2 NCHCH2CIIH) CDC13) :8=1.27-1.48 and .

204 1.7 0-1.7 4 (m, 1H; NCHCHHCH2) 1.8 5-1.9 6 (m, 1H; NCHCH2ChTH) , 2.06 (bs, 2H; CHHN3 and NCHHCH2CH2) ,2 49 (bs 1H; . . NCHHCH2CH2) 2 69-2 71 (m, 1H; NCHCH2) 25-3 34 (2 . . ,3 . . x d, i = 13.7 Hz, 3H; NCH2HetAr and CHHN3) 5.2 0 (s 2H; NCH2Ph) , , 6.13 (d, J=1.5 Hz, 1H; HetArH3) 6.72 (d, , J 1.5 Hz, 1H; 13 HetArH5), 7.05-7.35 (m, 5H; NCH2PhH) PPM; C NMR (100 MHz,

CDC13): 23.1 (NCHCH2CH2) 29.1 (NCHCH2CH2) . 50.5 (NCH2Ph) 52 (NCH2CH2CH2) 54 (HetArCH2N) 57 (NCHCH2 .7 , .0 , .1 CH2N3) and 578 (CHetArI) 117 CHetAr3H) 12 6.5 (NCH2CPhH) , -1 , r 12 (CHetAr5H) CPhH) 12 7.4 12 CPhH) F 7.5 (NCH2 8.7 (NCH2 130.7 and (CHetArCH2N 138.1 and CphCH2) PPM; MS (CI,. NH3): MIZ (%): 422 (100) [M + H+] 394 (15) [M N2 H+] 296 (95) , - + , [M -I+H + H+] HRMS (CI, NH3) : calcd for C17H21IN5: 422.0842, found 422 0853 [M H+1 C17H20IN5 . + elemental analysis calcd (%) for (421 08) :C 48 47 H4 79, N 16.62 found: C 48.52, H4 87, . . . . N 16.53.

(S)-l-Azido-N-benzyl-N-((I-benzyl-4-iodo-lH-pyrrol-2-yl) methyl)-3-methylbutan-2-amine 191

N3 N

Ph 191

DEAD (1.6 mL, 10.1 mmol) was added dropwise over a period of 5 min to a stirred solution of triphenylphosphine (2.65 g, 10.1 mmol) in dry THF (40 mL) at 0 'C under an inert atmosphere of nitrogen. The resulting solution was allowed to reach room temperature and stirred for 10 min. A solution of aminoalcohol 190 (2.47 g, 5.06 mmol) in THF (50 mL) was added quickly via a cannula, followed after 5 min by diphenyl phosphorylazide (2.2 mL. 10.1 mmol). The resulting mixture was stirred at room temperature for 24 h,

205 then distilled water (0.91 mL) was added and the stirring for further was continued a hour. The solvent was removed in vacuo and purification of the crude product by flash column chromatography (Si02; hexane/ethyl acetate 10: 0 to

8 5: 1.5) af f orded 191 as a clear oil (2 47 95%) Rf . . g, . = 0.4 4 (Si02; hexane/ethyl 9: 1) 20 acetate [(X] D = -17.6 (c = 0.51 in DCM) ; IR: Vmax = 2095 (N3) CM- 1; 1H NMR (400 MHz,

CDC13,, 4: 1 mixture of rotamers) :8=0.7 6 (d, J=6.7 Hz , 0.6H; CH3CHCH3) 0.87 (d, J=6.7 0- . Hz, 6H; CH3CHCH3) 0- 90 (d, J=6.7 H 2.4H; CH3CHCH3) (d, J=6.7 z, .0-99 H z, 2.4 H; CH3CHCH3) 1.65-1.68 (m, 0.2H; CH3CHCH3) 1.90-1-99 (m . . f 0.8H; CH3CHCH3) 2 48-2 57 (m, 0.8H; NCHCH2) 88-2.91 (m, . . ,2 . 0.2H; NCHCH2) 3.4 3 (d, J= 13.2 Hz, IH; HetArCHHN) 3.4 6- , , 3.67 (m, 5H; HetArCH2NCH2Ph, HetArCHHN and CH2N3), 3.86 (d, i= 13.2 Hz, 1H; HetArCHHN), 4.86 (d, J 16.0 Hz, IH;

NCHHPh), 4 94 (d, J= 16.0 Hz,, 1H; NCHHPh) 6.18 (d, . J= 1.5 Hz,, 0.2H; HetArH3) 6.20 (df J=1.5 Hz, 0.8H;

HetArH3) 6.64 (d, J 1.5 Hz, 2.8H; 0.8 2 , HetArH5 and NCH2PhH) 6.71 (d, J 1.5 Hz, 0.2H; HetArH5) 7 18-7 42 , . . 13 (m. 8H; NCH2PhH) PPM; C NMR (100 MHz, CDC13,, mixture of

17 3,, 19.8,20.1 21.3 (CH3CHCH3 4) rotamers) :6= . and x r 28.1 31.0 (CH3CHCH3). 46.4 (HetArCH2NCH2Ph) 49.3 and , (CH2N3)f 50.1f 50.3 51.0 (NCH2Ph) 54.4 (HetArCH2N) and , , 5 6.8 (NCHCH2) (CHetArI) 62 (NCHCH2) 67 (NCHCH2) .57.9 , .2 , .3 . 117 CHetAr3H) 12 0.2 (NCH2 CPhH) 12 6.4 (NCH2 CPhH) 12 6.8 .7 F r and 127.1 (CHetAr5H) 127.3,128.4,128.5,129.4 130.1 f and (NCH2CPhH) 137.7f 138.4,139.5 149.8 (CHetArCH2N and , and CPhCH2) PPM; MS (CI,, NH3) : InIZ M 514 (100) [M + H+] 486 (3 5) ], 457 (15) M+ CH2N31 (7 0) [MI- M- N2 + H+ - ,296 CH2Ph H+] HRMS (CI NH3) for C24H29IN5: 5 14 14 67 + ; . calcd . f found 514 14 66 [M + H+] analysis calcd (%) for . ; elemental C24H28IN5 (513.14): C 56.14, H 5.50f N 13.64; found: C

56.19F H 5.50f N 13.72.

206 ( (S) -I- ( (1-Benzyl-4-iodo-lH-pyrrol-2-yl) methyl) pyrrolidin- 2-yl)methanamine 187

N N NH2 Ph"i 187

Triphenylphosphine (4.23 g, 16.1 mmol) and distilied water

(1.5 mL. 80.7 mmol) were added in one portion to a stirred solution of azide 186 (3.40 g, 8.1 mmol) in THF (35 mL) at room temperature. The resulting solution was heated up to

50 'C and stirred for 16 h. The solvent was removed in vacuo and purification of the crude product by flash column chromatography (Si02; ethyl acetate then methanol/triethylamine 10: 0.5) afforded 187 as a clear oil

(2.01 g, 63%) Rf 0.51 (Si02; methanol/triethylamine 20 10: 0.5); a]D _10 8 (c = 0.4 6 in DCM) IR: 'Omax =3423 1H (NH2) cm-1; NMR (400 MHz, CDC13r 1: 1 mixture of rotamers): = 1.05-1.07 (m, 0.5H; NCHCH2CHH), 1.35-1.44 (m, 0.5H; NCHCHHCH2). 1.56-1.63 (m, 3H; NH2,0.5 NCHCH2CHH and 0.5 NCHCHHCH2). 1.64-1.68 (m, 0.5H; NCHCHHCH2). 1.72- 1.74 (m, 0.5H; NCHCH2CHH), 1.80-1.89 (m, 1H; 0.5 NCHCH2CHH and 0.5 NCHCHHCH2). 1.90-1.97 (m, 0.5H; CHHNH2). 2.13-2.19

(m,, 1H; NCHHCH2CH2), 2.29-2.43 (m, 0.5H; NCHCH2CH2), 2.50-

2.58 (m, 1H; CHHNH2), 2.61-2.69 (m, O. SH; CHHNH2), 2.70-

2.74 (m, 0.5H; NCHCH2CH2), 2.84-2.88 (m,, 1H; NCHHCH2CH2)f

0.5H; NCHHHetAr) 3.27 (d, J= 13.7 3.20 (d, J= 13.5 Hz, , 1H; NCHHHetAr) 3.68 (d, J= 13 Hz, 0.5H; NC.HHHetAr) Hz, , -5 , (mr 2H; NCH2Ph) 6.08 (d, J=1.6 Hz, O. SH; 5.10-5.21 , He tArH3) 6.11 (d, J=1.6 Hz, 0. SH; He tArH3) 63 (d,, J= , ,6 . 6.65 (d, J=1.6 Hz, 0.5H; 1.6 Hz, 0.5H; HetArH5) , 13 6-9 9-7 (m,, 5H; NCH2PhH) PPM; C NMR (100 MHz, HetArH5) .29 23 23.4 (NCHCH2CH2) CDC13,, mixture of rotamers) :5= -1 and r

207 28.3 and 33.8 (NCHCH2CH2) 44 (NCH2Ph) 47.9 (NCHCH2) .5 , , 53.2 (NCH2HetAr) 54.2 (NCH2HetAr) 54.4 , . (NCH2Ph and NCH2HetAr) 54.8 , (NCH2CH2CH2) and 58.0 (CHetArI) 62 ,57.9 .I (CH2NH2) 65 (NCHCH2CH2) 116.1 116.8 (CHetAr3H) . .6 . and r 126.5 (NCH2 CPhH) 12 6.6 (NCH2 CPhH) 12 6.8 and 12 7.0 (CHetAr5H) 127.5 f f (NCH2 CPhH) 128.7 (NCH2CPhH) 131 4,132 7,1 38 138.1 r . . -0 and (CHetArCH2N and CPhCH2) PPM; MS (CI, NH3) : MIZ : 396 (100) [M + H+] 365 (20) [M+ CH2NH21 270 (25) , - , [M I+H+ H+] ; HRMS (CI, NH3) : calcd for Cj-7H231N3: 396.0937, found 396.0938

[M + H+1 ; elemental analysis caicd M for C17H221N3 (395.09): C 51.65( H 5.61f N 10.63; found: C 51.67, H 5.61, N 10.59.

(S) ((1-benzyl-4-iodo-lH-pyrrol-2-yl)methyl) -N2-Benzyl-N2- - 3-methylbutane-1,2-diamine 192

Ph r

N N NH2 Ph 192

Triphenylphosphine (3.38 g, 12.9 mmol) and distilled water

(1.2 mL, 64.7 mmol) were added in one portion to a stirred

solution of azide 191 (3.34 g, 6.5 mmol) in THF (40 mL) at

room temperature. The resulting solution was heated up to

50 'C and stirred for 16 h. The solvent was removed in

vacuo and purification of the crude product by flash column

chromatography (Si02; hexane/ethyl acetate/triethylamine

7: 3: 0.5 to 5: 5: 0.5) afforded 192 as a clear oil (2.91 g,

92%). Rf 0.13 (Si02; hexane/ethyl acetate /triethylamine

20 (c in CH2C12) IR: 6: 4: 0.5); [a] D -19.7 =3.04 -Vmax = 1H 2956 (NH2) cm-1; NMR (400 MHz, CDC13,3: 1 mixture of

Hz, 0.75H; CH3CHCH3) 0.84 rotamers) :5=0.75 (d, J=6.7 . 0.75H; CH3CHCH3) 0-90 (d, i=6.7 Hz, (d, i=6.7 Hz, . 208

wrfftqýýt "ý 2.25H; CH3CHCH3) 00 (d, J 6.7 Hz, 2.25H; CH3CHCH3) .1- , 1- 51 (s, 2H; NH2) 1.97-2.04 IH; CH3CHCH3) 2.25-2.30 , , 0.25H; NCHCH2) 2 35-2.39 (m, 0.75H; NCHCH2) 2 52-2.55 . . 0.25H; CH2NH2) 2 68-2 77 (m, 1.75H; CH2NH2) 3.26 . . , (d, i 13.2 Hz, 0.25H; NCHHHetAr) 3.33 (d, J= 13.2 Hz 0.25H; . 3.47-3.60 NCHHHetAr), (m, 2.5H; 0.5 NCHHHetAr and 2

HetArCH2NCH2Ph) 3.68 (d, J= 13.2 Hz, 0.25H; NCHHHetAr) , . 3.74 (d, J= 13.2 Hz,, 0.75H; NCHHHetAr) 83 (s, 1.75H; ,4 . NCH2Ph) 5.03 (s, 0.25H; NCH2Ph) 6.17 (d, J=1.6 Hz, 1H; , , HetArH3) 6.62 (d, J 1.6 Hz, 2.7 5H; 0.7 5 , HetArH5 and 2 NCH2PhH) 6.66 (d, J 1.6 Hz, 0.25H; HetArH5) 7 13-7.30 , . 13 (m, 8H; NCH2PhH) ppm; C NMR (100 MHz, CDC13, mixture of rotamers) :6= 17 4,19.5,20.1 20.5 (CH3CHCH3 4) . and x , 27 (CH3CHCH3) 39.4 (CH2NH2) (HetArCH2NCH2Ph) 50.0 .2 .46.2 , (NCH2Ph) 50.7 54 (HetArCH2N) 58 (CHetArI) 59.0 , and .0 , .0 and 59.3 (HetArCH2N NCHCH2) 65.8 (NCHCH2) 117 117 and , .6 and .7 (CHetAr3H) 126 (NCH2CPhH) 126 126 (CHetAr5H) 127 1f 1 .3 .7 and .9 r . 127.3,128 4,128.5 129.4 (NCH2CPhH) 131.6,131.9, . and 137.6,138.8 and 139.9 (CHetArCH2N and CPhCH2) PPM; MS (CI,

NH3) (%) 488 (100) [M + H+] 457 (5) [M+ CH2NH21 MIZ : , - . for 362 (5) [M -I+H+ H+] ; HRMS (CI, NH3) calcd

C24H31IN3: 488.1563f f 488 1561 [M + H+] elemental ound . analysis calcd (%) for C24H30IN3 (487.15) C 59.14,, H 6.20,

N 8.62; found: C 59.14, H 6.14, N 8.54.

209 N-(((S)-l-((I-Benzyl-4-iodo-lH-pyrrol-2-yl)methyl) pyrrolidin-2-yl)methyl)acrylamide 188

N N NH Ph') 188 0

Triethylamine (2.2 mL. 16.2 mmol) and DMAP (0.003 gr 0.02 mmol) were added in one portion to a stirred solution of amine 187 (0.790 g, 2.0 mmol) in dry DCM (40 mL) at room temperature. The resulting solution was cooled down to 0 'C and a solution of acryloyl chloride (0.49 mL, 6.1 mmol) in dry DCM (25 mL) was added dropwise over a period of 20 min.

The reaction mixture was allowed to reach room temperature and stirred for 18 h then the solvent was removed in vacuo.

Purification of the crude product by flash column chromatography (Si02; hexane/ethyl acetate 5: 5 to 0: 10) afforded 188 as a colourless solid (0.243 g, 27%) Rf

(mixture of rotamers) = 0.58 (one rotamer) and 0.36 (one rotamer) (Si02; ethyl acetate); M. P. 150-152 'C;

20 0.27 in DCM) IR (DCM) 1545 100 D = -29.4 (c = : ")max =: (C=C) 1657 (C=O) 3395 (N-H) 1H NMR (400 MHz, CDC13) : , cm-1; 6=1.49-1.64 (m, 2H; NCHCHHCH2 and NCHCH2CHH), 1.66-1.73

(m, 1H; NCHCHHCH2). 1.85-1.96 (m, IH; NCHCH2CHH), 2.21-2.28

(m, 1H; NCHHCH2CH2), 2.67-2.68 (m, IH; NCHCH2), 2.96-3-00

(m, 1H; NCHHCH2CH2), 3.08-3.13 (m,, 1H; C-HHNHCO), 3.27 (d,, J 1H; CHHNHCO), 3.73 = 13.7 Hz, 1H; NCHHHetAr), 3.43-3.49 (m. (d, J= 13.7 Hz,, 1H; NCHHHetAr) 5.07 (d,, J= 16.0 Hz 1H; 16.0 1H; NCHHPh) 5.53 (dd, J NCHHPh) 5.15 (df J= Hz,, , IH; 5.60 (bs, 1H; NHCO) 10.3,1.2 Hz NHCOCH=CHH, cis) , 1H; NHCOCH=CH2) 6.14-6 15 and 5.68 (dd, J =: 16.8,10.3 Hz, , . J= 16.8,1.2 Hz, 1H; NHCOCH=CHH trans) 6.18 - 6.19 (dd, . . 1H; 6.17 (d, J=1.5 Hz, 1H; HetArH3), 6.66 (d, J=1.5 Hz,

210

A HetArH5) 6.99-7 34 (m,, SH; 13 . NCH2PhH) ppM; C NMR (100 MHz, CDC13) 23.2 : (NCHCH2CH2) 28.3 (NCHCH2CH2) 41.2 . . (CH2NHCO) ,50.0 (N CH2H e tAr) (N CH2 Ph) (N CH2CH2) .50.2 ,54.8 . 58.4 (CHetArI) 62.4 (NCHCH2) 116.3 (CHetAr3H) 126.2 f , (NHCOCH=CH2) 126.4 . (NCH2 CPhH) 126.8 CHetAr5H) 127 , r .7 and 128.9 (NCH2CPhH) 130.6 , (NHCOCH=CH2) 132.3 and 137.8 (CHetArCH2N and CPhCH2) 165.7 (NHCOCH=CH2) f PPM; MS (CI, NH3) : M/Z M: 450 (45) [M + H+1 324 (75) , [M -I+H+ H+] ; HRMS (CI,, NH3) : calcd for C20H25IN30: 450.1042,. found 450.1035 [M

+ H+1 ; elemental analysis calcd (%) for C20H24IN30 (4 4 9.10)

C 53.46f H 5.38f N 9.35; found: C 53.47, H 5.44, N 9.31.

N-((S)-2-(N-Benzyl-N-((l-benzyl-4-iodo-IH-pyrrol-2-yl)

methyl)amino)-3-methylbutyl)acrylamide 193

Ph r N N -,-

Ph 193

Triethylamine (1.1 m.L, 8.0 =ol) and DMAP (0.001 g, 0.01 mmol) were added in one portion to a stirred solution of amine 192 (0.487 g, 1.0 mmol) in dry DCM (30 mL) at room temperature. The resulting solution was cooled down to 0 'C and a solution of acryloyl chloride (0.24 mL, 3.0 mmol) in dry DCM (20 mL) was added dropwise over a period of 30 min.

The reaction mixture was allowed to reach room temperature and stirred for 18 h then the solvent was removed in vacuo.

Purification of the crude product by flash column chromatography (Si02; hexane/ethyl acetate 10: 0 to 6: 4) afforded 193 as a colourless solid (0.270 g, 50%) Rf

(mixture of rotamers) = 0.69 (one rotamer) and 0.48 (one rotamer) (Si02; hexane/ethyl acetate 5: 5) ; m. p. 42-44 'C;

I. ID 20 OC =+45.9 (c=0.65in DCM) ;IR (DCM) : -v,,,,, = 15 55

211 (C=C) 1651 (C=O) 3296 (N-H) 1H , f CM-1; NMR (400 MHz, CDC13) : 6=0.93 (d, J=6.7 Hz. 3H; CH3CHCH3) (d, J=6.7 .1.03 Hz, 3H; CH3CHCH3) 2.01-2.08 (m, 1H; CH3CHCH3) 2.4 6-2.51 , (m, 1H; NCHCH2) 3.13 3.19 (m, 1 H; CHHNHCO) 3.4 5-3.5 0 (m, , - , IH; CH.HNHCO) 3.53 (d, J 13.1 Hz, 1H; NCHHHetAr) 3.58 . . (d, J=1.0 Hz, 2H; HetArCH2NCH2Ph) 3.7 9 (d, J= 13.1 Hz, , 1H; NCHHHetAr) 4.79 (df J= 16.0 Hz, IH; NCHHPh) 4.85 (df , , i= 16. Hz,, 1H; NCHHPh) 5.59 (dd, J= 10.3,1.2 Hz, 1H; ýO , NHCOCH=C. HH,, 5.6 4 (b 1H; NHCO) (dd, J= 17.0, ci s) r s, F5.86 10.3 Hz, 1H; NHCOCH=CH2) 6.15-6.16 6.19-6.20 (dd, J= , and 17.0,1.2 Hz, 1H; NHCOCH=CHH, trans) 6.17 (d, J=1.5 Hz, , 1H; HetArH3) 6.66 (d, J=1.5 Hz, 3H; HetArH5 2 . and NCH2PhH) 7 08-7 34 (m. 8H; NCH2PhH) 13C NMR (100 MHzF . . PPM; CDC13) 20.1 (CH3CHCH3) 22.4 (CH3CHCH3) 27.7 :6 . (CH3CHCH3) 37.6 (CH2NHCO) 45.4 (HetArCH2NCH2Ph) 49.9

(NCH2Ph) 53.8 (NCH2HetAr) 58.4 CHetArI )f 62.9 (NCHCH2) , . 126.0 (NCH2CPhH) 126.1 (COCH=CH2) 127.0 117.7 ( CHetAr3H) f , (CHetAr5H) 127 3,127 5,128 6,128 and 129.3 (NCH2CPhH) r . . . .6 , 131.0 (COCH=CH2) 132.06,, 137.3 and 139.7 (CHetArCH2N and

Cpk,CH2) 165.2 (NHCOCH=CH2) PPM; MS (CI NH3) I'VZ (%) : 542

(100) [M H+] 416 (35) [M H+] ; HRMS (CI,, NH3) + , -I+H+ 542.1675 [M + H+] calcd for C27H33IN30: 542.1668f found C27H32IN30 (541.16): C elemental analysis calcd Mf or 58.89f H 5.96F N 7.76; found: C 58.98, H 6-02f N 7.78.

212 5.3.3 Typical procedure for the Heck coupling reactions

A two-necked flask containing a stirrer bar and fitted with a condenser was placed under an inert atmosphere of nitrogen and charged with the appropriate Heck acceptor alkene 160,162,168,169,188 and 193 (1-On mmol) which was dissolved in dry dimethy1formamide (0.05 M).

Palladium(II) acetate (0.1n mmol), sodium hydrogen

carbonate (2-5n mmol) and tetra-n-butyl ammonium chloride

(1.0n mmol) were then added and the resulting mixture was

heated up to 110 'C and stirred for 16 h. After cooling,

the product mixture was filtered over a short pad of celite

and concentrated in vacuo to afford the crude products.

Macrocycle 158

0 NH HN

N 158

Purification of the crude product by flash column 1: 0 chromatography (Si02; acetone /methanol /triethylamine 9:

to 9: 1: 0.1) afforded 158 as a colourless crystalline solid

(0.130 40%) Rf 0.32 (Si02; acetone/methanol/ g, . 20 (c triethylamine 9: 1: 0.5); m. p. 268-270 'C; 10ý1D = +21.3 1514 (C=C) 1658 (C==O) = 0.14 in DCM) IR (DCM) : vm,,ý = , , 1H (bs, 1H; 3361 (N-H) cm-1; NMR (400 MHz,, CDC13) :6=1.52 IH; NCHCHHCH2). 1.67 (bs, 1H; NCHCH2CHH), 1.87-1.92 (m, 1H; NCHCH2CHH) 2.02-2.04 (m, 1H; NCHCHHCH2) 2.74-2.77 (m, , . 1H; CHHNHCO), 2.88-2.90 (mr 1H; NCHHCH2) 3.02 (bs,

213 NCHCH2) 3-27-3-31 (mf 1H; CHHNHCO) 3.42 , , (d, J= 12.8 Hz, 2H; ArCH2N) 3.85-3-87 (Mf 1H; NCHHCH2) 5.60 (bs 1H; . NHCO) 5.7 9 (d, f J= 15.6 Hz,. 1H; NHCOCH=CHAr) 7.2 0 (d, i= 15.6 Hz, 1H; NHCOCH=CHAr) 7.38-7.47 (m, 4H; ArH) ppm; 13C

NMR (100 MH z,, CDC13) :6 23.9 (NCHCH2CH2) 28.1 . (NCHCH2CH2) 42 (CH2NHCO) .3 56.4 (NCH2CH2) 60.6 (ArCH2N) ', 62.5 (NCHCH2) 120.9 (NHCOCH=CHAr), 128.0 CAr3,5H) 13 0.0 , r (CAr2,6H) 134 (CArCH=CH) 138.7 .8 f (NHCOCH=CHAr),, 142.0 (CArCH2N) 165.2 (NHCO) ppm; MS (FAB/+) : inlz (%) : 485 (35) [M H+] 242 + , (47) [M+/21; HRMS (FAB/+): calcd for C30H37N402: 485.2917, found 485.2939 [M + H+] .

Macrocycle 178

N MeOOC,, " NHH HN''"'I COOMe C N

178

The crude product was dissolved in DCM (200 mL), the

organic layer was washed with water (3 x 100 mL) and dried

over anhydrous MgS04- Evaporation of the solvent and

purification of the crude product by flash column

chromatography (Si02; hexane/ethyl acetate/triethylamine

10: 0: 0.5 to 7.5: 2.5: 0.5) afforded 178 as a colourless

crystalline solid (0.021 g, 16%). Rf 0.42 (Si02; hexane/ethyl acetate/triethylamine 6: 4: 0.5); m. p. 104-106

OC; 20 in DCM) (DCM) 3377 [(XI D =: -37.0 (c =0.08 ; IR : 'Vinax = (N-H) 1722 (C=O) 1628 (C=C) cm-1; 1H NMR (400 MHz, CDC13) : 1 f 6 0.29-0.39 (M 1H; NCHCHHCH2) 0.82-0.88 (m, IH; r . NCHCHHCH2) 1.22-1.29 (m, 1H; NCHCH2CHH) 1.33-1.39 (m, 1H; . ,

214 NCHHCH2) 1.4 4 7 (m, IH; NCHCH2CHH) 2.13-2.18 (mf 1H; . -1.4 . NCHHCH2) 2.21-2.24 (ddf J= 11.2f 1.6 Hz, 1H; NCHCHHNH) . . 2.90 (df J= 12.5 Hz, 2H; NCHCHHNH and ArCHHN), 3.24 (dr J

16.3 Hz, 1H; ArCHHC=CH) 3.4 7 (m. 1H; NCHCH2) 3.64 (df J = , 12.5 Hz, 1H; ArCHHN) 3.7 4 (s, 3H; COOCH3) 4.18 (d, J= = , , 16.3 Hz, 1H; ArCHHC=CH) 5.31 (dd, J= 14.0,8.6 Hz, 1H;

NH) 7 16 (dr J7 Hz,, 2H; ArH2,6) 30 (d, J=7 Hz, . .7 .7 . .7 2H; ArH3,5) 7 48 (d, J= 14 Hz, 1H; NHCH=C) 13C NMR . .0 ppm; (100 MHz. CDC13) 19.3 (NCHCH2CH2) 30.5 (ArCH2C=CH) 31.0 . (NCHCH2CH2) 51 (COOCH3) 51.6 (NCH2CH2CH2) 52.7 (NCHCH2) . -0 f . . 59.2 (NCHCH2NH) 63.0 (ArCH2N) 97.5 (CH=CCH2CAr) 128.1 , f (CAr3,5H) 129.3 (CAr2,6H) 136.1 (CH=CCOOCH3) 139.7 f r (NCH2 CAr) 14 6.1 (NHCH=C) 17 0.0 (COOCH3) MS (FAB/+) : r , PPM; (%) 573 (30) [M H+] 541 (7) [M+ OCH31 HRMS m1z : + f - ; (FAB/+) : calcd for C34H45N404: 573.3441, found 573.3449 [M +

H+] ; elemental analysis calcd (%) for C34H44N404 (572.34) C 71.30f H 7.74f N 9.78; found: C 71.33f H 7.65f N 9.70.

Macrocycle 179 Y

0 0

179

by flash Purification of the crude product column 10: 0 to 4: 6) chromatography (Si02; hexane/ethyl acetate (O. Oý8 g, afforded 179 as a colourless crystalline solid 5: 5); 31%) Rf 0.21 (Si02; hexane/ethyl acetate m. p. . = 20 11 in DCM) (DCM) : -\)m,, 252-256 OC; I (XID =- 17 7.0(c=0- ;IR x 1H 1664 (C=O) 1499 (C=C) cm-1; NMR (400 MHz, = 3387 (N-H) , , 3H; CH3CHCH3) 1.2 0 (d, J= CDC13) 1-01 (d, J=6.7 Hz 215 6.7 Hz, 3H; CH3CHCH3) 2.07-2 14 (m, 1H; CH3CHCH3) 2.34- , . , 2.39 (m, 1H; NCHCH2) 2.79-2 85 (m, 1H; CHRNHCO) 3.62 (d, , . , i= 13.2 Hz,. IH; ArCHHNH) 3.64 (d, J= 12.8 Hz, 1H;

ArCHHNH) 3.7 3 (d, J= 13.2 Hz 1H; ArCHHNH), , , 3.75 (m. IH; CHHNHCO) 4.03 (df J= 12.8 , Hz,, 1H; ArCHHNH), 5.82 (df J= 8.0 Hz, 1H; NHCO),, 5.91 (d, J= 15.6 Hz, 1H; NHCOCH=CHAr),

6.98 (d, J=8.0 Hz 2H; ArH2,6) 7 33 (d,, J= 15.6 . . Hz, 1H; NHCOCH=CHAr)f 7.36-7.38 and 7.43-7.47 (m, 5H; NCH2PhH),

7.41 (d, J 8.0 Hz, 2H; ArH3,5) PPM; 13C NMR (100 MHz,, CDC13): 20.2 (CH3CHCH3) 23.2 (CH3CHCH3) 28.8 (CH3CHCH3).

38.2 (CH2NHCO) 52.2 and 54.7 (ArCH2NH PhCH2NH) 63 r and . .6 (NCHCH2) 120 (NHCOCH=CHAr) 127 (CPhH) 127 (CAr3,5H) . .8 , .4 r .9 f 128.7 129.6 (CPhH) 129.7 (CAr2,6H) 134.1 (CA, CH=CH) and r , f 139.0 (NHCOCH=CHAr) 140.3 141.9 (CArCH2N CPhCH2N) , and and , 164.9 (NHCO) MS (FAB/+) (%) 669 (55) [M H+] ppm; m1z : + r 334 (5) [M+/21 ; HRMS (FAB/+) calcd for C44H53N402: 669.4169,

found 669.41815 [M + H+1 ; elemental analysis calcd (%) for

C44H52N402 (668.41) :C 79-00f H 7.84f N 8.38; found: C 78.94, H 7.79f N 8.28.

MacrocYcle 180 MeOOC

NBn B

5ýý 1HN Z-, , ___j MeOOd 180

(200 the The crude product was dissolved in DCM mL) r dried organic layer was washed with water (3 x 100 mL) and over anhydrous MgS04. Evaporation of the solvent and by flash purification of the crude product column chromatography (Si02; hexane/ethyl acetate/triethylamine

216 10: 0: 0.5 to 7: 3: 0.5) afforded 180 as a white crystalline solid (0.041 g, 25%) Rf = 0.22 (Si02; hexane/ethyl acetate 7 3) 110-112 OC; 25 : ; m. p. 10ý1D = -51.9 (c = 0.80 in DCM); IR (DCM) : 'Vmax 2924 (N-H) 1674 (C=O) 1632 (C=C) = r r cm-1; 1H NMR (400 MHz, CDC13) :6-: -- 0- 90 (d, J 6.7 Hz, 3H; CH3CHCH3) 1.03 (df J=6.7 Hz, 3H; r CH3CHCH3) 2.03-2.08 (m,, 1H; CH3CHCH3) 45-2.48 (m,, 1H; CH2NCHCH2) 3.13-3.82 ,2 . (m, 11H; NCH2Ph, NCHCH2NH, ArCH2N,, ArCH2C=CH and COOCH3), 4.60-

4.63 (m, 1H; NH), 7.11-7.23 (m, 9H; ArH and PhH), 7.45 (d, j= 14 Hz, 1H; NHCH=C) 13C NMR (125 MHz, CDC13) 20.0 .0 PPM; : (CH3CHCH3) 22.6 (CH3CHCH3) 26.7 (CH3CHCH3). 30.4 . . (ArCH2C=CH) 45 (NCHCH2NH) 50.8 (COOCH3) 53.1 54.9 .7 . f and (PhCH2N ArCH2N) 63.1 (NCHCH2) 97 (CH=CCH2CAr) 127 1, and , r .1 r - 128.3,128.4,128.9 129.0 (CArH CPhH) 137.4 and and , (CH=CCOOCH3) 139.7 140.2 (NCH2CAr NCH2CPh)f 147.1 . and and (NHCH=C), 169.7 (COOCH3) PPM; MS (FAB/+): m1z (%): 757 (30)

[M H+1 725 (5) [ M+- OCH31 (2 0) [M/2 + H+] HRMS + , ,379 ; (FAB/+) for C48H61N404: 757 4693, found 757 4699 [M + calcd . . H +1 .

Macrocycle 194

0 N NH N\ Bn Bn Bn HN NB N

194

(200 the The crude product was dissolved in DCM mL), 100 dried organic layer was washed with water (3 x mL) and MgS04- the and over anhydrous Evaporation of solvent by flash olumn purification of the crude product c (Si02; 10: 0 to 4: 6) chromatography hexane/ethyl acetate (0.042 gr 35%). afforded 194 as a white crystalline solid

217 Rf 0.32 (Si02; hexane/ethyl acetate 3: 7) ; m. P. 124-126 25 OC; [(XI 139.6 (c 0.35 in D _ = DCM) ; IR (DCM) : "Omax = 1659 (C=: O) 14 94 (C=C) 1H , cm-1; NMR (4 00 MHz,, CDC13,, 4: 1 mixture of rotamers) :8=0- 90 (d, J=6.0 Hz 3H; CH3CHCH3) 97 . .0- (df J=6.0 Hz,, 3H; CH3CHCH3) 1.92-1.94 (m,. 1H; CH3CHCH3) , 2.41-2.44 (m,. 1H; NCHCH2) 3.18 (bs, 1H; CHHNHCO) 3.45 , . (bs, 1H; CHHNHCO), 3.56-3.78 (mf 4H; NCH2HetAr and HetArCH2NCH2Ph) 61 (d, J= 15.5 Hz, 0.2H; .4 . NCHHPh) 4.71 (d, J= 15.5 Hz, 0.2H; NCHHPh) 4 92 (d, J= 15.5 Hz 0.8H; . , NCHHPh) 5.02 (d, J= 15.5 Hz, 0.8H; NCHHPh) 6.01 (d, J= , 15.3 Hz, 1H; NHCOCH=CHHetAr) 6.0 8 (bs, 1H; NHCO) 6.33 , , (bs, 1H; HetAr. H3) 6.82-6.85 (m, 3H; HetArH5 2 NCH2PhH) , and , 7.25-7.30 (m, 8H; NCH2PhH), 7.51 (dr J= 15.3 Hz, 1H; 13 NHCOCH=CHHetAr) PPM; C NMR (100 MHz, CDC13,, mixture of rotamers): 20.1 and 20.3 (CH3CHCH3) 21.5 and 22.0

(CH3CHCH3) 28.9 (CH3 CHCH3) 37-6 (CH2NHCO) 4 5.6 ,28-7 and (HetArCH2NCH2Ph) 4 9.9 (NCH2Ph) and 54 (NCH2HetAr) ,53.6 .2 ', 63 64 (NCHCH2) 105 109.3 (CHetAr3H) 115.8 .7 and .0 .9 and , and 116.2 (NHCOCH=CHHetAr) 120.0 (CHetArCH=CH) 124 125.2 , .8 and ( CHetAr5H) 126.2,127.3,127.4,127.6,128.4,128.5,128.8, r 129.2,129.6 and 130.0 (NCH2CPhH) 134.1 and 134.3

(NHCOCH=CHHetAr) 133.6,137 2,, 13 9.4 13 9.8 (CHetArCH2N , . and CPhCH2) 166.3 166.9 (NHCOCH=CHAr) MS (FAB/+) and r and ppm; : (%) 827 (35) [M + H+1 414 (17) [M/2 + H+1 HRMS M/Z : , ;

(FAB/+) : calcd for C54H63N602: 827.5013, found 827.5049 [M +

H+] ; elemental analysis calcd (%) for C54H62N602 (826.50) C

78.42r H. 7.56f N 10.16; found: C 78-32, H 7.50f N 9.99.

218 Macrocycle 195 PN 0, ', 'Bn NH HN Bn\ No

195

The crude product was dissolved in DCM (200 mL) the organic layer was washed with water (3 x 100 mL) and dried over anhydrous MgS04- Evaporation of the solvent and purification of the crude product by flash column chromatography (Si02; ethyl acetate/acetone/triethylamine 5: 5: 0.5) afforded 195 as a white crystalline solid (0.052

9f 39%) Rf 0.38 (Si02; . ethyl acetate/acetone/ triethylamine 5: 5: 0.5); M. P. (dec. P. ) 226-228 'C;

ID 25 I (I- = -40.4 (c=0.10 in DCM) ;IR (DCM) : 'ý)iuax 16 57

(C=O) 1496 (C=C) cm-1; 1H NMR (400 MHz, CDC13) :81.62- 1.8 9-1.91 (m, 1H; 1.73 (m, 3H; NCHCH2CH2 and NCHCH2CHH) , 1H; 2.79 (bs, 1H; NCHCH2ChTH), 2.28 (bs, NCHHCH2CH2) , NCHCH2) 3.10-3.55 (m, 4H; CH2NHCO NCHHCH2CH2 and . ,, 1H; 5.03 (dr NCHHHetAr) 3.60 (d, J= 15.0 Hz, NCHHHetAr) . 1H; 5.11 (d, J= 16.0 Hz, 1H; J= 16.0 Hz, NCHHPh) , NCHHPh) 6.02 (d, J= 15.2,1H; NHCOCH= CHHetAr) 6.2 0 (m, , , 1H; NHCO) 6.4 2 (bs, 1H; HetArH3) 6.7 9 (bs,. 1H; HetArH5) , , . 6.95-7.34 (m, 5H; NCH2PhH), 7.43 (d, i= 15.2,1H;

13 NHCOCH=ChTHetAr) ppm; C NMR (100 MHz, CDC13) :6= 22.9 48 (NCHCH2CH2) 28.7 (NCHCH2CH2) 40.5 (CH2NHCO) . .9 (NCH2Ph) 54.6 (NCH2HetAr) 55.1 (NCH2HetAr) 50.8 , , (NCH2CH2) 61.6 (NCHCH2) 104.8 ( CHetAr3H) 116.7 . . f 124.8 ( CHetAr5H) 126.3, (NHCOCH=CHAr),, 120.2 (CHetArCH=CH) f F 127 128 (NCH2CPhH) 133.6 (NHCO CH=CHHetAr) 133.9 .8 and .9 , CPhCH2) 167.1 172.5 and 137.8 (CHetArCH2N and r and

219 (NHCOCH=CHAr) ppm; MS (FAB/+) (%) 643 : m1z : (15) [M + H+] ; HRMS (FAB/+) calcd for C40H47N602: 643.3761, found 643.3735 [M + H+] ; elemental analysis calcd (%) for C40H47N602

(642.37) :C 74.74f H 7.21f N 13.07; found: C 74.49F H 7.12, N 13.13.

5.3.4 Experimental of Section 4.4

[1761 ((Z)-l-Phenylprop-l-enyloxy)trimethylsilane 201

OSiMe3

201

Propiophenone (5.0 mL, 37.6 mmol) was slowly added to a

stirred solution of LDA (20.7 mL. 2.0 M in THF/heptane/ethylbenzene, 41.4 mmol) in THF (80 mL) at -78

'C and the resulting mixture was stirred for 1 h. Me3SiCl

(5.2 mL, 41.4 mmol) was added and the solution was stirred

for 20 h. A solution of NH4Cl(sat. ) (100 mL) was added and the mixture extracted with diethyl ether (3 x 200 mL). The

combined organic layers were dried over MgS04 and the

solvent evaporated under reduced pressure. Purification of

the crude product by flash column chromatography (Si02;

hexane) afforded 201 as a clear oil (4.42 g, 57%) Rf =

0.67 (Si02; hexane/ethyl acetate 9: 1); IR: Vmax 1652 (C=C)

1; 1H 9H; (CH3) cm- NMR (300 MHz, CDC13) :5=0.17 (s, Si 3) r 1.76 (d, J=6.8 Hz, 3H; C=C(H)CH3), 5.36 (q,, j=6.8 Hz, 13 1H; C=C(H)CH3), 7.18-7.50 (m, 5H; PhH) ppra; C NMR (75 MHz,

CDC13): 6 0.6 (Si (CH3) 11.7 (C=C (H) CH3) 105.4 3) r (C=C (H) CH3) 125 (CPhH) 127.3 (CPhH) 12 8.0 (CPhH) 139.2 f -2 f F (CPhC=C) 149.8 (CPhC=C) MS (CIf NH3) InIZ (%) : 207 f PPM; (100) EM + H+I; HRMS (CIr NH3): calcd for C12H19OSi:

207.1205, found 207.1198 [M + H+] . 220 Typical procedure for the Mukaiyama aldol reaction catalysed by RE trif lates

3-Hydroxy-2-methyl-1,3-diphenylpropan-l-one 203

OH 0

Ph Ph

203

To a solution of RE (OTf) 3 (see Table 3, section 4.5.2)

(0.040 mmol, 20 mol% for entry 1-6 or 0.024 mmol, 12 mol% for entry 7) in H20/THF (1/9,, 0.1 mL) at 0 'C was added a solution of the appropriate macrocycle (0.048 mmol, 24 mol%) in H20/THF (1/9,0.4 mL). The mixture was left stirring at the same temperature for 15 min. A solution of benzaldehyde 202 (0.012 g, 0.020 mmol) in H20/THF (1/9,0.3 mL) and a solution of 201 (0.062 g, 0.030 mmol) in H20/THF

(1/9f ý0.3 mL) were then added. Stirring continued for 18 h at the same temperature. The reaction was quenched by addition of aqueous NaHC03 (1 mL). The mixture was extracted with DCM (2 x3 mL), dried over MgS04 and concentrated in vacuo. Purification of the crude product by flash column chromatography (Si02; hexane/ethyl acetate

10: 0 to 7: 3) afforded 203 (as a mixture of diastereomers) as a colourless oil (for yields, d-e-'s and e. e. 's see

Table 2. section 4.5.2). Rf = 0.15 (Si02; hexane/ethyl 3468 (OH) 1677 (C=O) 1H NMR acetate 6: 1) ; IR: = f cm-1; 1.07 (d, J=7 Hz, 3H; CH3, anti) (300 MHz. CDC13) : .3 , Hz, 3H; CH3,, 18 (bs, IH; OHj, 1.20 (d, i=7.3 s_vn) ,3 . 3.69-3 74 (m,, 2H; CHCH3 and OH, s_yn) 3.84 (q, J= anti) , . , ti) 5.0 0 (dd, J=4.6,8.1 Hz 1H; 7.3 Hz, 1H; CHCH3, an , , 1H; 7.28-7.98 CHOH, anti) 5.24 (t, j=2.4 Hz, CHOH,, s_yn) . 13 CDC13) (m. 1OH; PhH, anti and s_vn) PPM; C NMR (75 MHz, :

221 6= 11.3 and 15.7 (CH3, anti and s_vn), 47.2 and 48.0

(CHCH3, anti and syn), 73.2 and 76.7 (CHOH, anti and s vn), _ 125.9,127.2,128.1,128.4,128.5, 128.6,128.8,129.7f

131.3,133.3,133.7,135.4,136. ý (CA rH and CArCH anti and (CArC=Of s_vn), 141.9 and 142.3 anti and s-Vn), 204.9 and 205.7 (C=O, anti and s_yn) ppm; MS (CIf NH3) : MIZ 258 (67) [M NH4+1 241 (100) [M H+] 223 (75) [M+ H201 + , + , r 105 (90) [C6H4CHO+] ; HRMS (CIf NH3): calcd for C16H1702: 241.1228f found 241.1220 [M H+] The diastereoselectivity + . and the enantioselectivity of the aldol adduct 203 were 1H [(Daicel ,determined by NMR and HPLC analysi s Chiralpack AD, hexane/iPrOH = 3011f flow rate = 1.0 mL/minf 254 nm); tR syn isomer: tR 19 min (major, R, R)f = 24 min (minor) anti isomer: tR 35 min (minor), tR = 40 min (major)].

Complex 204

Ih W241

Mal wri

in A solution of macrocycle 158 (0.0062 g,, 0.013 mmol) ion Pr(N03)3-6H20 ethanol (0.1 mL) was added to a solut of (0.0083 g, 0.019 mmol) in ethanol (0.5 mL) at room temperature. A white precipitate immediately formed, and 80 'C (oil bath dissolved by addition of water (100 pL) at temperature) The resulting so lution was allowed to stand the which at 5 'C under ethanol vapour to give crystals, 204 (0.006 63%) as were filtered to afford comp lex g, 25 ) 190-192 'C; [(XID colourless thin needles. M. p. (dec. p. (N03-) in DCM) IR (nuj 'Vmax = 1369 f =- 15.7 (c = 0.10 ; ol) : 998 (10) [M + 2399.6 (H20) cm-1; MS (FAB/+) : m1z ( %) : 3- Section 6.3. Pr (N03) 6 + H+ + H+] For X-ray data see 222 Chapter 6

Av%LaPp endix

223 6.1 Crystal data for macrocycle 158

0(8A)

//d

0(40)

/d "'

Figure 42. ORTEP view of macrocycle 158.

The included aqua molecule 0(40) is disordered. This was resolved into two partial occupancy orientations, and potential proton positions for the major orientation (ca. 83%) were located from a delta-F map. Figures 43 and 44 show the molecular structure of "upper" and "lower" macrocyclic rings, respectively.

224 Figure 43. ORTEP view of "upper" macrocyclic ring 158.

r, t,)n, i

C(6')

Figure 44. ORTEP view of "lower" macrocyclic ring 158.

Table 3. Crystal data and structure refinement for 158.

Identification code 158 Empirical formula C30 H37 N4 02.50

Formula weight 493.64 Temperature 173(2) K

Diffractometer, wavelength OD Xcalibur PX Ultra, 1.54248

Crystal system, space group Monoclinic, P2(l) Aa= Unit cell dimensions 11.5469(5) 90'

b= 17.6488(8) Ap =107.469(4)

225 c= 13.8139(6) A7= 90'

Volume, Z 2685.3(2) A3,4

Density (calculated) 1.221 Mg/M3

Absorpt ion coefficient 0.622 mm-1 F(OOO) 1060 Crystal colour / morphology Colourless blocks

Crystal size 0.22 x 0.12 x 0.09 MM3 0 range for data collection 4.02 to 71.11'

Index ranges -14<=h<=10, -21<=k<=19, -13<=l<=16 Reflns collected / unique 25064 / 9511 [R(int) = 0.03731 Reflns observed [F>4(Y(F)] 8661

Absorption correction Numeric analytical

Max. and min. transmission 0.94822 and 0.89911

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 9511 /7/ 688

Goodness-of-fit on F2 1.031

Final R indices [ F>4cy (F) I Rl = 0.0326, wR2 = 0.0793

Rl+ = 0.0326, wR2+ = 0.0793

Rl- = 0.0327, wR2- = 0.0796

R indices (all data) Rl = 0.0360, wR2 = 0.0814

Absolute structure parameter 0.07(13), x- = 0.93(13) Extinction coefficient 0.00 11o(11)

Largest diff. peak, hole 0.144, _0.161 eA-3

Mean and maximum shift/error 0.000 and 0.000

Table 4. Bond lengths [AO] and angles ['1 for 158.

N (1) -C (2) 1.464 (2) N (1) -C (5) 1.470 (2) N (1) -C (34) 1.470 (2) C (2) -C (6) 1.523(2) C (2) -C (3) 1.542 (2) C (3) -C (4) 1.536(3) (3) C (4) -C (5) 1.517 (2) C (6) -N (7) 1.451 N (7) -C (8) 1.338(2) 1.2413(19) c (8) -0 (8) 1.479 (2) c (8) -C (9) 1.325(2) c (9) -C (10) C(10)-C(11) 1.471 (2) C(Il)-C(12) 1.395(2) C(11)-C(16) 1.399(2) C(12)-C(13) 1.391 (2) 1.387 (2) C (13) -C (14) C(14)-C(15) 1.403 (2) C(14)-C(17) 1.503(2) C(15)-C(16) 1.384(2) 226 C(17) -N(18) 1.479 (2) N(18) -C(22) 1.480 (2) N(18) -C (19) 1.493 (2) C(19) -C(23) 1.526 (2) C(19) -C(20) 1.536(2) C(20) -C(21) 1.524(3) C(2l) -C(22) 1.512(3) C(23) -N(24) 1.449 (2) N(24) -C(25) 1.341 (2) C(25) -0(25) 1.2370(19) C(25) -C(26) 1.481 (2) C(26) -C(27) 1.327 (2) C(27) -C(28) 1.471 (2) C(28) -C(33) 1.395(2) C(28) -C(29) 1.398 (2) C(29) -C(30) 1.385(2) C(30) -C(31) 1.392 (2) C(3l) -C(32) 1.387(2) C(3l) -C(34) 1.515 (2) C(32) -C(33) 1.395 (2) N(1') 1 467 (2) -C(34') . N(l ') -C(5' ) 1.471 (2) N(1') -C(2') 1.477(2) C(2') -C(6') 1.533(2) C(2') -C(3') 1.549(2) C(3') -C(4') 1.520(3) C(4') -C(5') 1.533(3) C(6') -N(7') 1.451(2) N(7') -C(8') 1.338(2) C(8') -0(8') 1.2433(19) C(8') 1 481 (2) -C(9') . C(91 ) -C(101 1.329 (2) C(101 )-C(lll 1.461 (2) C(111 )-C(12') 1.399(2) C(Ill )-C(16') 1.402(2) C (12 -C (13 1.385(2) C (13 -C (14 1.387 (2) C(141 )-C(15' 1.397 (2) C(141 )-C(17') 1.505(2) C (15 ' ) -C (16' ) 1.379(2) C(17' )-N(18') 1.471(2) N(18 ' ) -C (22 ') 1.473(2) N(18' )-C(19') 1.491(2) C(19' )-C(23') 1.526(2) C (19' ) -C (20 ') 1.553(2) C(20' )-C(2l') 1.532(2) C(2l' )-C(22') 1.517(2) C(23' )-N(24') 1.446(2) N(241 )-C(25') 1.343(2) C(25' )-0(25') 1.234(2) C (25 ' ) -C (26' ) 1.484(2) C(26' )-C(27') 1.329(3) C (27 -C (28 1.470(3) C (28 -C (33 1.397(2) C(28') -C(29') 1.399(2) C(29')-C(30') 1.374(2) C(30') -C(3l') 1.399(2) C(3l')-C(32') 1.382(3) C(3l') -C(34') 1.510(3) 1.387(3) C (32 ') -C (33 ')

104.40 (13) C (2) -N (1) -C (5) 115.81 (13) C (2) -N (1) -C (34) 227 C (5) -N (1) -C (34) 113.33(13) N (1) -C (2) -C (6) 113.57 (13) N (1) -C (2) -C (3) 103.95(12) C (6) -C (2) -C (3) 112.78 (13) C (4) -C (3) -C (2) 104.98 (13) C(5)-C(4)-C(3) 104.33 (14) N(l)-C(S)-C(4) 103.37 (14) N(7)-C(6)-C(2) 110.01 (12) C (8) -N (7) -C (6) 121.84 (13) 0(8)-C(8)-N(7) 122.07 (15) 0(8)-C(8)-C(9) 122.82 (14) N(7)-C(8)-C(9) 115.08 (14) c (10) -C (9) -C (8) 121.47 (14) c (9) -C (10) -C (11) 126.76 (15) C (12) -C (11) -C (16) 117.79 (15) C (12) -C (11) -C (10) 119.29(14) C (16) -C (11) -C (10) 122.53 (14) C (13) -C (12) -C (11) 121.04 (15) C (14) -C (13) -C (12) 121.02 (15) C (13) -C (14) -C (15) 118.05 (15) C (13) -C (14) -C (17) 121.83 (15) C (15) -C (14) -C (17) 120.08 (15) C (16) -C (15) -C (14) 120.81 (15) C(15)-C(16)-C(11) 121.09 (15) N(18)-C(17)-C(14) 112.54 (12) C (17) -N (18) -C (22) 110.84 (12) C (17) -N (18) -C (19) 114.14 (13) C (22) (18) (19) 107 62 (13) -N -C . N(18)-C(19)-C(23) 111.63(13) N(18)-C(19)-C(20) 105.38 (13) C (23) -C (19) -C (20) 109.26(13) C (21) (20) (19) 102 5ý (14) -C -C . C(22)-C(2l)-C(20) 101.49 (14) N(18)-C(22)-C(21) 104.97 (13) N(24)-C(23)-C(19) 112.61 (13) C (25) -N (24) -C (23) 123.06 (13) 0 (25) -C (25) -N (24) 122.25 (15) 0(25)-C(25)-C(26) 122.78 (14) N (24) -C (25) -C (26) 114.96(13) C(27)-C(26)-C(25) 122.56 (14) C (26) -C (27) -C (28) 126.29 (15) C(33)-C(28)-C(29) 117.68 (15) C (33) -C (28) -C (27) 120.09 (15) C (29) -C (28) -C (27) 122.18 (14) C(30)-C(29)-C(28) 120.71 (15) C(29)-C(30)-C(31) 121.31 (15) C(32)-C(3l)-C(30) 118.28 (16) C (32) -C (31) -C (34) 122.30 (15) C (30) -C (31) -C (34) 119.43 (15) C (31) -C (32) -C (33) 120.47 (15) C (32) -C (33) -C (28) 121.26(15) N(l)-C(34)-C(31) 112.20 (13) C (34 ) (I' ) (5' 111 2ý (13) -N -C . C (34 ) -N (1' ) -C (2' 111.41 (12) C (5' -N (1' -C (21 104.29(13) N (1 -C (2 -C (6' 109.68 (12) N (1 -C (2 -C (3 1 106.80 (13) C (6' -C (2' -C (31 112.29(13) C(4')-C(3')-C(21) 105.80 (14) (15) C (3' -C (4 ') -C (5 1 104.09 (14) N (1 1 -C (5' -C (4 y 106.70 (13) N (7 -C (6' -C (2 ' 111.68 122.15(14) C (8 -N (7 ' -C (61 228 0(8')-C(8')-N(71) 122.00(15) 0(8') -C(8')- C(91) 122.56(14) N(7') -C(8')- C(9') 115.44(14) C(101 )-C(91) -C(8, 121.96(14) C(9') -C(10') -C(11') 126.73(15) C(12' )-C(11' )-C(16') 117.52(15) C(12 ' ) -C (11 ' ) -C (10' ) 119.28(14) C(16' )-C(11' )-C(10') 123.19(14) C(13' )-C(12' )-C(11') 121.21(16) C(12' )-C(13' )-C(14') 120.94(15) C(13' )-C(14' )-C(15') 118.15(15) C(13' )-C(14' )-C(17') 121.32(15) C(15' )-C(14' )-C(17') 120.54(15) C(16' )-C(15' )-C(14') 121-15(15) C(15' )-C(16' )-C(11') 120.97(15) N(18' )-C(17' )-C(14') 112.25(12) C(17' )-N(18' )-C(22') 110.65(12) C(17' )-N(18' )-C(19') 112.01(12) C(22' )-N(18' )-C(19') 104.33(12) N(18' )-C(19' )-C(23') 109.28(13) N(18' )-C(19' )-C(20') 107.37(13) C(23' )-C(19' )-C(20') 112.39(13) C(2l' )-C(20' )-C(19') 104.35(13) C(22' )-C(2l' )-C(20') 101.66(14) N(18' )-C(22' )-C(2l') 105.81(14) N(24' )-C(23' )-C(19') 111.59(13) C(25' )-N(24' )-C(23') 123.90(15) 0(25' )-C(25' )-N(24') 123.16(17) 0(25' )-C(25' )-C(26') 122.38(17) N(24' )-C(25' )-C(26') 114.45(14) C(27' )-C(26' )-C(25') 122.84(16) C(26' )-C(27' )-C(28') 125.57(16) C(33' )-C(28' )-C(29') 117.07(16) C(33' )-C(28' )-C(27') 121.11(15) C(29' )-C(28' )-C(27') 121.81(15) C(30' )-C(29' )-C(28') 121.32(15) C(29' )-C(30' )-C(3l') 121.42(16) C(32' )-C(3l' )-C(30') 117.63(17) C(32 ' ) -C (31 ' ) -C (34 ') 121.91(15) C(30' )-C(3l' )-C(34') 120.45(15) C(3l' )-C(32' )-C(33') 121.17(16) C(32' )-C(33' )-C(28') 121.38(16) N(1')-C(341) -C(3l') 112.42(13)

229 6.2 Crystal data for macrocycle 179

r(in)

--, C(19)

Figure 45. ORTEP view of 179.

Table 5. Crystal data and structure refinement for 179.

Identification code 179 Empirical formula C44 H52 N4 02 1.5H20 . Formula weight 695.92 Temperature 293(2) K

Diffractometer, wavelength OD Xcalibur PX Ultra, 1.54248 Crystal system, space group Tetragonal, P4 (3) 2 (1) 2

Unit cell dimensions a= 10.2540(8) A (x = goo 10.2540(8) Ap= goo 40.323(4) Ay= goo

Volume, Z 4239.7(6) A3,4

Density (calculated) 1.090 Mg/M3

Absorption coefficient 0.542 mm-1 F(OOO) 1500

Crystal colour / morphology Colourless needles

Crystal size 0.25 x 0.05 x 0.05 MM3

range for data collection 4.84 to 71.36'

Index ranges -12<=h<=11, -12<=k<=12, -45<=l<=49 0.1312] Reflns collected / unique 42041 / 4068 [R(int) = 230 Reflns observed [F>4(7(F)l 3864

Absorption correction Numeric analytical Max. and min. transmission 0.97090 and 0.92935

Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4068 /1/ 244

Goodness-of-fit on F2 1.379

Final R indices [F>4cy(F)] Rl = 0.1323, wR2 = 0.3032

Rl+ = 0.1323, wR2+ = 0.3032 Rl- = 0.1323, wR2- = 0.3032 indices (all data) Rl = 0.1375, wR2 = 0.3064 Absolute 0-3 (11) 0 (11) structure parameter x+ = , x- = .7 Chirality ind etermi nate, assigned by internal reference on known chirality at C(2)

Extinction coefficient 0.0006(3)

Largest diff. peak, hole 0.316, -0.177 eA-3 Mean and maximum shift/error 0.000 and 0.000

Table 6. Bond lengths [A] and angles ['] for 179.

N (1) -C (14) #1 1.458 (7) N (1) -C (15) 1.470 (7) N (1) -C (2) 1.493 (7) C (2) -C (22) 1.554 (8) C (2) -C (3) 1.556 (7) C (3) -N (4) 1.438 (7) N (4) -C (5) 1.344 (8) C (5) -0 (5) 1.235(7) C (5) -C (6) 1.471 (8) C (6) -C (7) 1.330 (8) C (7) -C (8) 1.475 (8) C (8) -C (9) 1.352 (8) C (8) -C (13) 1.383 (8) c (9) -C (10) 1.395(9) C(10)-C(11) 1.367 (8) C(11)-C(12) 1.389 (8) C(11)-C(14) 1.486(8) C(12)-C(13) 1.381 (8) C(14)-N(1)#l 1.458(7) C(15)-C(16) 1.516(8) C(16)-C(21) 1.355(8) C(16)-C(17) 1.388(9) C(17)-C(18) 1.371(9) C(18)-C(19) 1.368(10) C(19)-C(20) 1.353(10) C(20)-C(21) 1.369(10) C(22)-C(24) 1.511(10) C(22)-C(23) 1.530(10)

C(14)#l-N(l)-C(15) 111.8(4) C (14) #1-N (1) -C (2) 112.1(4) C(15)-N(l)-C(2) 114.2(4) 231 N (1) -C (2) -C (22) 117.5 (4) N (1) -C (2) -C (3) 109.4 (4) C (22) -C (2) -C (3) 113.1 (5) N (4) -C (3) -C (2) 111.0 (5) C (5) -N (4) -C (3) 121.3 (5) 0 (5) -C (5) -N (4) 120.2 (5) 0 (5) -C (5) -C (6) 122.7 (5) N (4) -C (5) -C (6) 117.0 (5) C (7) -C (6) -C (5) 120.3 (6) C (6) -C (7) -C (8) 130.3 (6) C (9) -C (8) -C (13) 117.2 (5) C (9) -C (8) -C (7) 119.4 (5) C (13) -C (8) -C (7) 123.3 (5) c (8) -c (9) -c (10) 121.6 (6) c (11) -c (10) -c (9) 122.0 (6) C (10) -C (11) -C (12) 116.3 (5) C (10) -C (11) -C (14) 122.7 (5) C(l2)-C(l1)-C(l4) 120.9 (5) C (13) -C (12) -C (11) 121.4 (6) C (12) -C (13) -C (8) 121.5 (6) N(1)#1-C(l4)-C(ll) 112.3 (4) N(l)-C(l5)-C(l6) 112.4 (5) C (21) -C (16) -C (17) 117.8 (6) C(21)-C(l6)-C(l5) 120.9 (6) C (17) -C (16) -C (15) 121.3 (5) C (18) -C (17) -C (16) 121.1 (7) C (19) -C (18) -C (17) 119.8 (7) C (20) -C (19) -C (18) 119.0 (7) C (19) -C (20) -C (21) 121.3 (6) C(l6)-C(21)-C(20) 121.0 (7) C (24) -C (22) -C (23) 110.2 (6) C (24) -C (22) -C (2) 116.6 (6) C (23) -C (22) -C (2) 108.1 (6)

Symmetry transformations used to generate equivalent atoms: #1 -y+l, -x+l, -z+3/2

232 6.3 Crystal data for complex 204.

(X51A),'

y hI ie \f 1 059A)'Co' ORS) 0(46) 0(51) 780) -ý, OGO) Iý ORPI, 0(66A) C 8)

Pr 0(60) 42J 4 N(47) 0(61) 10(561 0(54) 0(59)

0(70A) 90) 1'

0(58A)

0C60A)

Figure 46. ORTEP view of the asymmetric unit with the

sandwiching of the Pr (N03) 6 trianion by the two unique macrocyclic dianions and the 14 unique hydrogen bonds

between these three species, the "free" N03 anion and the 3 hydrates.

The "lower"' macrocycle is disordered in the double bond (N24 to C33) This into two region . was resolved partial occupancy orientations of ca. 74% and 26% occupancy whose overlay is shown in Figure 49.

233 C(23) ,d C133) C(321 mwý ýC(31)C(34) 1ý(27) A

A6ý)0(25) 1--l C(30) c- C(29) C(2) 0(8) C(5) C(13) C(12) 03) N(18) 011) C(9) NM C(B) ýC(10) CO C(17) C(14) 0(43) c C(16) b c 0(56)

Figure 47. ORTEP view of the "lower" macrocycle and its hydrogen bonds.

0(49)

its Figure 48. ORTEP view of the "upper"' macrocycle and hydrogen bonds.

234 ' 0(60A)

\d' C132A)

l,a

0(43) ',b

0(561

Figure 49. ORTEP view of "lower"' macrocycle showing an overlay of both the major (ca. 74% occupancy) and the minor (ca. 26% occupancy) orientations.

0(59A)

ji I I -CO(70)

-IM

0(60010

N(471

0(59) Ox 1) Ij I I I in 1 0(70A) 0(90110

'O(S$A)

Ficjure 50. ORTEP view of the Pr(N03)6 moietyf the "free" N03 anion and the 3 hydrates, and their hydrogen bonds.

Table 7. Crystal data and structure refinement for 204.

Identification code 204 3H20 Empirical formula (C30H38N402) 2 [Pr (N03) 61 (N03) .

Formula weight 1602.32

235 Temperature 173 (2) K

Diffractometer, wavelength OD Xcalibur PX Ultra, 1.54248 Crystal system, space group Orthorhombic, P2(1)2(1)2(l) Unit dimensions A cell a=9.9189(9) (x = 90' b= 14.1243(14) A go-

c= 49.275(5) A 900

Volume, Z 6903.3(11) A3r 4

Density (calculated) 1.542 Mg/M3

Absorption coefficient 6.244 mm-1 F(OOO) 3320

Crystal colour / morphology Colourless thin needles

Crystal size 0.24 x 0.01 x 0.01 mm3 range for data collection 3.61 to 71.22'

Index ranges -12<=h<=11, -17<=k<=16, -57<=I<=59 Reflns collected / unique 61876 / 13046 [R(int) = 0.13411

Reflns observed [F>4cy(F) 10746

Absorption correction Numeric analytical

Max. and min. transmission 0.92670 and 0.50946

Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 13046 / 99 / 958

Goodness-of-fit on F2 1.086

Final R indices [ F>4(7 (F) I Rl = 0.0778, wR2 = 0.1053

Rl+ = 0.0778, WR2+ = 0.1053

Rl- = 0.1546, WR2- = 0.2711

R indices (all data) Rl = 0.1013, wR2 = 0.1142

Absolute structure parameter x+ = 0.084(4), x- = 0.916(4) -3 Largest diff. peak, hole 0. ý78, -0.75 eA Mean and maximum shift/error 0.000 and 0.000

236 Table 8. Bond lengths [A*] and angles [01 for 204.

N (1) -C (5) 1.507 (8) N (1) -C (34) 1.510 (9) N (1) -C (2) 1.546 (9) C (2) -C (6) 1.492 (10) C (2) -C (3) 1.540 (11) C (3) -C (4) 1.527 (11) C (4) -C (5) 1.507 (9) C (6) -N (7) 1.438 (9) N (7) -C (8) 1.353 (8) C (8) -0 (8) 1.247 (8) C (8) -C (9) 1.471 (10) c (9) -C (10) 1.333 (9) c (10) -C (11) 1.460 (10) C (11) -C (16) 1.389 (9) C (11) -C (12) 1.402 (9) C(12)-C(13) 1.379 (10) C(13)-C(14) 1.390 (9) C(14)-C(15) 1.405 (9) C(14)-C(17) 1.498 (10) C (15) -C (16) 1.376(10) C(17)-N(18) 1.513(9) N(18)-C(22) 1.497 (9) N(18)-C(19) 1.539 (8) C (19) -C (23) 1.505(10) C(19)-C(20) 1.555(10) C(20)-C(21) 1.528 (11) C(2l)-C(22) 1.508(10) C(23)-N(24) 1.406(11) C(23)-N(24A) 1.72(3) N(24)-C(25) 1.356(13) C(25)-0(25) 1.206(13) C(25)-C(26) 1.484(13) C(26)-C(27) 1.323(11) C(27)-C(28) 1.482(10) C(28)-C(29) 1.3900 C(28)-C(33) 1.3900 C(29)-C(30) 1.3900 C (30) -C (31) 1.3900 C(3l)-C(32) 1.3900 C(3l)-C(34) 1.522(8) C(32)-C(33) 1.3900 N(24A)-C(25A) 1.36(2) C(25A)-0(25A) 1.20(2) C (2 5A) -C (2 6A) 1.47(2) C(26A)-C(27A) 1.309(18) C (2 7A) -C (2 8A) 1.497(16) C(28A)-C(29A) 1.3900 C(28A)-C(33A) 1.3900 C (2 9A) -C (3 OA) 1.3900 C (3 OA) -C (3 1A) 1.3900 C (31A) -C (32A) 1.3900 C(31A)-C(34) 1.494(16) C(32A)-C(33A) 1.3900 N(Il)-C(34') 1.497(10) N(1')-C(5') 1.518(9) N(1')-C(2') 1.537(9) C(2l)-C(6') 1.500(11) C(2')-C(3') 1.528(10) C(3')-C(4') 1.513(11) C(4')-C(5') 1.488(10)

237 C(6' ) -N(7 ') 1.449 (8) N(7')-C(81) 1.358 (8) C(8')-0(8') 1.240 (8) C(8')-C(91) 1.467 (10) c (9, ) -C (10 ,) 1.323 (9) C(101)-C(lll ) 1.487 (9) C (11 -C (12 ) 1.377 (8) C (11 -C (16 ) 1.405 (9) C (12 -C (13 ) 1.387 (9) C (13 -C (14 ) 1.386(9) C (14 -C (15 ) 1.398 (8) C(14')-C(17') 1.511(10) C (15 ') -C (16' 1.363 (9) C (17 ') -N (18 ' 1.523 (9) N(18')-C(22') 1.494(9) N (18 ') -C (19 1.512 (8) C (19' ) -C (20 1.517 (11) C(19')-C(23') 1.545(11) C(201)-C(2l') 1.489(12) C(211)-C(221 ) 1.519(10) C(23')-N(24') 1.454(10) N(24')-C(25') 1.314(13) C(25')-0(25') 1.232(12) C(25')-C(26') 1.572(16) C (26' ) -C (27 ') 1.221(13) C(27')-C(28') 1.514(14) C(281)-C(33') 1.389(12) C(281)-C(29') 1.402(12) C(291)-C(30') 1.335(12) C(301)-C(3l') 1.381(11) C(3l')-C(32') 1.385(11) C(3l')-C(34') 1.500(11) C(32')-C(33') 1.381 (12) Pr-0(56) 2.548 (5) Pr-0(46) 2.581 (5) Pr-0(53) 2.581(5) Pr-0(43) 2.583(5) Pr-0(50) 2.585(5) Pr-0(49) 2.586(4) Pr-0(52) 2.620 (6) Pr-0(47) 2.628 (5) Pr-0(41) 2.671(6) Pr-0(55) 2.674 (5) Pr-0(58) 2.687(5) Pr-0(44) 2.702 (6) N(4l)-0(42) 1.226(8) N(4l)-0(43) 1.264(8) N(4l)-0(41) 1.276(7) N(42)-0(45) 1.217(8) N(42)-0(44) 1.263(8) N(42)-0(46) 1.298 (8) N(43)-0(48) 1.224(7) N(43)-0(49) 1.255(7) N(43)-0(47) 1.272(7) N(44)-0(51) 1.231(9) N(44)-0(50) 1.271(8) N(44)-0(52) 1.279(8) N(45)-0(54) 1.217(8) N(45)-0(55) 1.260(8) N(45)-0(53) 1.270(8) N(46)-0(57) 1.229(8) N(46)-0(58) 1.249(8) N(46)-0(56) 1.282 (8) 238 N(47)-0(61) 1.243 (9) N(47)-0(59) 1.251 (8) N(47)-0(60) 1.258(9)

C (5) -N (1) -C (34) 112.9(6) C(5)-N(l)-C(2) 106.1(5) C(34)-N(l)-C(2) 113.9(5) C(6)-C(2)-C(3) 113.1(6) C(6)-C(2)-N(l) 113.7(6) C(3)-C(2)-N(l) 104.6(5) C(4)-C(3)-C(2) 105.6(6) C (5) -C (4) -C (3) 103.7(6) N(l)-C(5)-C(4) 102.8(5) N(7)-C(6)-C(2) 116.0(6) C(8)-N(7)-C(6) 121.0(6) 0(8)-C(8)-N(7) 120.5(6) 0 (8) -C (8) -C (9) 123.6(6) N(7)-C(8)-C(9) 115.8(6) C(10)-C(9)-C(8) 123.0(7) C(9)-C(10)-C(11) 127.5(7) C (16) -C (11) -C (12) 117.5(6) C(16)-C(11)-C(10) 122.6(6) C (12) -C (11) -C (10) 119.9(6) C (13) -C (12) -C (11) 121.9(6) C (12) -C (13) -C (14) 119.9(6) C(13)-C(14)-C(15) 118.6(6) C (13) -C (14) -C (17) 121.7(6) C (15) -C (14) -C (17) 119.6(6) C (16) -C (15) -C (14) 120.6(7) C(15)-C(16)-C(11) 121.3(6) C (14) -C (17) -N (18) 110.4(6) C (22) -N (18) -C (17) 114.5(6) C(22)-N(18)-C(19) 104.5(5) C(17)-N(18)-C(19) 112.8(5) C (23) -C (19) -N (18) 110.5(6) C(23)-C(19)-C(20) 112.0(6) N(18)-C(19)-C(20) 104.5(6) C(2l)-C(20)-C(19) 105.8 (6) C (22) -C (21) -C (20) 103.1(6) N (18) -C (22) -C (21) 103.3(6) N (24) -C (23) -C (19) 111.1 (7) N(24)-C(23)-N(24A) 18.2(10) C(19)-C(23)-N(24A) 115.8(13) C(25)-N(24)-C(23) 120.0(8) 0(25)-C(25)-N(24) 123.2(8) 0(25)-C(25)-C(26) 124.9(11) N (2 4) -C (25) -C (2 6) 111.8(9) C (27) -C (26) -C (25) 123.7(9) C(26)-C(27)-C(28) 126.5(8) C (29) -C (28) -C (33) 120.0 C(29)-C(28)-C(27) 118.3(6) C (33) -C (28) -C (27) 121.6(6) C(28)-C(29)-C(30) 120.0 C (31) -C (30) -C (29) 120.0 C (32) -C (31) -C (30) 120.0 C(32)-C(3l)-C(34) 122.1(7) C(30)-C(3l)-C(34) 117.8(7) C(33)-C(32)-C(31) 120.0 C(32)-C(33)-C(28) 120.0 C (25A) -N (24A) -C (23) 125 (2) 0(25A)-C(25A)-N(24A) 120 (2) 125(3) 0 (2 5A) -C (2 5A) -C (2 6A) N(24A)-C(25A)-C(26A) 114(2) 239 C (2 7A) -C (2 6A) -C (2 5A) 127 (2) C (26A) -C (27A) -C (28A) 128 (2) C (2 9A) -C (2 8A) -C (3 3A) 120.0 C (29A) -C (28A) -C (27A) 120.9(15) C (33A) -C (28A) -C (27A) 119.1 (15) C(30A)-C(29A)-C(28A) 120.0 C(31A)-C(30A)-C(29A) 120.0 C (30A) -C (31A) -C (32A) 120.0 C(30A)-C(31A)-C(34) 124.3 (19) C(32A)-C(31A)-C(34) 115.7 (19) C(33A)-C(32A)-C(31A) 120.0 C(32A)-C(33A)-C(28A) 120.0 C(31A)-C(34)-N(l) 108.8 (19) C (31A) -C (34) -C (31) 5(2) N(l)-C(34)-C(31) 111.3 (8) C(34')-N(1')-C(S') 111.6(6) C(34')-N(1')-C(2') 114 (6) .1 C(5')-N(1')-C(2') 105.4 (5) C (6') (2') (3') 114 (7) -C -C .9 C (6) -C (2') -N (1') 111.7 (6) C (3') -C (2') -N (1') 104.3 (6) C(4')-C(3')-C(2') 106.1 (6) C(5')-C(4')-C(31) 102.2 (6) C(4')-C(5')-N(11) 103.5 (5) N (7') -C (6' ) -C (2 v) 115.0 (6) C (8') -N (7') -C (61 ) 120.7 (6) 0(8')-C(8')-N(7v) 120.4 (6) 0 (8, ) -C (8, ) -C (91 ) 123.9 (6) N (7') -C (8') -C (91 ) 115.7 (6) C (10' ) -C (9, -C (8, 122.8 (6) c (91 ) -C (10 1 -C (11 1 125.6 (6) C(12')-C(11')-C(16') 118.8 (6) C(12')-C(Il')-C(10') 119.5 (6) C(16')-C(11')-C(10') 121.6 (6) C(11')-C(12v)-C(13') 121.0 (6) C (14' ) -C (13' ) -C (12' ) 120.3(6) C(13v)-C(14')-C(15') 118.4 (6) C (13' ) -C (14 ') -C (17' ) 122.5(6) C(15')-C(14')-C(17') 119.1 (6) C (16' ) -C (15' ) -C (14' ) 121.4 (6) C(15')-C(16')-C(11') 120.0 (6) C(14')-C(17')-N(18') 109.5 (5) C (22' ) -N (18' ) -C (19' 104.2 (6) C (22' ) -N (18' ) -C (17' 114.1 (6) C (19' ) -N (18' ) -C (17' 111.6(5) N(18')-C(19')-C(20') 105.3 (6) N (18' -C (19' -C (23' ) 108.7 (6) C (20' -C (19 v -C (23' ) 113.8 (6) C(2l')-C(20')-C(19') 107.3 (6) C(20')-C(2l')-C(22') 104.1 (6) N(18')-C(22')-C(2l') 103.1 (5) (7) N (24 v) -C (23' ) -C (19' 112.5 (8) C (25' ) -N (24 1) -C (23' 122.4 0(25v)-C(25')-N(24') 124.3 (9) 127.4 (11) 0 (25' ) -C (25' ) -C (26 v 108.3 (11) N (24 ') -C (25' ) -C (26' 119.5 (12) C (27' ) -C (26' ) -C (25' C(26')-C(27')-C(28') 124.8 (13) C(33')-C(28')-C(29') 117.6(8) C(33')-C(28')-C(27') 127.2 (9) ) 115.2 (10) C (29' ) -C (28' ) -C (271 C(30')-C(29')-C(28') 120.7 (9) C(29')-C(30')-C(3l') 122.4 (7) 240 C(301)-C(311)-C(32') 118.2(7) C(30')-C(3l')-C(34') 119.9(7) C(32')-C(3l')-C(34') 121.7(7) C(33')-C(32')-C(3l') 119.9(8) C(32')-C(33')-C(28') 121.2(8) N(1')-C(34')-C(3l') 112.5(6) 0(56)-Pr-0(46) 112.01(17) 0(56)-Pr-0(53) 69.35(17) 0(46)-Pr-0(53) 170.88(18) 0(56)-Pr-0(43) 67.22 (17) 0(46)-Pr-0(43) 103.81(17) 0(53)-Pr-0(43) 68.04(17) 0(56)-Pr-0(50) 107.21(17) 0(46)-Pr-0(50) 69.38(16) 0(53)-Pr-0(50) 119.28(18) 0(43)-Pr-0(50) 169.47 (16) 0(56)-Pr-0(49) 174.65(18) 0(46)-Pr-0(49) 72.70(16) 0(53)-Pr-0(49) 106.44(16) 0(43)-Pr-0(49) 114.75(16) 0(50)-Pr-0(49) 71.65(16) 0 (56) -Pr-O (52) 72.64 (17) 0 (4 6) - Pr-O (5 2) 114.98(16) 0(53)-Pr-0(52) 74.12(18) 0(43)-Pr-0(52) 132.04(17) 0 (50) -Pr-O (52) 49.76(16) 0 (4 9) -Pr-O (52) 103.26(16) 0(56)-Pr-0(47) 125.68(17) 0 (4 6) -Pr-O (47) 113.98(15) 0(53)-Pr-0(47) 69.83(16) 0(43)-Pr-0(47) 124.97(16) 0(50)-Pr-0(47) 65.56(17) 0(49)-Pr-0(47) 48.99(15) 0(52)-Pr-0(47) 62.82(16) 0(56)-Pr-0(41) 111.73(16) 0(46)-Pr-0(41) 68.98(17) 0(53)-Pr-0(41) 102.01(18) 0(43)-Pr-0(41) 49.02 (16) 0(50)-Pr-0(41) 130.86(16) 0(49)-Pr-0(41) 72.02(16) 0(52)-Pr-0(41) 173.04(16) 0 (4 7) - Pr-O (4 1) 110.55(16) 0(56)-Pr-0(55) 110.13(16) 0 (4 6) -Pr-O (55) 124.94(18) 0(53)-Pr-0(55) 48.39(17) 0(43)-Pr-0(55) 63.10(16) 0(50)-Pr-0(55) 127.29(17) 0 (4 9) - Pr-O (5 5) 67.71(15) 0(52)-Pr-0(55) 110.24(17) 0(47)-Pr-0(55) 62.68(17) 0(4l)-Pr-0(55) 63.45(18) 0 (56) (58) 48 94 (16) -Pr-O . 0(46)-Pr-0(58) 73.48(16) 0(53)-Pr-0(58) 111.92(16) 0(43)-Pr-0(58) 104.69(16) 0(50)-Pr-0(58) 66.05(16) 0 (4 9) -Pr-O (58) 132.72(15) 0 (52) -Pr-O (58) 63.69 (16) 0(47)-Pr-0(58) 123.11(17) 0(4l)-Pr-0(58) 123.27(17) 0(55)-Pr-0(58) 158.75(15) 0(56)-Pr-0(44) 71.57(17) (14) 0 (4 6) -Pr-O (4 4) 48.60 241 0(53)-Pr-0(44) 126.53(15) 0(43)-Pr-0(44) 63.92(15) o(50)-Pr-0(44) 106.15(17) 0 (4 9) -Pr-0 (4 4) 113.78(16) o(52)-Pr-0(44) 125.43(17) 0(47)-Pr-0(44) 161.85(15) 0(41)-Pr-0(44) 61.53(17) 0(55)-Pr-0(44) 120.09(17) 0(58)-Pr-0(44) 61.75(18) 0 (42) -N (41) -0 (43) 121.0 (7) 0(42)-N(41)-0(41) 120.6(8) 0(43)-N(41)-0(41) 118.4(7) 0(45)-N(42)-0(44) 121.9(7) 0(45) -N(42) -0(46) 121.7 (7) 0(44) -N (42) -0 (46) 116.4 (6) 0(48)-N(43)-0(49) 122.6(6) 0 (48) -N (43) -0 (47) 119.8 (7) 0(49) -N (43) -0 (47) 117.6 (6) o(48)-N(43)-Pr 169.5(5) o(49)-N(43)-Pr 58.2(3) 0(47)-N(43)-Pr 60.2(3) 0(51)-N(44)-0(50) 122.0(7) 0(51) -N (44) -0(52) 119.7 (8) 0(50)-N(44)-0(52) 118.3(7) 0 (51) -N (44) -Pr 175.5(6) 0(50)-N(44)-Pr 58.4(4) o(52)-N(44)-Pr 60.0 (4) 0(54)-N(45)-0(55) 121.3(7) 0(54)-N(45)-0(53) 121.9(7) 0(55)-N(45)-0(53) 116.8(6) 0 (57) -N (4 6) -0 (58) 122.0 (7) 0 (57) -N (46) -0 (56) 119.7 (7) 0 (58) -N (46) -0 (56) 118.2 (6) N(41)-0(41)-Pr 94. l(5) N(41)-0(43)-Pr 98.6(4) N (4 2) (4 4) 94 (4) -0 -Pr .9 N(42)-0(46)-Pr 99.7 (4) N (4 3) (4 7) 94 (4) -0 -Pr .9 N(43)-0(49)-Pr 97 (4) .4 N(44)-0(50)-Pr 96.8(4) N (44) -0 (52) -Pr 94.9(5) N(45)-0(53)-Pr 99.4 (4) N (45) -0 (55) -Pr 95.2 (4) N(46)-0(56)-Pr 99.3 (4) N(46)-0(58)-Pr 93.5 (4) 0 (61) -N (47) -0 (59) 119.7 (8) 0(61)-N(47)-0(60) 120.0(7) 0 (59) -N (47) -0 (60) 120.2 (8)

242 Chapter 7

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