Asymmetric Catalysis and Sensing with Rigid C2- Symmetric Ligands and Development of Heme-Targeted Antimalarials

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ASYMMETRIC CATALYSIS AND SENSING WITH RIGID C2- SYMMETRIC LIGANDS AND DEVELOPMENT OF HEME-TARGETED ANTIMALARIALS

A Dissertation submitted to the Faculty of the Graduate School of Arts and Sciences of Georgetown University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry

Kimberly Yearick Spangler

Washington, DC August, 2009

ASYMMETRIC CATALYSIS AND SENSING WITH RIGID C2-

SYMMETRIC LIGANDS AND DEVELOPMENT OF HEME-TARGETED

ANTIMALARIALS

Kimberly Yearick Spangler

Thesis Advisor: Christian Wolf, Ph. D.

ABSTRACT

The first general procedure for the ligand-catalyzed nucleophilic addition of diethylzinc to trifluoromethyl ketones was developed. A range of 2-aryl-1,1,1- trifluorobutan-2-ols have been prepared in up to 99% yield using 10 mol % of TMEDA to favor alkylation over β-hydride elimination. These findings provide a new route for the asymmetric synthesis of trifluoromethyl-derived tertiary alcohols which are important components in many pharmaceuticals. Accordingly, the first asymmetric variant of this reaction was introduced. Screening of 16 chiral ligands revealed that excellent yields and ee’s up to 61% can be obtained with TBOX as catalyst.

The first general procedure utilizing a bisoxazolidine – copper(I) complex in the asymmetric Henry reaction was developed. A range of aromatic nitroaldol compounds have been prepared in up to 95% yield and up to 89% ee using 10 mol % of the bisoxazolidine catalyst. The reaction of aliphatic substrates proved even more successful, and the corresponding nitroaldol products were obtained in up to 97% yield and 97% ee.

An interesting switch in enantioselectivity when employing the same chiral ligand with

either copper(I) acetate or dimethylzinc was also discovered. In both cases, nitroaldol

products are obtained in high yields and ee’s but with opposite chiral induction.

1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene N,N’-dioxide was

introduced to new asymmetric catalysis and enantioselective sensing applications. The

synthesis of the ligand was successfully scaled-up, and 1 gram of material was prepared.

A chiral HPLC method was developed that allowed convenient preparative isolation of the enantiomers of this ligand. Initial progress made towards the asymmetric desymmetrization of meso-epoxides is promising from both a synthetic protocol development and enantioselective sensing standpoint. N-Oxide units of the ligand can also be protonated by a strong acid, which is accompanied by a significant UV-response.

This finding opens entries towards the development of a Brønsted acid sensor.

Twelve heme-targeted antimalarials have been prepared by systematically varying side chain lengths, N-terminal branching and substitutions, and heteroatom substitution at the 4-position of quinoline. This study reveals that methodical variation of the side chain of chloroquine provides affordable heme-targeted antimalarials that may overcome the ever-increasing problem with worldwide drug resistance.

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Acknowledgements

I would like to thank my advisor Dr. Christian Wolf for his unwavering support and guidance throughout the course of my Ph. D. studies. Christian truly led by example and taught me to work diligently, effectively, and with purpose. In my future endeavors, I will always aspire to be as successful as a manager as Christian. Thank you so much for all of your help.

I would also like to sincerely thank my committee members: Dr. Travis Holman,

Dr. Paul Roepe, and Dr. Timothy Warren. All of my committee members challenged me to think critically about scientific problems and helped me to truly become a well- rounded researcher.

I also appreciate the hard work of my undergraduate collaborators, Michelle

Corder and Rhia Martin. I especially thank Michelle for helping with the daunting task of synthesizing our ligand.

I would also like to current and former group members of the “Wolf pack:” Dr.

Gilbert Tumambac, Dr. Xuefeng Mei, Dr. Rachel Lerebours, Dr. Shuanglong Liu, Dr.

Kekeli Ekoue-Kovi, Daniel Iwaniuk, Marwan Ghosn, Hanhui Xu, Brian Reinhardt, Mikki

Boswell, Max Moscowitz, and Peng Zheng. I would especially like to thank Daniel

Iwaniuk for his constant support and scientific discussion.

I would also like to thank Dr. Robert Fairchild, Dr. Marie Melzer, and Matthew

Varonka for their scientific insights. I would especially like to thank Matthew Varonka for helping me with geometry optimizations.

I would like to thank the members of the Georgetown Malaria Collaboration, the de Dios group, the Roepe group, and the Wolf group. Specifically, I would like to thank

John Alumasa for his antimalarial activity measurements and Dr. Kekeli-Ekoue Kovi,

Daniel Iwaniuk, John Alumasa, and Dr. Jayakumar Natarajan for synthesizing the complementary compounds in the antimalarial drug series.

Thank you also to Mrs. Kay Bayne and Mrs. Inez Traylor for all of the administrative support during my time at Georgetown University.

I would also like to thank my parents, Patrick and Susan Yearick for their support

from when I was a child until now. Without them, I would not understand the value of

hard work and education.

Words cannot express how much I sincerely appreciate the love and support I

receive from my husband, Ryan Spangler. I cannot imagine experiencing the challenges

of graduate school without him by my side, and I am truly indebted for all of the

sacrifices he made for me. Thank you so much!

Lastly, I would like to thank the Department of Chemistry, the Graduate School

of Arts and Sciences, and Georgetown University for the opportunity to complete my

graduate studies. I have many great memories from Georgetown, and my experiences

here have shaped who I am today.

Table of Contents

Abstract……………………………………………………………………………... ii

Acknowledgements…………………………………………………………………. iv

Table of Contents…………………………………………………………………… vi

List of Figures………………………………………………………………………. x

List of Schemes……………………………………………………………………... xiii

List of Tables……………………………………………………………………….. xvi

List of Abbreviations…………………………………………………...... xvii

I. Introduction……………………………………………………………………….. 1

1.1 The importance of chirality……………………………………………….... 1

1.2 Enantioselective reactions………………………………………………….. 4

1.3 Stereoselective analysis…………………………………………………….. 11

1.4 Development of heme-targeted antimalarials combating chloroquine resistant malaria………………………………………………………………...... 17

1.5 References………………………………………………………………...... 23

II. Objectives………………………………………………………………………... 29

III. Asymmetric catalysis with a bisoxazoline ligand………………………………. 34

3.1 Introduction to bisoxazoline catalysts…………………………………… 34

3.2 The application of bisoxazoline catalysts in the asymmetric addition of

diethylzinc to trifluoromethyl ketones……………………………………………… 37

3.2.1 Racemic addition of diethylzinc to trifluoromethyl ketones………… 39

3.2.2 Enantioselective addition of diethylzinc to trifluoromethyl ketones... 44

3.3 Conclusions………………………………………………………………... 50

3.4 Experimental details……………………………………………………….. 51

3.4.1 Synthesis of chiral ligands…………………………………………... 51

3.4.2 TMEDA catalyzed synthesis of racemic trifluoromethyl alcohols….. 53

3.4.3 Enantioselective synthesis of trifluoromethyl alcohols……………... 53

3.4.4 Purification and characterization of trifluoromethyl alcohols………. 54

3.5 References……………………………………………………………….... 61

IV. Asymmetric catalysis with a bisoxazolidine ligand…………………………….. 65

4.1 Introduction to the bisoxazolidine catalyst………………………………... 65

4.2 The application of the bisoxazolidine catalyst in the asymmetric Henry reaction……………………………………………………………………………… 67

4.2.1 Henry reaction optimization and substrate scope determination……... 69

4.2.2 Metal-controlled reversal of enantioselectivity………………………. 75

4.2.4. Application of the Henry reaction in the synthesis of alkaloid precursors…………………………………………………………………………… 82

4.3 Conclusions………………………………………………………………... 82

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4.4 Experimental details……………………………………………………….. 84

4.4.1 Synthetic procedures…………………………………………………. 84

4.4.2 Characterization of nitroaldol products……………………………… 85

4.4.3 Synthesis and characterization of methyl 4-hydroxy-4- nitropentanoate……………………………………………………………………… 91

4.4.4 Synthesis and characterization of 5-hydroxypiperidin-2-one………. 92

4.5 References………………………………………………………………….. 93

V. Asymmetric catalysis and enantioselective sensing with a sterically congested

N,N '-dioxide………………………………………………………………………… 98

5.1 Introduction……………………………………………………………….. 98

5.2 Synthesis of 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene

N,N’ -dioxide……………………………………………………………………….. 102

5.3 Applications of 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene

N,N’ -dioxide in asymmetric catalysis………………………………………………. 107

5.3.1 Introduction…………………………………………………………... 107

5.3.2 Applications of 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl) naphthalene N,N’ -dioxide as a chiral catalyst for reactions utilizing silicon compounds………………………………………………………………………….. 109

5.4 Applications of 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene

N,N’ -dioxide as a Brønsted acid sensor…………………………………………….. 111

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5.4.1 Introduction…………………………………………………………... 112

5.4.2 Synthesis and applications of a strong Brønsted acid sensor………… 114

5.5 Conclusions………………………………………………………………… 120

5.6 Experimental details………………………………………………………... 120

5.7 References………………………………………………………………….. 127

VI. The development of heme-targeted antimalarials………………………………. 130

6.1 Introduction………………………………………………………………… 130

6.2 Synthesis of antimalarial drug candidates………………………………….. 137

6.2.1 Synthesis of 4-aminoquinolines with symmetrically branched side

chains…………………………………………………………………………….. 137

6.2.2 Synthesis of 4-oxoquinolines with linear and branched side chains.. 138

6.2.3 Synthesis of sulfonamide derived CQ derivatives…………………… 140

6.3 Antimalarial activity of synthesized CQ analogs…………………………... 141

6.3.1 Antimalarial activity of 4-aminoquinolines with symmetrically branched side chains……………………………………………………………… 142

6.3.2 Antimalarial activity of 4-oxoquinolines with linear and branched side chains…………………………………………………………………………... 145

6.3.3 Antimalarial activity of sulfonamide derived CQ derivatives……….. 148

6.4 Conclusions…………………………………………………………………. 150

6.5 Experimental details………………………………………………………… 150

6.6 References…………………………………………………………………… 167 ix

List of Figures

Figure 1.1 . Structures of ( S)-thalidomide and ( R)-thalidomide ……………………. 2

Figure 1.2 . Structures of Nexium and Lipitor ……………………………………. .. 4

Figure 1.3 . Energy profile for a kinetically controlled enantioselective reaction….. 9

Figure 1.4 . “Privileged Ligands” ...………………………………………………... 10

Figure 1.5 . Commonly employed CDA’s………………………………………….. 14

Figure 1.6 . Chiral stationary phases…………………………………...... 15

Figure 1.7 . Common fluorescence sensors………………………………...... 17

Figure 1.8 . 4-Substituted quinoline derivatives used as antimalarial drugs………... 20

Figure 1.9 . Heme ferriprotoporphyrin IX (FPIX)………………………………….. 21

Figure 1.10 . Artemisinin and its derivatives artemether and artesunate………….... 22

Figure 2.1 . Structure of 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene-

N,N ’-dioxide………………………………………………………………………… 32

Figure 3.1 . Commonly employed BOX catalysts………………………………...... 34

Figure 3.2 . Structures of chiral ligands screened…………………………………... 45

Figure 4.1 . Illustration of the favored intermediate in the bisoxazolidine-copper(I)

catalyzed Henry reaction……………………………………………………………. 78

Figure 4.2 . Illustration of the disfavored intermediate in the bisoxazolidine-

copper(I) catalyzed Henry reaction…………………………………………...... 79

Figure 4.3 . Illustration of the favored intermediate in the bisoxazolidine-zinc(II)

catalyzed Henry reaction …………………………………………………. 81

Figure 4.4 . Illustration of the disfavored intermediate in the bisoxazolidine-

zinc(II) catalyzed Henry reaction …………………………………………………... 82

Figure 5.1 . Conformationally stable 6,6’-dinitrobiphenyl-2,2’-dicarboxylic acid and conformationally unstable biphenyl-2,2’-dicarboxylic acid...... 98

Figure 5.2 . Sterically congested and confomationally stable 1,8-diquinolyl- and

1,8-diacridylnaphthalenes developed by Wolf et al. …………………………...... 101

Figure 5.3. HPLC chromatograms for the separation of the enantiomers of 1,8- bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene N,N’ -dioxide…..…………….. 106

Figure 5.4 . Calix[4]crown employed by Kubo et al. in the enantioselective sensing

of amino alcohols and amino acids……..…………………………………………... 113

Figure 5.5 . p Ka values of selected substituted pyridine N-oxides………………….. 114

Figure 5.6 . Titration of 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene

N,N’ -dioxide with HCl……………………………………………….……………... 115

Figure 5.7 . Titration of diprotic 1,8-bis(3’-(3,5-dimethylphenyl)-9’-

acridyl)naphthalene N,N’ -dioxide with Et 3N……………………………………….. 115

Figure 5.8 . Structures of selected aminoalcohols screened………………………. 116

Figure 5.9 . Titration of diprotic 1,8-bis(3’-(3,5-dimethylphenyl)-9’-

acridyl)naphthalene N,N’ -dioxide with threoninol…………………………………. 117

Figure 5.10 . Structures of alcohols, ketones, esters, and carboxylic acids screened 118

Figure 5.11 . Structure of maleic acid triethylammonium dicarboxylate…………… 119

Figure 5.12 . Titration of diprotic 1,8-bis(3’-(3,5-dimethylphenyl)-9’- acridyl)naphthalene N,N’ -dioxide with the triethylammonium dicarboxylate of maleic acid………………………………………………………………………… 119

Figure 6.1 . 4-Substituted quinoline derivatives used as antimalarial drugs….…….. 131

Figure 6.2 . Representation of the acidic parasitic DV containing FPIX with Pfcrt membrane transport protein participating in active CQ efflux...…………………… 133

Figure 6.3. Important functional sites of the CQ structure…………………….…... 136

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List of Schemes

Scheme 1.1. Enzymatic reduction of deuteroacetaldehyde by coenzyme NADH and yeast alcohol dehydrogenase. …………………………………………………... 1

Scheme 1.2 . Enantioselective synthesis (R and R’ do not contain a chiral element and R ≠ R’)………………………………………………………………………….. 7

Scheme 1.3 . Enantiofacial control with a C 2-symmetric bisoxazoline catalyst……. 11

Scheme 2.1 . 1,2-Addition of diethylzinc to a trifluoromethyl ketone and structure

of 1………………………………………………………………………………….. 30

Scheme 2.2 . Synthesis of bisoxazolidine ligand, 2…... ………………...... 31

Scheme 3.1 . Generic synthesis of a BOX ligand………………………….………... 35

Scheme 3.2 . Cyclopropanation of styrene catalyzed by a BOX-copper(I) triflate complex …………………………………………………………………………….. 36

Scheme 3.3 . Diels-Alder reaction catalyzed by a BOX-FeCl 2I complex……….... 36

Scheme 3.4 . Asymmetric addition of CF 3TMS to aromatic ketones and alternative

approach to trifluoromethyl-derived tertiary alcohols using trifluoromethyl ketones

and diethylzinc……………………………………………………………………… 38

Scheme 3.5 . Reduction of a trifluoromethyl ketone by β-hydride elimination from diethylzinc ..………………………………………………………………………… 39

xiii

Scheme 4.1. Synthesis of bisoxazolidine catalyst 1……………………………...... 65

Scheme 4.2 . The bisoxazolidine catalyzed synthesis of a chiral propargylic

alcohol…………………………………...... 66

Scheme 4.3 . The bisoxazolidine catalyzed synthesis of a chiral β-hydroxy nitroalkane…………………………………………………………………………... 67

Scheme 4.4 . Evans’ bisoxazoline catalyzed addition of nitromethane to

benzaldehyde……………………………………………………...... 68

Scheme 4.5. Bisoxazolidine – CuOAc catalyzed Henry reaction…………………. 70

Scheme 4.6 . Enantioselectivity switch with bisoxazoline catalyst 1………………. 76

Scheme 4.7. CuOAc promoted Henry reaction with bisoxazolidine catalyst 1...... 77

Scheme 4.8 . Me 2Zn promoted Henry reaction with bisoxazolidine catalyst 1...... 80

Scheme 4.9 . Synthesis of ( S)-5-hydroxypiperidin-2-one………………………….. 83

Scheme 5.1 . Synthesis of 1,8-di(2-methyl-1’-phenyl)naphthalene, 1. ……………... 99

Scheme 5.2 . Rotational energy barriers between anti - and syn - isomers of 1,8-

disubstituted naphthalenes ...... ….. 100

Scheme 5.3. Synthesis of 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene

N,N’ -dioxide, 5……………………………………………………….……………... 104

Scheme 5.4 . Lewis base catalysis using 5 in the asymmetric allylation of aldehydes and Lewis acid catalysis using 5 in a stereoselective Diels-Alder reaction……………………………………..……………………………………….. 108

xiv

Scheme 5.5 . The asymmetric allylation of benzaldehyde…………………………. 109

Scheme 5.6 . 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene N,N’ -dioxide catalyzed desymmetrization of cis -stilbene oxide by silicon tetrachloride…………. 111

Scheme 6.1 . Synthesis of symmetrically branched N-(7-chloro-4-quinolyl)-1,9- bis(diethylamino)-5-aminononan acid and N-(7-chloro-4-quinolyl)-1,9-

bis(diisopropylamino)-5-aminononane………………………...…………………… 138

Scheme 6.2 . Synthesis of linear 4-oxosubstituted quinolines………………….….. 139

Scheme 6. 3. Synthesis of branched 4-oxosubstituted quinolines…………………... 140

Scheme 6. 4. Synthesis of sulfonamide derived CQ derivatives…………………… 141

List of Tables

Table 3.1 Screening of the ligand-catalyzed nucleophilic addition of Et 2Zn to

2,2,2-trifluoroacetophenone, 6……………………………………………………… 40

Table 3. 2 TMEDA-catalyzed addition of Et 2Zn to 2,2,2-trifluoroacetophenone, 6... 42

Table 3. 3. Chiral ligand screening results …………………………………………. 46

Table 3. 4. TBOX-catalyzed addition of Et 2Zn to 2,2,2-trifluoroacetophenone, 6…. 48

Table 4.1. Screening of the bisoxazolidine catalyzed Henry reaction…...... 69

Table 4.2 . Enantioselective Henry reaction of aromatic aldehydes………………... 71

Table 4.3 . Enantioselective Henry reaction of aliphatic aldehydes ………...... 73

Table 6.1 . Antiplasmodial activity of the symmetrically branched 4- aminoquinolines…………………………………………………………………….. 143

Table 6.2 . Antiplasmodial activity of 4-oxoquinolines with linear and branched sidechains…………………………………………………………………………… 145

Table 6.3 . Antiplasmodial activity of sulfonamide derived CQ derivatives……… 148

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List of Abbreviations

BOX bisoxazoline

CDA chiral derivatizing agent

CF 3TMS (trifluoromethyl)trimethylsilane

CDMT 2-chloro-4,6-dimethoxy-1,3,5-triazine

CLSR chiral lanthanide shift reagent

CQ chloroquine

CQR chloroquine resistant malaria

CQS chloroquine sensitive malaria

CSA chiral solvating agent

DIEA N,N-diispropylethyl amine

DV digestive vacuole

FDA U.S. Food and Drug Administration

FPIX heme ferriprotoporphyrin IX

GC gas chromatography

Hb hemoglobin

HPLC high performance liquid chromatography

MsCl methanesulfonyl chloride

NAD + nicotinamide adenine dinucleotide

xvii

Pybop benzotriazol-1-yl-oxytripyrrolidinophosphonium

hexafluorophosphate

SI selectivity index

TBOX 2,2'-isopropylidenebis[(4 S)-4-tert -butyl-2-oxazoline]

TBAF tetrabutylammonium fluoride t-BuOK / t-BuOH potassium tert -butoxide in tert -butanol

TMEDA N,N,N’,N’ -tetramethyl ethylenediamine

xviii

I. Introduction

1.1 The importance of chirality

Nature often serves as inspiration for innovation and scientific breakthroughs. In

1953, Westheimer et al. published two reports showing that enzymes can control the stereoselective outcome of asymmetric reactions.1,2 In the first paper, they showed that the reduction of nicotinamide adenine dinucleotide (NAD +) was accomplished diastereoselectively by yeast alcohol dehydrogenase through the transfer of deuteride from 1,1-dideuteroethanol. In their second report, they revealed that the reduction of deuteroacetaldehyde by the coenzyme NADH is enantioselective when mediated by yeast alcohol dehydrogenase (Scheme 1.1).

NADH NAD+ O OH + + H H D yeast alcohol D dehydrogenase

Scheme 1.1. Enzymatic reduction of deuteroacetaldehyde by coenzyme NADH and yeast alcohol dehydrogenase. It was later confirmed that the ( S)-enantiomer was produced. 3

Together, these findings proved that enzymes are able to act as chiral agents by

participating in diastereoselective and enantioselective reactions.4 1

Due to the ability of enzymes to act as asymmetric catalysts and because of the inherently chiral structure of receptors, antibodies, DNA, etc., the enantiomers of many biologically active compounds such as flavors, fragrances, nutrients, and pharmaceuticals can have distinctly different biochemical and pharmacological activities. For a chiral pharmaceutical, one enantiomer may possess the desired activity and high potency, while the other enantiomer could be inactive, antagonistic, severely toxic, or have an altogether different effect.5 The chiral drug thalidomide was promoted as a non-barbituate sedative

capable of easing nausea in pregnant women and distributed primarily in Europe from

1957-1961. 6-8 In 1961, thalidomide was abruptly pulled from the market when it was discovered that the drug is teratogenic. Thalidomide had been sold in racemic form, and it was later discovered that the (S)-enantiomer of the drug causes severe birth defects while the (R)-enantiomer causes no birth defects even at four times the dose of its enantiomer

(Figure 1.1). 9,10 Furthermore, thalidomide is now known to racemize rapidly (within

minutes or hours) under physiological conditions such that administration of an

enantiomerically pure sample would be futile. 11

O O

N O N O NH NH O O O O

(S)-thalidomide (R)-thalidomide

Figure 1.1 . Structures of ( S)-thalidomide and ( R)-thalidomide

In 1992, the U.S. Food and Drug Administration (FDA) published the Policy Statement for the Development of New Stereoisomeric Drugs in which guidelines for newly developed chiral drugs were outlined. Specifically, the isomeric composition of a drug must be quantified and the pharmacokinetics evaluated for each stereoisomer in vivo .12

Among the drugs approved by the FDA between 1998 and 2001, 30% were single enantiomers with several chiral centers, 7% were single enantiomers with one chiral center, and 7% were racemates. 13 Moreover, worldwide sales of enantiopure drugs are

staggering. For example, Nexium had third quarter 2008 sales of $1.3 billion 14 and

Lipitor had second quarter 2007 sales of $2.7 billion (Figure 1.2).15

O F N H N

OH O O O Nexium Ca 2008 3Q Earnings: $1.3 Billion O O O H HO N S O O N O N H N F O

Lipitor 2007 2Q Earnings: $2.7 Billion

Figure 1.2. Structures of Nexium and Lipitor

With such compelling clinical and economic impetus, the development of syntheses producing enantiomerically pure compounds continues to be an area of intense research.

1.2 Enantioselective reactions

In spite of the significance of stereochemical purity, chiral compounds are often produced via racemic syntheses followed by separation of the enantiomeric products 4 using chromatography or other means. A major drawback of this practice is that it is time-intensive, and moreover, the maximum theoretical yield of a single enantiomer is

50% assuming the reaction produces 100% of the desired product. For enantiopure drugs with earnings of over $1 billion per quarter, this is not a compelling scenario.

Asymmetric reactions, however, can provide enantiopure products in up to 100% yield when a chiral reagent or auxiliary (diastereoselective synthesis), or a catalyst

(enantioselective synthesis) is employed. If applicable, catalysis is always the best choice as it requires only substoichiometric amounts of the chirality inducing agent thereby providing an amplification of chirality. Asymmetric syntheses can be accomplished by the following stereodifferentiations:16

A. Enantioselective synthesis

a. Enantiotopos-differentiating reactions

b. Enantioface-differentiating reactions

c. Enantiomer-differentiating reactions

B. Diastereoselective synthesis

a. Diastereotopos-differentiating reactions

b. Diastereoface-differentiating reactions

c. Diastereomer-differentiating reactions

The rhodium catalyzed ring opening of a cyclobutane followed by trapping with a phenolic nucleophile is an example of an enantiotopos-differentiating reaction (Scheme

1.2).17 In this case, enantiotopic C—C σ-bonds are activated by insertion of a chiral 5 rhodium catalyst. Prochiral carbonyl compounds can be attacked on either the Re or Si face to yield opposite enantiomeric products in an enantioface-differentiating reaction. A representative example is the Reformatsky reaction catalyzed by a BINOL derivative in conjunction with dimethylzinc where one of the faces of the prochiral aldehyde is attacked preferentially. 18 A kinetic resolution is an example of an enantiomer- differentiating reaction where enantiomeric starting materials are consumed at different rates. In the hydrolytic ring-opening of epoxides catalyzed by extremely low catalytic loadings of a Salen-cobalt complex and acetic acid, one of the enantiomers of the racemic epoxide reacts much faster than the other. 19 If the reaction is stopped at 50% conversion, the diol is obtained in 98% ee and the unreacted epoxide is enriched to 99% ee. A remaining drawback of a kinetic resolution is the maximum theoretical yield of 50%. The diastereoselective variants of these reactions can be visualized by exchanging R or R’ with a chiral element in Scheme 1.2.

1) Enantiotopos-differentiating reactions

Y X Y X X Y Y X ' ' R R R R R R' Representative example: O

O PPh2 O PPh2 [{Rh(cod)(OH)} ] O 2 (16 mol %) (7 mol %) O O O OH 77% yield, >99% ee 2) Enantioface-differentiating reactions Y X Y X Y Y X

R R' R R' R R' Representative example: TMS

OH OH Me2Zn OH O TMS OEt O O (20 mol %) H + I OEt 72% yield, 84% ee

3) Enantiomer-differentiating reactions

X H H X XY Y H H X + + R R' R R' R R' R R'

Representative example:

H H N N Co O O

CH3CO2H OH (0.4 mol %) OH O (0.2 mol %) + H2O 50% yield, 98% ee H3C

Scheme 1.2. Enantioselective synthesis (R and R’ do not contain a chiral element and R

≠ R’) 7

Eliel has developed the following criteria for evaluating an asymmetric synthesis procedure: 16

1. The reaction must be highly stereoselective.

2. Chiral auxiliaries must be easily removed from the chiral element without

racemization.

3. The chiral auxiliary or catalyst should be recovered in good yield without

racemization.

4. The chiral auxiliary, reagent, or catalyst should be inexpensive and readily

available in the desired enantiomeric form.

Because enantiomers are isoenergetic, enantioselective reactions must be conducted under kinetic control through reaction pathways traversing diastereomeric transition states (Figure 1.3). The ratio of enantiomeric products is solely determined by the difference in free energies of activation ( ∆∆ Gǂ) for the transitions states at a given temperature (Equation 1.1). Given that selectivity is exponentially dependent on ∆∆ Gǂ,

relatively small changes in transition state energies can have drastic consequences on the

enantiomeric excess.

S A R

E -∆∆G ∆GR

∆GS A

S R

Figure 1.3. Energy profile for a kinetically controlled enantioselective reaction

[S] kS = = e-∆∆G/RT [R] kR (Eq. 1.1)

Several so-called “privileged ligands” have been synthesized over the years and proven to be broadly applicable to a wide variety of catalytic asymmetric reactions

(Figure 1.4).20

O O OH PPh2 N N OH PPh2 R R

BINOL BINAP BOX

R R R O P R OH N N R O OH P R OH HO R R R R R R

salen DUPHOS TADDOL

Figure 1.4. “Privileged Ligands”

While the molecular structures and compositions of the ligands are clearly different, they are all rigid, bidentate, and C 2-symmetric. C2-Symmetry plays an important role in asymmetric catalysis by limiting the number of possible transition states for a reaction

(Scheme 1.3). In the case of a generic bisoxazoline catalyzed Diels-Alder reaction, the dienophile has the option to isoenergetically dock into the catalyst with the double bond oriented to the “right” or to the “left”. Because of the C 2-symmetry of the chiral Lewis acid, either approach results in the same transition state favoring formation of the same enantiomer. As a rule of thumb, C 2-symmetric catalysts provide superior asymmetric induction compared to other catalyst designs and are more readily optimized due to a less complicated transition state structure analysis. 10

O O Re-face is blocked N N O O R 2+ R H )( Cu O O N O (S) O O N O Si-face endo-selective N N is accessible approach from the rear O O R Cu2+ R N O

different substrate orientation affords the same TS O O Re-face H N N is blocked ON R 2+ R (S) Cu )( O O O O ON endo-selective approach from the front Si-face is accessible

Scheme 1.3. Enantiofacial control with a C 2-symmetric bisoxazoline catalyst

1.3 Stereoselective analysis

During the development of an enantioselective reaction, it is necessary to determine the stereoselectivity which is generally expressed as the enantiomeric excess of the chiral product (Equation 1.2).

| [R]-[S] | enantiomeric excess = x 100% (Equation 1.2) [R] + [S]

This can be accomplished by polarimetric analysis of the rotation of plane-polarized light by the purified scalemic product mixture. A compound’s specific rotation is defined by the following equation (Equation 1.3):

α (observed) [α] = (Equation 1.3) c * l

α (observed) = rotation observed in polarimeter c = concentration (g/mL) l = length of cell (dm)

Because the specific rotation varies with solvent, wavelength, and temperature, these must also be specified. The enantiomeric excess can then be determined by the following equation if it is proven for that compound that the enantiomeric excess varies linearly with the observed rotation (Equation 1.4): 21

observed rotation enantiomeric excess = x 100% (Equation 1.4) rotation of pure enantiomer

While polarimetry is straightforward and measurements are easily obtained, Equation 1.4 highlights the drawback of polarimetry. A standard is required because one needs to know the rotation of the pure enantiomer. Also, small impurities can have drastic effects on the observed rotation especially if the compound has a small specific rotation and the

impurity has a large specific rotation. Lastly, because optical rotation does not always

increase linearly with enantiomeric purity, it can be misleading.22

Liquid and gas chromatography have been successfully employed in numerous

analyses of the enantiomeric composition of chiral compounds.5 Indirect

chromatographic separations rely on the use of a chiral derivatizing agent (CDA) to form

a mixture of diastereomers representative of the stereochemical composition of the

enantiomeric starting materials. Because diastereomers are not inherently isoenergetic,

they can be separated on an achiral stationary phase. This method requires that the CDA

itself is enantiopure and that the covalent bond is stable under the analytical conditions.

Unfortunately, derivatization requires another reaction step and can be time-consuming.23

Amino acids, isocyanates, amines, and acyl chlorides have all been used as CDAs for high performance liquid chromatography (HPLC) and gas chromatography (GC) (Figure

1.5).5

HS OH NCO HN O

N-acetyl-(R)-cysteine (S)-1-(naphthyl)ethyl isocyanate

O NH 2 Cl

(S)-1-(naphthyl)ethylamine (R)-2-phenylbutyryl chloride

Figure 1.5. Commonly employed CDA’s

Because of the difficulties in derivatizing enantiomers for stereochemical analysis, direct chromatography on a chiral stationary phase is a more desirable method for quantification of enantiomeric excess. Throughout the course of separation, the chiral analytes form transient diastereomeric complexes with the stationary phase and are moved forward with different velocities by the mobile phase. Since the enantiomers form non-isoenergetic diastereomeric complexes using non-covalent interactions, they can be separated without the need for derivatization. Chiral small molecules and macromolecules (cellulose, proteins, cyclodextrins) have all been used for chiral stationary phases (Figure 1.6).5

t or pp su a ilic OR S Si O ONH RO O OR n O2N NO2 Silica support

(S,S)-Whelk-O Cellulose derivatives

HO O O O OH HO OH O OH HO O HO OH O O O R H O R OH HN N O HO O N N OH OH R H O R H O O OH OH OH O O OH OH O OOH n HO O OH

Silica support Silica support

Cyclodextrin derivatives Protein derivatives

Figure 1.6. Chiral stationary phases

NMR spectroscopy can also be used to determine the enantiomeric composition

of a mixture. Diastereomers often have different chemical shifts in an NMR spectrum.

Therefore, CDAs are used just as in indirect chromatography to form diastereomers from a pair of enantiomers, and the integration of the diastereomeric peaks provides a means to determine enantiomeric excess. It is important that no kinetic resolution occurs during the derivatization. CDAs used for NMR spectroscopy are usually amines, alcohols, and carboxylic acids. 24 Chiral solvating agents (CSAs) can also be used to determine enantiomer excess, but instead of forming non-reversible covalent bonds as with CDAs,

CSAs bind through non-covalent intermolecular forces. Cyclodextrins and crown ethers are often used as CSAs and form diastereomeric inclusion complexes. Lastly, chiral lanthanide shift reagents (CLSR) are CSAs that exploit the paramagnetism of the lanthanide to cause shifts in the NMR spectrum of the analyte which results in superior resolution. A limitation of NMR spectroscopy is the inherently low sensitivity (compared to chromatographic visualization techniques such as UV spectroscopy) and larger amounts of sample are needed. As a result, minor enantiomers present in less than 5% may not be detected.

UV and fluorescence spectroscopy provide additional methods to quantify enantiomeric excess while addressing some of the limitations in the aforementioned techniques. Both offer high sensitivity, inexpensive instrumentation, waste reduction, and the capability to perform real-time analyses of enantiomeric mixtures.25 The use of UV or fluorescence sensors for enantioselective anaylsis is contingent on the formation of diastereomers or diastereomeric complexes in solution which can modulate (increase,

decrease, or shift) the UV or fluorescence response of the sensor at a certain wavelength

(Figure 1.7).

OH NH2 OH NH2

HO OH (M )-Hexahelicene-11,14-diol (R)-BINOL (R)-BINAM

Figure 1.7. Common fluorescence sensors 26

1.4 Development of heme-targeted antimalarials combating chloroquine resistant malaria

The World Health Organization currently estimates that there are between 350

and 500 million cases and over 1 million deaths attributed annually to malaria. 27 Malaria

is among the most widespread and devastating diseases worldwide, and is found

primarily in tropical and subtropical regions of the world, an area accounting for 41% of

the world’s population. 28 90% of all infections are reported in Africa,29 and in 2002,

malaria infections accounted for 10.7% of all children’s deaths in developing countries. 28

Characteristic malaria symptoms include: periodic chills, rigors, high fevers and

17 subsequent profuse perspiration in cycles lasting between 48 and 72 hours. 29 Progression of the disease can lead to lethal complications such as cerebral malaria, anemia, and kidney failure. 30

Malaria is caused by a mosquito-borne parasite that is transmitted to humans through the saliva of an infected female Anopheles mosquito. 31 Humans can be infected with one of five species of malarial parasites: Plasmodium falciparum , P. vivax , P. malariae , P. ovale, or P. knowlesi (the only zoonotic species), with P. falciparum and P.

vivax most commonly infecting humans. 32,33 P. falciparum is the most deadly protozoan parasite. The lifecycle of the P. falciparum parasite includes both human and mosquito

hosts. 28,34 When an infected mosquito feeds off human blood, malaria parasites in the sporozoite stage of their life cycle will be transmitted through the mosquito’s saliva. The sporozoites initially infect human liver cells, and a single sporozoite can produce between

30,000 and 40,000 daughter cells. The daughter cells mature into merozoites and are released into the blood after cell rupture. Now in the blood stream, the merozoite then infects red blood cells. Upon infection of the red blood cells, some merozoites can undergo asexual reproduction producing 8-24 daughter cells per merozoite after 48 hours.

The merozoites are released into the blood stream after cell rupture with the ability to infect more red blood cells. Blood stage parasites are responsible for the symptoms of the disease. Some merozoites commit at the ring-trophozoite boundary to form gametocytes.

These gametocytes are then ingested by the mosquito during a blood feeding. Once residing in the stomach of the mosquito host, the gametocytes unite to eventually mature 18 into zygotes. The zygotes then multiply and form sporozoites in the mosquito saliva, effectively restarting the cycle.

Several compounds have been used to treat malaria in the past. Three centuries ago, the bark of the Cinchona tree in South America was found to be the first effective treatment for P. falciparum malaria. 35 In 1817, the antimalarial compound quinine was isolated from the bark. Since the discovery of the antimalarial potency of quinine and other cinchona alkaloids, a variety of drugs exhibiting a 4-substituted quinoline pharmacophore have been introduced. In particular, chloroquine (CQ), mefloquine, sontoquine, and amodiaquine have proved to be among the most effective antimalarial drugs (Figure 1.8). 36-38 Since it’s discovery in the 1940’s, CQ was the most effective antimalarial to emerge since quinine. 35 Moreover, CQ is inexpensive, and it costs just

$0.13 to treat a case of malaria. 27

HN HO HO N N HN OMe F3C N N N Cl CF3 quinine chloroquine mefloquine

OH N N HN HN

N Cl N Cl sontoquine amodiaquine

Figure 1.8. 4-Substituted quinoline derivatives used as antimalarial drugs

Unfortunately, there has been a recent resurgence of multi-drug resistant

parasites. 39 CQ was used extensively in the 1960’s with the intent to eradicate malaria. 40

This widespread use most likely contributed to the increased incidence of CQ resistance.

An effective malaria vaccine is the ultimate goal in combating the disease, however, the malaria vaccine SPF66 41 , 42 and multi-component DNA vaccines have not yet been successfully implemented. 43 Noteworthy, the RTS,S malaria vaccine developed by

GlaxoSmithKline Biologicals in collaboration with the Walter Reed Army Institute of

Research entered Phase 3 trials in 2009, marking the furthest progress towards a malaria vaccine to date. 44,45 While it is hoped that a malaria vaccine will be developed, research

20 continues on understanding the mechanism of CQ-resistance malaria and the development of new pharmaceuticals to target CQ-resistant malaria.

The mechanism of CQ resistance is not yet fully understood. Intraerythrocytic malaria parasites proteolyze hemoglobin in the red blood cells to acquire amino acids and provide room for growth in the red blood cells. 46 A metabolic by-product of the digestion is heme ferriprotoporphyrin IX (FPIX) (Figure 1.9).

Cl N N Fe N N

HO O O OH

Figure 1.9. Heme ferriprotoporphyrin IX (FPIX)

FPIX is toxic to the parasites, but they have developed a strategy to limit the amount of free FPIX by converting it into a non-toxic insoluble crystalline form called hemozoin. It is postulated that aminoquinolines inhibit the conversion of FPIX to hemozoin by either binding to soluble heme or the face of the growing hemozoin crystals. 46-50 Because the parasites do not have genetic control over the hemozoin from the host or enzymes that can degrade heme, the membrane transport of the drug is probably altered through an integral membrane protein, Pfcrt, in the digestive vacuole to develop CQ resistance. 51,52 21

New therapeutics are continually being developed to combat chloroquine resistant malaria (CQR). CQR reversal agents have been implemented in an attempt to resensitize the malaria parasites to treatment with CQ. 53 In 1987, verapamil, a known calcium channel blocker, was shown to resensitize P. falciparum clones to CQ by likely blocking the increased release of drug often seen in multidrug resistance cells.54 There is also incentive to apply FDA-approved drugs to malaria that originally were intended to treat other diseases. A large library screening of pharmaceuticals has found 19 known drugs that inhibited the growth of P. falciparum .55

Artemisinin was discovered in 1971 and has proven to be effective in combating malaria. 56 Lacking a 4-substituted quinoline ring common to CQ and its derivatives, artemisin is an endoperoxide sesquiterpene lactone. 57 Artemether and artesunate are artemisinin derivatives that also exhibit good therapeutic indices and have found use as antimalarial drugs (Figure 1.10). 58

OH O H O H OCH3 O H O O O H O H O O O O O O H O O O

Artemisinin Artemether Artesunate

Figure 1.10 . Artemisinin and its derivatives artemether and artesunate

Unfortunately, however, artemisinin is very expensive and is still isolated as a natural product. 57 Moreover, artemether and artesunate are usually administered as co-

components of a combination therapy because of their short half lives and consequent

low bioavailability. 57,59,60 Most importantly, in spite of their only recent implementation, resistance to endoperoxides has already been reported.61,62 It remains a monumental task to simultaneously understand the mechanism of CQR and develop new antimalarials to circumvent the resistance problem.

1.5 References

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II. Objectives

In spite of the massive efforts already directed towards the development of asymmetric reactions for the synthesis of chiral products in high yields and ee’s,1 there still remains an ever-increasing need to expand the breadth and efficacy of asymmetric catalysis. Additionally, the improvement of methods for stereoselective analysis is imperative to rapidly screen the efficiency of asymmetric reactions and to evalauate the purity and stereochemical stability of chiral compounds such as pharmaceuticals. As described in the previous chapter, polarimetry, NMR spectroscopy, and chromatography have limitations that need to be addressed by new techniques to provide improved means for fast and sensitive analysis of the enantiomeric excess of asymmetric reactions.

Malaria is one of the world’s most devastating diseases and due to the increased incidence of multi-drug resistant parasites, malaria threatens to become an even greater problem. Current research must address the need for new antimalarial drugs and the understanding of the mechanism of drug resistance in the parasites.

The main objectives of this thesis were:

(a) to develop new asymmetric reactions employing bisoxazoline catalysts

At the beginning of this study, bisoxazoline ligands, including 2,2'-

isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] (TBOX), 1, had already been

successfully used for a wide variety of asymmetric reactions.2,3 Based on their 29

general usefulness, we envisioned that TBOX could be applied to the

enantioselective addition of diethylzinc to trifluoromethyl ketones, a

transformation never successfully completed in racemic or enantioselective

fashion. If successful, this reaction would provide convenient access to a variety

of pharmaceutically relevant trifluoromethyl-derived tertiary alcohols such as the

anti-HIV agent efavirenz.4

O O N N O ? OH CF3 + Et2Zn CF3 Et 1 2,2'-isopropylidenebis[(4S)- 4-tert-butyl-2-oxazoline]

Scheme 2.1. 1,2-Addition of diethylzinc to a trifluoromethyl ketone and structure of 1

(b) to develop new applications for a chiral bisoxazoline catalyst

The bisoxazolidine catalyst 2 synthesized by N,O-diketal formation from 1,2-

cyclohexanedione and (1R,2S)-cis-1-amino-2-indanol had already been

successfully employed in a variety of dialkylzinc reactions (Scheme 2.2).5 We

anticipated that the ligand would be equally applicable to carbon-carbon bond

forming reactions controlled by other transition metals such as copper.

(S) O O (R) OH HCO2H O HN + (S) (S) (S) (S) (R) NH O NH2 (R) 2

Scheme 2.2. Synthesis of bisoxazolidine ligand 2

diacridylnaphthalene N,N’-dioxide and to implement it in asymmetric

catalysis and enantioselective sensing applications

Wolf and Mei had successfully synthesized and separated the enantiomers of

1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene N,N’-dioxide, 3, on a

small scale and demonstrated its usefulness as an enantioselective UV and

fluorescence sensor (Figure 2.1).6 It was expected that the synthesis of the ligand

could be scaled-up and that a more effective chiral separation procedure could be

developed. The aim was to produce sufficient amounts of the enantiopure ligand

to evaluate new applications in asymmetric catalytic reactions and

enantioselective sensing.

N N O O

Figure 2.1. Structure of 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene

N,N’-dioxide

(d) to develop new rationally designed antimalarials to probe the structure –

function relationships of chloroquine resistant malaria

The increased occurrence of multi-drug resistant malaria has inspired great

efforts in developing new antimalarials such as mefloquine, tafenoquine, and

amodiaquine. We predicted that the synthesis of rationally designed chloroquine

derivatives would enable us to find new effective antimalarials and better

understand the mechanism of drug resistance.

References:

1 a) Senanayake, C. H; Krishnamurthy, D.; Gallou, I. Handbook of Chiral Fine

Chemicals, Ager, D., Ed., Taylor & Francis Ed.: New York, 2005. b) Christmann, M.; Brase, S. Asymmetric Synthesis- the Essentials, Wiley-VCH: Verlag,

2007. 32

2 Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691-1693.

3 For a recent review, see: Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006,

106, 3561-3651.

4 (a) Corbett, J. W.; Ko, S. S.; Rodgers, J. D.; Gearhart, L. A.; Magnus, N. A.; Bacheler,

L. T.; Diamond, S.; Jeffrey, S.; Klabe, R. M.; Cordova, B. C.; Garber, S.; Logue, K.;

Trainor, G. L.; Anderson, P. S.; Erickson-Vittanen, S. K. J. Med. Chem. 2000, 43, 2019-

2030. (b) Choudhury- Mukherjee, I.; Schenck, H. A.; Cechova, S.; Pajewski, T. N.;

Kapur, J.; Ellena, J.; Cafiso, D. S.; Brown, M. L. J. Med. Chem. 2003, 46, 2494-2501. (c)

Schenck, H. A.; Lenkowski, P. W.; Choudhury-Mukherjee, I.; Ko, S.-H.; Stables, J. P.;

Patel, M. K.; Brown, M. L. Bioorg. Med. Chem. 2004, 12, 979-993. (d) Xue, Y.; Chao,

E.; Zuercher, W. J.; Willson, T. M.; Collins, J. L.; Redinbo, M. R. Bioorg. Med. Chem.

2007, 15, 2156-2166.

5 a) Wolf, C.; Liu, S. J. Am. Chem. Soc. 2006, 128, 10996-10997. b) Liu, S.; Wolf, C.

Org. Lett. 2007, 9, 2965-2968. c) Liu, S.; Wolf, C. Org. Lett. 2008, 10, 1831-1834.

6 a) Wolf, C.; Mei, X. J. Am. Chem. Soc. 2003, 125, 10651-10658. b) Mei, X.; Wolf, C. J.

Am. Chem. Soc. 2004, 126, 14736-14737. c) Mei, X.; Martin, R. M.; Wolf, C. J. Org.

Chem. 2006, 71, 2854-2861.

III. Asymmetric catalysis with a bisoxazoline ligandi

3.1 Introduction to bisoxazoline catalysts

Bisoxazoline (BOX) chiral catalysts belong to the set of “privileged ligands” that have been shown to be broadly applicable across a wide variety of reactions including asymmetric aziridination, aldol, Michael, Diels-Alder, and cyclopropanation reactions.1,2

Classified by two oxazoline rings joined by a spacer, BOX ligands are C2-symmetric, bidentate, and rigid (Figure 3.1). BOX ligands generally coordinate to transition metals to form chiral Lewis acids such that at least one Lewis acidic site is available on the metal for reactant coordination and activation.

O O O O N O O N N N N N

Figure 3.1. Commonly employed BOX catalysts

The synthesis of BOX ligands is relatively straightforward and allows easy modification for ligand tunability. The synthesis commences with the amide bond formation between a

symmetrically substituted malonic acid derivative and a chiral β-amino alcohol (Scheme

3.1). The ring forming cyclization step can then occur through a variety of methods such as reaction with thionyl chloride followed by cyclization under basic conditions or with triphenylphosphine and triethylamine.

1. SOCl2 2. OH- NH2 R R R R HO O O R R R' O O O O OH OH NH HN N N Cl Cl R' R' R' R' PPh3, Et3N

Scheme 3.1. Generic synthesis of a BOX ligand

Two seminal papers were published simultaneously in 1991 and initiated the intense exploration of asymmetric reactions catalyzed by BOX complexes. In the first paper, Evans et al. reported the asymmetric cyclopropanation of styrene with ethyl diazoacetate catalyzed by a BOX-copper(I) triflate complex.3 Employing 1 mol %

catalytic loading, they were able to accomplish the cyclopropanation in 77% overall yield

with each diastereomer produced in enantiomeric excesses exceeding 97% ee (Scheme

3.2).

O O N N

CuOTf

OEt (1 mol %) Ph N + 2 Ph CO Et + O 2 Ph CO2Et 99% ee 97% ee 73 : 27 77% overall yield

Scheme 3.2. Cyclopropanation of styrene catalyzed by a BOX-copper(I) triflate complex

In the other report, Corey et al. relayed a Diels-Alder reaction catalyzed by a BOX-FeCl2I

complex.4 The reaction of the bidentate dienophile, 3-acryloyl-1,3-oxazolidin-2-one, and cyclopentadiene in the presence of 10 mol % of the BOX-FeCl2I complex provided the

endo product in 85% yield and 82% ee (Scheme 3.3).

O O N N Ph Ph FeCl I 2 H O O (10 mol %) O O N + + N O O N O H O O 85%, 82% ee

96 : 4

Scheme 3.3. Diels-Alder reaction catalyzed by a BOX-FeCl2I complex

3.2 The application of bisoxazoline catalysts in the asymmetric addition of

diethylzinc to trifluoromethyl ketones

Numerous examples of asymmetric additions of diethylzinc to aldehydes, ketones,

and imine analogues have been reported to date, but to the best of our knowledge, this

otherwise extensively studied reaction has not been successfully applied to trifluoromethyl ketones.5 Despite the significance of trifluoromethyl-substituted tertiary

alcohols, which exhibit an important subunit in several pharmaceuticals including

anticonvulsants, anesthetics, and Merck’s anti-HIV agent efavirenz,6 enantioselective

carbon-carbon bond formation with trifluoromethyl ketones and organometallic reagents

has been barely developed and is restricted to nucleophiles devoid of a β-hydrogen.7 As a

result, the synthesis of chiral trifluoromethyl-derived tertiary alcohols mostly relies on the

asymmetric cinchona alkaloid-catalyzed addition of (trifluoromethyl)trimethylsilane,

(CF3TMS) to aryl ketones followed by tetrabutylammonium fluoride (TBAF)-promoted

cleavage of the intermediate silyl ethers (Scheme 3.4).8

1. CF3SiMe3

N HO Ar

O O HO CF3 N R2Zn R R CF3 2. TBAF ?

Scheme 3.4. Asymmetric addition of CF3TMS to aromatic ketones and alternative

approach to trifluoromethyl-derived tertiary alcohols using trifluoromethyl ketones and

diethylzinc

It is noteworthy that the catalytic enantioselective synthesis of tertiary trifluoromethyl

alcohols has also been accomplished via Sharpless dihydroxylation,9 Friedel-Crafts acylation,10 ene reaction,11 and aldol reaction.12

The lack of a method that allows direct alkylation of trifluoromethyl ketones with

organometallic reagents originates from the unique reactivity of these substrates. Unlike

the well established nucleophilic additions of organozinc reagents to aldehydes or other

carbonyl functionalities, trifluoromethyl ketones have been known to undergo

predominant reduction upon addition of diethylzinc due to β-hydride elimination

(Scheme 3.5).13

Et O ZnEt Zn O Zn O CF3 + H H - H2C CH2 CF3 CF3

Scheme 3.5. Reduction of a trifluoromethyl ketone by β-hydride elimination from diethylzinc

3.2.1 Racemic Addition of Diethylzinc to Trifluormethyl Ketones

We anticipated that activation of diethylzinc by bidentate ligands might favor carbon-carbon bond formation over β-hydride elimination and subsequent reduction, thus providing a new entry toward the synthesis of trifluoromethyl derived tertiary alcohols.14

Initial screening of catalytic amounts of ethylenediamine, 1, N,N’-dimethyl

ethylenediamine, 2, N,N,N’,N’-tetramethyl ethylenediamine (TMEDA), 3, 1,2-

dimethoxyethane, 4, and morpholine, 5, in toluene at -10 °C indicated that this can be

achieved with 3 equivalents of Et2Zn although the alkylation of 2,2,2-

trifluoroacetophenone, 6, appeared to be relatively slow and was accompanied by

substantial reduction unless TMEDA was used (Table 3.1).

Table 3.1 Screening of the ligand-catalyzed nucleophilic addition of Et2Zn to 2,2,2- trifluoroacetophenone, 6

O OH Et2Zn (3 equiv.) HO CF3 + CF3 CF3 Et 1 - 5 (10-20 mol %) 6 o 7 8 toluene, -10 C

Ligand Yield (%) Entry Time (h) (mol %) 6 7 8 1 / 24 7 93 /

H2N NH2 2 1 4 77 22 1 (20)

H N N 3 H 20 63 28 9 2 (10)

N N

4 3 24 36 3 61 (10)

O O 5 4 4 66 31 3 (10)

O 6 4 62 27 11 N H 5 (10)

In particular, ligands 1 and 4 did not favor the alkylation, and more than 20% of 2,2,2-

trifluoro-1-phenylethanol, 7, was formed within 4 hours (entries 2 and 5). Employing

ligands 2 and 5 in the reaction showed little improvement. The desired 1,1,1-trifluoro-2-

phenylbutan-2-ol, 8, was produced in low yields, and the reduction was still significantly

faster (entries 3 and 6). By contrast, the reaction outcome changed dramatically in the

presence of 10 mol % of TMEDA: 8 was obtained in 61% yield, while only 3% of the

reduction product 7 was isolated and 36% of the starting material was recovered (entry 4,

Table 3.1).

Further optimization of the catalyst loading, reaction temperature, and amount of

diethylzinc revealed that aromatic trifluoromethyl ketones undergo fast ethylation in the

presence of 5-10 mol % of TMEDA and 1.2 equivalents of Et2Zn at 10 °C (Table 3.2).

Under these conditions, trifluoroacetophenone gives 1,1,1-trifluoro-2-phenylbutan-2-ol in

93% yield within 1 hour (entry 1, Table 3.2). We found that this reaction furnishes a wide range of tertiary alcohols in 81-99% yield, and ester, nitrile, nitro, halo, and other aryl substituents are tolerated (entries 2-11). Aliphatic substrates proved to be significantly less reactive and required the use of stoichiometric amounts of TMEDA. Nevertheless, 2-

41 cyclohexyl-1,1,1-trifluorobutan-2-ol and 2-(cyclohexylmethyl)-1,1,1-trifluorobutan-2-ol were obtained in 82-84% yield (entries 12 and 13).

a Table 3.2 TMEDA-catalyzed addition of Et2Zn to 2,2,2-trifluoroacetophenone, 6

O Et2Zn (1.2 equiv.) HO CF3 CF Et 6 3 TMEDA 8 (5-10 mol %) o toluene, 10 C

Yield Time Entry Ketone Product (%) (h)

O OH 1 CF 93% 1 CF3 3

O OH 2 Br Br CF3 93% 1 CF3

O OH 3 Cl Cl CF3 94% 1 CF3

O OH 4 O O CF3 99% 1 CF3

O OH 5 S S CF3 96% 1 CF3

O OH b 6 CF3 93% 2.5 CF3

O OH c 7 NC NC CF3 81% 2 CF3

EtO O EtO OH 8 CF3 89% 1 O CF3 O

O OH 9 87% 1 CF3 CF3

O2N O2N OH 10d O 92% 1 CF3 CF3

Cl Cl OH 11e O 84% 1 CF3 CF3

O OH f 12 CF3 82% 4 CF3

f CF3 13 HO CF 84% 4 O 3 a All reactions were performed on a 0.24 mmol scale using 5 mol % of TMEDA and 1.2

b c equiv of Et2Zn in toluene at 10 °C unless otherwise noted. 5 °C. -10 °C, 10 mol % of 43

TMEDA. d -10 °C. e 5 °C, 10 mol % of TMEDA. f 1 equiv. of TMEDA and 2.4 equiv. of

Et2Zn.

3.2.2 Enantioselective addition of diethylzinc to trifluormethyl ketones

With a racemic method in hand, we decided to explore an asymmetric variant. On the basis of the success with TMEDA, chiral diamines and bisoxazolines as well as other

ligands that have proved to be very useful in asymmetric additions of diethylzinc to

carbonyl electrophiles were screened (Figure 3.2).

H N N N N N N N N H H 9 10 11 12

Ph O O O O OH O O N N N N N Ph N N H

13 14 15 16

O O O O N N O O Ph Ph N N N N Ph Ph Bn Bn 17 18 19

O O O O O O N N N N N Bn N N Bn

20 21 22

O O NH NH N N O S O S O O

OH HO 23 24

Figure 3.2. Structures of chiral ligands screened 45

Diamines 9-12 and bisoxazolines 15-18 and 21 proved to effectively catalyze the formation of tertiary alcohol 8 which was obtained in 80-99% yield within 4 hours albeit in low ee’s (entries 1-4, 7-10, and 13, Table 3.3). The competing reduction of 6 to 7 was favored in the presence of prolinol 13, bisoxazolines 19, 20, 22, and 23, and disulfonamide 24, which was used in conjunction with titanium tetraisopropoxide (entries

5, 11, 12, and 14-16). The most promising results were observed with 14, TBOX.

Literally quantitative amounts of 8 exhibiting 37% ee were produced when 10 mol % of this bisoxazoline was employed in an apolar solvent system at 5 °C (entry 6).

Table 3.3. Chiral ligand screening results a

O Et2Zn (1.2 equiv.) HO CF3 CF3 Et 6 ligand 9-24 8 (10 mol %)

Yield (%) Entry Ligand Time (h) ee (%) 6 7 8

1 9b 4 10 10 80 14

2 10 0.5 4 1 94 5

3 11 0.5 1 2 97 6

4 12b 4 10 10 80 0

5 13 5 23 76 0 n/a

6 14 0.5 1 0 99 37

7 15 0.1 2 0 98 8

8 16 0.2 12 0 88 1

9 17 0.5 0 0 99 7

10 18 0.5 0 0 99 0

11 19c 0.5 78 21 0 n/a

12 20 5 24 63 13 n.d.

13 21d 0.6 3 0 97 0

14 22c 0.4 76 21 3 n/a

15 23 0.5 86 13 1 n/a

e 16 24 3 40 60 0 n/a aAll reactions were performed on a 0.24 mmol scale using 10 mol % of the ligand and

o b 1.2 equiv of Et2Zn at 5 C in hexanes/toluene (1/1 v/v) unless otherwise noted. hexanes. c d o e o hexanes/THF (1/1). -35 C. 25 C, 1 equiv of Ti(Oi-Pr)4.

Variation of reaction parameters showed that the best results are obtained when the asymmetric nucleophilic addition of diethylzinc to aryl trifluoromethyl ketones is conducted in the presence of 10 mol % of TBOX in hexanes/toluene (3/1 v/v) at -35 °C

(Table 3.4).

a Table 3.4. TBOX-catalyzed addition of Et2Zn to 2,2,2-trifluoroacetophenone, 6

O Et2Zn (1.2 equiv) HO CF3 CF3 Et 6 TBOX 14 8 (10 mol %) o -35 C

Yieldb Time Entry Ketone Product ee (%) (%) (h) O OH 95% 51% 0.5 1 CF CF3 3 85%b 63% 2

O OH 2 Br Br CF3 99% 38% 1 CF3

O OH 3 Cl Cl CF3 99% 41% 1 CF3

O OH 4 O O CF3 83% 56% 1.1 CF3

O OH 5 S S CF3 99% 52% 0.9 CF3

O OH 6 CF3 75% 60% 0.5 CF3

O OH 7 NC NC CF3 71% 16% 3 CF3

EtO O EtO OH 8 CF3 92% 25% 2 O CF3 O

O OH 9 99% 54% 0.5 CF3 CF3

O2N O2N OH 10 O 83% 7% 2 CF3 CF3

Cl Cl OH 11 O 99% 12% 1 CF3 CF3

O OH c 12 CF3 78% 2% 4 CF3

CF c 3 13 HO CF 76% 0% 4 O 3 a All reactions were performed on a 0.24 mmol scale in toluene/hexanes (1/3 v/v) using

b c 10 mol % of TBOX and 1.2 equiv of Et2Zn at -35 °C unless otherwise noted. -78 °C.

50 mol % of TBOX, 25 °C.

Although superior results can be achieved in some cases when pure hexanes are used, we decided to continue with a binary solvent mixture consisting of 25% toluene in hexanes to maintain a homogeneous solution throughout the reaction. Under these conditions, the reaction is generally completed in less than 3 hours and the corresponding 2-aryl-1,1,1-

trifluorobutan-2-ols are obtained in 77-99% yield. A further decrease in the reaction

temperature slightly increased ee’s, but yields were usually lower (entry 1, Table 3.4).

We found that the enantioselectivity of this reaction varies considerably. 2,2,2-

Trifluoroacetophenone and its methoxy, methylthio, methyl, and tert-butyl analogues

gave tertiary alcohols in 51-60% ee (entries 1, 4, 5, 6, and 9), but significantly lower ee’s

were obtained when aryl halides, nitriles, esters, and nitro groups were present (entries 2,

3, 7, 8, 10, and 11). In analogy to the cinchona alkaloid-catalyzed C-C bond formation

using CF3TMS and aliphatic ketones, unsatisfactory yields and ee’s were produced with aliphatic substrates (entries 12 and 13).

3.3 Conclusions

In conclusion, we have developed the first general procedure for ligand-catalyzed nucleophilic addition of diethylzinc to trifluoromethyl ketones. A range of 2-aryl-1,1,1- trifluorobutan-2-ols have been prepared in up to 99% yield using 10 mol % of TMEDA to favor alkylation over β-hydride elimination. The reaction of aliphatic substrates proved more difficult and was found to require stoichiometric ligand amounts. These findings provide a new route for asymmetric synthesis of trifluoromethyl-derived tertiary alcohols

which are important components in many pharmaceuticals. Accordingly, we have

introduced the first asymmetric variant of this reaction. Screening of 16 chiral ligands

revealed that excellent yields and ee’s up to 61% can be obtained with TBOX as catalyst.

3.4 Experimental details

3.4.1 Synthesis of chiral ligands

All commercially available ligands, reagents, and solvents were used without further

purification. NMR spectra were obtained at 400 MHz (1H NMR) and 100 MHz (13C

NMR). Chemical shifts are reported in ppm relative to TMS. Reaction products were purified by column chromatography on silica gel (particle size 32-63 μm).

Preparation of (S)-N-ethyl-2-(pyrrolidin-1-ylmethyl)pyrrolidine

To a solution of (S)-(+)-2-(pyrrolidin-1-ylmethyl)pyrrolidine (80 mg, 0.52 mmol) in 4

o mL of glacial acetic acid at 5 C was slowly added NaBH4 (471 mg, 12.45 mmol). The

solution was then heated to 50 oC for 18 hours. Upon completion of the reaction, the flask

was allowed to cool to room temperature, basified with concentrated NaOH and then

extracted with dichloromethane. Solvents were removed under reduced pressure, and the

residue was purified by chromatography (dichloromethane:ethanol:triethylamine

1 1:1:0.01) to give 31 mg (0.17 mmol, 33%) of a yellow oil. H NMR (400 MHz, CDCl3) δ

= 1.11 (t, J = 7.2 Hz, 3 H), 1.60-1.83 (m, 7 H), 2.00 (m, 1 H), 2.11 (m, 1 H), 2.23 (m, 1

13 H), 2.37-2.64 (m, 7 H), 2.96 (m, 1 H), 3.17 (m, 1 H). C NMR (100 MHz, CDCl3) δ =

+ 22.6, 23.5, 30.7, 49.1, 53.8, 55.0, 62.0, 63.5. HRMS (ESI) calcd. for C11H22N2 [M+H]

183.1861; found 183.1752.

Preparation of (1R,2R)-N,N,N’,N’-tetraethyl-1,2-diphenylethane-1,2-diamine15

To a solution of (1R,2R)-(+)-1,2-diphenylethylenediamine (110 mg, 0.52 mmol) in 4 mL

o of glacial acetic acid at 5 C was slowly added NaBH4 (1.0 g, 26 mmol). The solution was

then heated to 50 oC for 18 hours. Upon completion of the reaction, the flask was allowed to cool to room temperature, basified with concentrated NaOH and then extracted with dichloromethane. Solvents were removed under reduced pressure to give 152 mg (0.47

1 mmol, 90%) of a yellow oil. H NMR (400 MHz, CDCl3) δ = 1.12 (t, J = 7.0 Hz, 12 H),

2.04-2.16 (m, 4 H), 2.79-2.88 (m, 4 H), 4.38 (s, 2 H), 7.00-7.11 (m, 10 H). 13C NMR (100

MHz, CDCl3) δ = 14.6, 43.2, 64.2, 126.3, 127.4, 129.3.

Preparation of N,N'-((1R,2R)-cyclohexane-1,2-diyl)bis(1-(2-hydroxy-7,7- dimethylbicyclo[2.2.1]heptan-1-yl)methanesulfonamide)

16,17 1 The ligand was prepared following literature procedure. H NMR (400 MHz, CDCl3)

δ = 0.84 (s, 6 H), 1.07 (s, 6 H), 1.10-1.15 (m, 2 H), 1.29-1.45 (m, 4 H), 1.48-1.57 (m, 2

H), 1.67-1.88 (m, 12 H), 2.14-2.20 (m, 2 H), 2.91 (d, J = 13.6 Hz, 2 H), 3.03-3.12 (m, 2

H), 3.34 (d, J = 3.8 Hz, 2 H), 3.49 (d, J = 13.6 Hz, 2 H), 4.05-4.12 (m, J = 4.0 Hz, 2 H),

13 5.09 (d, J = 7.1 Hz, 2 H). C NMR (100 MHz, CDCl3) δ = 19.9, 20.5, 24.7, 27.3, 30.6,

34.8, 39.0, 44.5, 48.8, 50.6, 54.1, 57.8, 76.6.

3.4.2 TMEDA catalyzed synthesis of racemic trifluoromethyl alcohols

To a solution of TMEDA (0.029 mmol in 0.05 mL of hexanes, 5 mol %) under nitrogen

at 10 oC was added diethylzinc (1.0 M in hexanes, 0.70 mL, 0.70 mmol). The solution was stirred for 10 minutes, and the trifluoromethyl ketone (0.57 mmol) was added. After the reaction was complete, it was quenched with saturated ammonium chloride solution, extracted with dichloromethane, and dried over MgSO4. The solvents were removed

under reduced pressure and the residue purified by flash column chromatography as

specified below.

3.4.3 Enantioselective synthesis of trifluoromethyl alcohols

To a solution of TBOX (14 mg, 0.048 mmol, 10 mol %) in anhydrous toluene (0.2 mL)

under nitrogen at -35 oC was added diethylzinc (1.0 M in hexanes, 0.58 mL, 0.58 mmol).

The solution was allowed to stir for 10 minutes, and the trifluoromethyl ketone (0.48

mmol) was added. After the reaction was complete, it was quenched with saturated

ammonium chloride solution, extracted with dichloromethane, and dried over MgSO4.

The solvents were removed carefully under reduced pressure, and the products were

isolated as specified below.

3.4.4 Purification and characterization of trifluoromethyl alcohols

1,1,1-Trifluoro-2-phenylbutan-2-ol18

Chromatographic purification (pentane:dichloromethane = 3:1) gave a colorless oil. The

ee was determined by HPLC on Chiralpak OD using hexanes:IPA (98:2) as the mobile

phase, t1 = 8.6 min, t2 = 9.7 min, α = 1.23. TMEDA catalysis: 55 mg (0.27 mmol, 93%);

1 TBOX catalysis: 95%, 51% ee. H NMR (400 MHz, CDCl3) δ = 0.80 (t, J = 7.5 Hz, 3

H), 2.05 (m, 1 H), 2.19-2.28 (m, 2 H), 7.32-7.42 (m, 3 H), 7.53 (d, J = 7.5 Hz, 2 H). 13C

NMR (100 MHz, CDCl3) δ = 6.5, 28.2, 78.0 (q, J = 29.2 Hz), 126.3 (q, J = 285.7 Hz),

126.4, 128.3, 128.3, 136.2.

2-(4-Bromophenyl)-1,1,1-trifluorobutan-2-ol18

Chromatographic purification (pentane:ethyl acetate = 10:1) gave a colorless oil. The ee

was determined by HPLC on Chiralpak AD using hexanes:EtOH (98:2) as the mobile

phase, t1 = 10.7 min, t2 = 13.8 min, α = 1.47. TMEDA catalysis: 152 mg (0.54 mmol,

1 93%); TBOX catalysis: 99%, 38% ee. H NMR (300 MHz, CDCl3) δ = 0.83 (t, J = 7.5

Hz, 3 H), 2.02 (m, 1 H), 2.15-2.27 (m, 2 H), 7.44 (d, J = 8.7 Hz, 2 H), 7.51-7.56 (m, 2

13 H). C NMR (75 MHz, CDCl3) δ = 6.4, 28.1, 77.1 (q, J = 38.0 Hz), 122.7, 125.6 (q, J =

325.8 Hz), 128.3, 131.3, 135.1.

2-(4-Chlorophenyl)-1,1,1-trifluorobutan-2-ol

Chromatographic purification (pentane:ethyl acetate = 95:5) gave a colorless oil. The ee

was determined by HPLC on Chiralpak AD using hexanes:EtOH (98:2) as the mobile

phase, t1 = 10.3 min, t2 = 13.0 min, α = 1.43. TMEDA catalysis: 129 mg (0.54 mmol,

1 94%); TBOX catalysis: 99%, 41% ee. H NMR (400 MHz, CDCl3) δ = 0.80 (t, J = 7.2

Hz, 3 H), 2.03 (m, 1 H), 2.16-2.25 (m, 2 H), 7.35-7.39 (m, 2 H), 7.48 (d, J = 8.7 Hz, 2

13 H). C NMR (100 MHz, CDCl3) δ = 6.4, 28.3, 77.1 (q, J = 20.0 Hz), 115.5 (q, J = 626.0

+ Hz), 127.4, 132.0, 141.3. HRMS (ESI) calcd. for C10H10ClF3O [M+H] 239.0451; found

239.0583.

2-(4-Methoxyphenyl)-1,1,1-trifluorobutan-2-ol

Chromatographic purification (pentane:ethyl acetate = 96:4) gave white crystals. The ee

was determined by HPLC on Chiralpak AD using hexanes:EtOH (98:2) as the mobile

phase, t1 = 15.1 min, t2 = 16.7 min, α = 1.14. TMEDA catalysis: 65 mg (0.29 mmol,

1 99%); TBOX catalysis: 83%, 56% ee. H NMR (400 MHz, CDCl3) δ = 0.81 (t, J = 7.2

Hz, 3 H), 2.01 (m, 1 H), 2.15-2.28 (m, 2 H), 3.82 (s, 3 H), 6.90-6.95 (m, 2 H), 7.44 (d, J

13 = 8.8 Hz, 2 H). C NMR (100 MHz, CDCl3) δ = 6.5, 28.0, 55.2, 77.0 (q, J = 32.6 Hz),

113.6, 125.8 (q, J = 283.6 Hz), 127.7, 128.0, 159.5. HRMS (ESI) calcd. for C11H13F3O2

[M+H]+ 235.0946; found 235.1001.

2-(4-Thiomethylphenyl)-1,1,1-trifluorobutan-2-ol

Chromatographic purification (pentane:dichloromethane = 4:1) and a gradual change to

100% dichloromethane gave light yellow crystals. The ee was determined by HPLC on

Chiralpak AD using hexanes : EtOH (98 : 2) as the mobile phase, t1 = 16.9 min, t2 = 20.9

min, α = 1.31. TMEDA catalysis: 58 mg (0.23 mmol, 96%); TBOX catalysis: 99%, 52%

1 ee. H NMR (400 MHz, CDCl3) δ = 0.80 (t, J = 7.5 Hz, 3 H), 2.03 (m, 1 H), 2.16-2.26

(m, 2 H), 2.49 (s, 3 H), 7.25-7.28 (m, 2 H), 7.44 (d, J = 8.8 Hz, 2 H). 13C NMR (100

MHz, CDCl3) δ = 6.5, 15.4, 28.0, 77.4 (q, J = 28.9 Hz), 125.7 (q, J = 283.7 Hz), 126.0,

+ 126.9, 132.7, 139.0. HRMS (ESI) calcd. for C11H13F3OS [M] 250.0639; found 250.0684.

2-(3-Methylphenyl)-1,1,1-trifluorobutan-2-ol19

Chromatographic purification (pentane:dichloromethane = 3:1) gave a colorless oil. The

ee was determined by HPLC on Chiralpak AD using hexanes:EtOH (98:2) as the mobile

56 phase, t1 = 7.4 min, t2 = 8.6 min, α = 1.34. TMEDA catalysis: 109 mg (0.50 mmol, 87%);

1 TBOX catalysis: 99%, 54% ee. H NMR (400 MHz, CDCl3) δ = 0.79 (t, J = 7.5 Hz, 3

H), 2.03 (m, 1 H), 2.22 (m, 1 H), 2.33 (s, 1 H), 2.37 (s, 3 H), 7.16 (d, J = 7.1 Hz, 1 H),

13 7.25-7.35 (m, 4 H). C NMR (100 MHz, CDCl3) δ = 6.5, 21.6, 28.1, 77.6 (q, J = 28.0

Hz), 123.4, 125.8 (q, J = 283.6 Hz), 127.0, 128.1, 129.1, 136.0, 137.9.

2-(2-Chlorophenyl)-1,1,1-trifluorobutan-2-ol

Chromatographic purification (pentane:dichloromethane = 5:1) gave a colorless oil. The ee was determined by HPLC on Chiralpak AD using hexanes : IPA (98 : 2) as the mobile phase, t1 = 8.3 min, t2 = 10.0 min, α = 1.39. TMEDA catalysis: 58 mg (0.24 mmol, 84%);

1 TBOX catalysis: 99%, 12% ee. H NMR (400 MHz, CDCl3) δ = 0.90 (t, J = 7.4 Hz, 3

H), 2.05 (m, 1 H), 2.74 (m, 1 H), 3.63 (s, 1 H), 7.27-7.34 (m, 2 H), 7.41 (m, 1 H), 7.67

13 (m, 1 H). C NMR (100 MHz, CDCl3) δ = 7.0, 27.2, 79.2 (q, J = 28.5 Hz), 125.7 (q, J =

284.9 Hz), 127.0, 130.0, 131.2, 132.3, 132.7. HRMS (ESI) calcd. for C10H10ClF3O

[M+H]+ 239.0451; found 239.0814.

2-(4-Ethylbenzoate)-1,1,1-trifluorobutan-2-ol

Chromatographic purification (dichloromethane:pentane = 2:1) gave white crystals. The ee was determined by HPLC on Chiralcel OD using hexanes:EtOH (98:2) as the mobile

phase, t1 = 10.9 min, t2 = 11.7 min, α = 1.13. TMEDA catalysis: 59 mg (0.21 mmol,

1 89%); TBOX catalysis: 92%, 25% ee. H NMR (400 MHz, CDCl3) δ = 0.79 (t, J = 7.5

Hz, 3 H), 1.40 (t, J = 7.1 Hz, 3 H), 2.07 (m, 1 H), 2.25 (m, 1 H), 2.39 (s, 1 H), 4.39 (q, J

= 7.1 Hz, 2 H), 7.63 (d, J = 8.3 Hz, 2 H), 8.06-8.09 (m, 2 H). 13C NMR (100 MHz,

CDCl3) δ = 6.4, 14.3, 28.3, 61.1, 77.4 (q, J = 26.6 Hz), 125.5 (q, J = 283.8 Hz), 126.5,

+ 129.5, 130.5, 140.9, 166.2. HRMS (ESI) calcd. for C13H15F3O3 [M+H] 277.1052; found

277.1108.

2-(4-t-Butylphenyl)-1,1,1-trifluorobutan-2-ol

Chromatographic purification (dichloromethane:pentane = 2:1) gave white crystals. The ee was determined by HPLC on Chiralpak AS using hexanes:EtOH (98.5:1.5) as the mobile phase, t1 = 9.7 min, t2 = 10.7 min, α = 1.39. TMEDA catalysis: 79 mg (0.30

1 mmol, 93%); TBOX catalysis: 75%, 60% ee. H NMR (400 MHz, CDCl3) δ = 0.81 (t, J

= 7.4 Hz, 3 H), 1.33 (s, 9 H), 2.05 (m, 1 H), 2.18-2.27 (m, 2 H), 7.39-7.45 (m, 4 H). 13C

NMR (100 MHz, CDCl3) δ = 6.6, 28.0, 31.3, 34.5, 77.5 (q, J = 25.0 Hz), 125.2, 125.8 (q,

+ J = 283.6 Hz), 126.0, 133.1, 151.2. HRMS (ESI) calcd. for C14H19F3O [M+H] 261.1466;

found 261.1439.

2-(4-Benzonitrile)-1,1,1-trifluorobutan-2-ol

Chromatographic purification (dichloromethane) followed by recrystallization from pentane gave white crystals. The ee was determined by HPLC on Chiralpak AD using hexanes:EtOH (95:5) as the mobile phase, t1 = 9.6 min, t2 = 13.8 min, α = 1.76. TMEDA

catalysis: 44 mg (0.19 mmol, 81%); TBOX catalysis: 71%, 16% ee. 1H NMR (400 MHz,

CDCl3) δ = 0.79 (t, J = 7.5 Hz, 3 H), 2.08 (m, 1 H), 2.30 (m, 1 H), 2.31 (s, 1 H), 7.70-

13 7.72 (m, 4 H). C NMR (100 MHz, CDCl3) δ = 6.4, 28.3, 77.3 (q, J = 23.3 Hz), 112.5,

118.4, 125.6 (q, J = 283.9 Hz), 127.4, 132.1, 141.3. HRMS (ESI) calcd. for C11H10F3NO

[M+H]+ 230.0793; found 230.0871.

2-(3-Nitrophenyl)-1,1,1-trifluorobutan-2-ol

Chromatographic purification (dichloromethane:pentane = 3:2) gave light yellow

crystals. The ee was determined by HPLC on Chiralpak AD using hexanes:EtOH (95:5)

as the mobile phase, t1 = 10.9 min, t2 = 11.7 min, α = 1.13. TMEDA catalysis: 52 mg

1 (0.21 mmol, 92%); TBOX catalysis: 83%, 7% ee. H NMR (400 MHz, CDCl3) δ = 0.82

(t, J = 7.5 Hz, 3 H), 2.12 (m, 1 H), 2.31 (m, 1 H), 2.39 (s, 1 H), 7.62 (m, 1 H), 7.89 (d, J

13 = 8.0 Hz, 1 H), 8.25 (m, 1 H), 8.46 (m, 1 H). C NMR (100 MHz, CDCl3) δ = 6.4, 28.3,

77.4 (q, J = 23.4 Hz), 122.0, 123.5, 125.2 (q, J = 283.7 Hz), 129.5, 132.6, 138.3, 148.4.

2-Cyclohexyl-1,1,1-trifluorobutan-2-ol

Chromatographic purification (pentane:dichloromethane = 3:1) gave a colorless oil. The

ee was determined by GC on octakis(2,6-di-O-methyl-3-O-pentyl)-γ-cyclodextrin, 85 oC, t1 = 28.3 min, t2 = 30.0 min, α = 1.07. TMEDA catalysis: 83 mg (0.40 mmol, 82%);

1 TBOX catalysis: 78%, 2% ee. H NMR (400 MHz, CDCl3) δ = 0.97 (t, J = 7.6 Hz, 3 H),

13 1.11-1.30 (m, 5 H), 1.68-1.84 (m, 8 H), 1.92 (s, 1 H). C NMR (100 MHz, CDCl3) δ =

7.1, 24.9 (m, 1C), 26.3, 26.6-26.9 (m, 2C), 42.3, 77.1 (q, J = 23.7 Hz), 126.2 (q, J = 286.9

+ Hz). HRMS (ESI) calcd. for C10H17F3O [M+H] 211.1310; found 211.1133.

2-(Cyclohexylmethyl)-1,1,1-trifluorobutan-2-ol

Chromatographic purification (pentane:dichloromethane = 7:1) gave a colorless oil. The ee was determined by GC on octakis(6-O-methyl-2,3-di-O-pentyl)-γ-cyclodextrin, 65 oC, t1 = 62.0 min, t2 = 64.5 min, α = 1.04. TMEDA catalysis: 91 mg (0.41 mmol, 84%);

1 TBOX catalysis: 76%, 0% ee. H NMR (400 MHz, CDCl3) δ = 0.95-1.34 (m, 7 H), 1.50-

13 1.89 (m, 11 H). C NMR (100 MHz, CDCl3) δ = 7.7, 26.1, 26.3, 26.4, 27.1, 32.5, 35.0,

35.2, 39.8, 76.3 (q, J = 27.0 Hz), 126.7 (q, J = 285.1 Hz).

3.5 References

1 Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691-1693.

2 For a recent review, see: Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006,

106, 3561-3651.

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113, 726-728.

4 Corey, E. J.; Imai, N.; Zhang, H-. Y. J. Am. Chem. Soc. 1991, 113, 728-729.

5 Selected examples of asymmetric 1,2-additions of diethylzinc to aldehydes:

(a) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071-

6072. (b) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem. Soc. 1987, 109, 7111-

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9800-9809. (f) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757-824. (g) Wolf, C.; Francis,

C. J.; Hawes, P. A.; Shah, M. Tetrahedron: Asymmetry 2002, 13, 1733-1741. (h) Wolf,

C.; Hawes, P. A. J. Org. Chem. 2002, 67, 2727-2729. (i) Kozlowski, M. C.; Dixon, S. L.;

Panda, M.; Lauri, G. J. Am. Chem. Soc. 2003, 125, 6614-6615. (j) Liu, S.; Wolf, C. Org.

Lett. 2007, 9, 2965-2968. Selected examples of asymmetric 1,2-additions of diethylzinc

to ketones: (k) DiMauro, E. F.; Kozlowski, M. C. Org. Lett. 2002, 4, 3781-3784. (l)

Garcia, C.; Larochelle, L. K.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 10970-10971. 61

(m) DiMauro, E. F.; Kozlowski, M. C. J. Am. Chem. Soc. 2002, 124, 12668-12669. (n)

Ramon, D.; Yus, M. Angew. Chem., Int. Ed. 2004, 43, 284-287. (o) Jeon, S.-J.; Li, H.;

Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 16416-16425. (p) Hui, A.; Zhang, J.; Fan, J.;

Wang, Z. Tetrahedron: Asymmetry 2006, 17, 2101-2107. (q) Forrat, V. J.; Ramon, D. J.;

Yus, M. Tetrahedron: Asymmetry 2006, 17, 2054-2058. (r) Forrat, V. J.; Prieto, O.;

Ramon, D. J.; Yus, M. Chem.-Eur. J. 2006, 12, 4431-4445. Recent reviews on nucleophilic additions to imines, see: (s) Riant, O.; Hannedouche, J. Org. Biomol. Chem.

2007, 5, 873-888. (t) Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541-2569.

(u) Ferraris, D. Tetrahedron 2007, 63, 9581-9597.

6 (a) Corbett, J. W.; Ko, S. S.; Rodgers, J. D.; Gearhart, L. A.; Magnus, N. A.; Bacheler,

L. T.; Diamond, S.; Jeffrey, S.; Klabe, R. M.; Cordova, B. C.; Garber, S.; Logue, K.;

Trainor, G. L.; Anderson, P. S.; Erickson-Vittanen, S. K. J. Med. Chem. 2000, 43, 2019-

2030. (b) Choudhury- Mukherjee, I.; Schenck, H. A.; Cechova, S.; Pajewski, T. N.;

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Schenck, H. A.; Lenkowski, P. W.; Choudhury-Mukherjee, I.; Ko, S.-H.; Stables, J. P.;

Patel, M. K.; Brown, M. L. Bioorg. Med. Chem. 2004, 12, 979-993. (d) Xue, Y.; Chao,

E.; Zuercher, W. J.; Willson, T. M.; Collins, J. L.; Redinbo, M. R. Bioorg. Med. Chem.

2007, 15, 2156-2166.

7 (a) Martina, S. L. X.; Jagt, R. B. C.; de Vries, J. G.; Feringa, B. L.; Minnaard, A. J.

Chem. Commun. 2006, 4093-4095. (b) Motoki, R.; Tomita, D.; Kanai, M.; Shibasaki, M.

Tetrahedron Lett. 2006, 47, 8083-8086. (c) Motoki, R.; Kanai, M.; Shibasaki, M. Org. 62

Lett. 2007, 9, 2997-3000. For a catalytic enantioselective nitroaldol reaction of

trifluoromethyl ketones, see: (d) Tur, F.; Saa, J. M. Org. Lett. 2007, 9, 5079-5082.

8(a) Iseki, K.; Nagai, T.; Kobayashi, Y. Tetrahedron Lett. 1994, 35, 3137-3138. (b)

Caron, S.; Do, N. M.; Larivee, A. Synthesis 2003, 1693-1698. (c) Mikami, K.; Itoh, Y.;

Yamanaka, M. Chem. Rev. 2004, 104, 1-16. (d) Ma, J.-A.; Cahard, D. Chem. Rev. 2004,

104, 6119-6146. (e) Billard, T.; Langlois, B. R. Eur. J. Org. Chem. 2007, 891-897. (f)

Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975-996.

9 Bennani, Y. L.; Vanhessche, K. P. M.; Sharpless, B. Tetrahedron: Asymmetry 1994, 5,

1473-1476.

10(a) Zhuang, W.; Gathergood, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2001,

66, 1009-1013. (b) Lyle, M. P. A.; Draper, N. D.; Wilson, P. D. Org. Lett. 2005, 7, 901-

904. (c) Torok, B.; Abid, M.; London, G.; Esquibel, J.; Torok, M.; Mhadgut, S. C.; Yan,

P.; Prakash, G. K. S. Angew. Chem., Int. Ed. 2005, 44, 3086-3089.

11(a) Aikawa, K.; Kainuma, S.; Hatano, M.; Mikami, K. Tetrahedron Lett. 2004, 45, 183-

185. (b) Mikami, K.; Aikawa, K.; Kainuma, S.; Kawakami, Y.; Saito, T.; Sayo, N.;

Kumobayashi, H. Tetrahedron: Asymmetry 2004, 15, 3885-3889. (c) Mikami, K.;

Kakuno, H.; Aikawa, K. Angew. Chem., Int. Ed. 2005, 44, 7257-7260.

12 (a) Gathergood, N.; Juhl, K.; Poulsen, T. B.; Thordrup, K.; Jørgensen, K. A. Org.

Biomol. Chem. 2004, 2, 1077-1085. (b) Wang, X.-J.; Zhao, Y.; Liu, J.-T. Org. Lett. 2007,

9, 1343-1345.

13 An asymmetric addition of organozinc reagents to trifluoromethyl ketimines has been described: Lauzon, C.; Charette, A. B. Org. Lett. 2006, 8, 2743-2745.

14 Yearick, K.; Wolf, C. Org. Lett. 2008, 10, 3915-3918.

15 Rangareddy, K.; Selvakumar, K.; Harrod, J.F. J. Org. Chem. 2004, 69, 6843-6850.

16 Balsells, J.; Walsh, P. J. J. Am. Chem. Soc. 2000, 122, 3250-3251.

17 Garcia, C.; LaRochelle, L. K.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 10970-10971.

18 Mizuta, S.; Shibata, N.; Akiti, S.; Fujimoto, H.; Nakamura, S.; Toru, T. Org. Lett.

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3579-3580.

IV. Asymmetric catalysis with a bisoxazolidine ligand

4.1 Introduction to the bisoxazolidine catalyst

In contrast to the widely diverse and well explored bisoxazoline ligands,1 structurally similar chiral bisoxazolidine catalysts have only recently been applied to asymmetric synthesis. While bisoxazolines are generally synthesized from chiral amino alcohols and malonyl dichloride derivatives, bisoxazolidine ligands can be synthesized by replacing the dichloride with a 1,2-diketone. Wolf et al. have reported the synthesis of the first C2-symmetric, diketone-derived bisoxazolidine catalyst prepared in 90% yield and

99% de by formic acid catalyzed N,O-diketal formation from 1,2-cyclohexanedione and

(1R,2S)-cis-1-amino-2-indanol (Scheme 4.1).2 With an average nitrogen–oxygen bond distance of 2.78 Å, bidentate coordination to transition metals is favorable.

(S) O O (R) OH HCO2H O HN + (S) (S) (S) (S) (R) 90% NH O NH2 (R) 1

Scheme 4.1. Synthesis of bisoxazolidine catalyst 1

The bisoxazolidine catalyst has been proven to be broadly useful for a variety of dialkylzinc promoted asymmetric reactions. By employing the catalyst with

dimethylzinc, alkynes and aldehydes, aromatic and aliphatic propargylic alcohols were formed in excellent yields and ee’s (Scheme 4.2).2

H O N NHO OH O (10 mol %) H + Me2Zn

90%, 93% ee

Scheme 4.2. The bisoxazolidine catalyzed synthesis of a chiral propargylic alcohol

Moreover, the catalyst facilitates the alkylation of aldehydes by alkylzinc reagents with

excellent yield and stereoselectivity while exhibiting a positive non-linear effect due to a

dual phase distribution of scalemic catalyst.3 Wolf et al. have most recently relayed a synthetic protocol for the asymmetric nitroaldol reaction utilizing the bisoxazolidine catalyst, nitromethane, and dimethylzinc to generate the reactive zinc nitronate in situ

(Scheme 4.3).4 Although the Henry reaction products were obtained in high yields and

ee’s, a remaining drawback of this procedure is that three equivalents of costly and

pyrophoric dimethylzinc are required.

H O N NHO O OH (8 mol %) H + MeNO2 Me2Zn NO (3 equiv.) 2 92%, 92% ee

Scheme 4.3. The bisoxazolidine catalyzed synthesis of a chiral β-hydroxy nitroalkane

4.2 The application of the bisoxazolidine catalyst in the asymmetric Henry reaction

The asymmetric Henry reaction has emerged as a powerful synthetic tool for the stereoselective formation of carbon-carbon bonds.5 The resultant β-hydroxy nitroalkanes

are synthetically relevant pharmaceutical precursors6 and can be readily transformed to β- amino alcohols and α-hydroxy carboxylic acids.7,8 Previously reported asymmetric Henry reaction protocols generally involve the use of a chiral catalyst derived from rare earth metals,9 Co(II),10 Mg(II),11 Zn(II),12 and Cu(II).13 Beginning with Evans’ seminal report

in 2003,13c the Cu(II)-bisoxazoline catalyzed Henry reaction has been well explored

(Scheme 4.4).14,15

O O N N Cu AcO OAc O OH (5 mol %) H + MeNO2

NO2 76%, 94% ee Scheme 4.4. Evans’ bisoxazoline catalyzed addition of nitromethane to benzaldehyde

However, catalytic protocols utilizing Cu(I) complexes have just recently been

reported.16- 20 Xiong et al. have shown that a tetrahydrosalen Cu(I) complex can

effectively catalyze the nitroaldol reaction for a variety of aromatic and aliphatic

substrates in good to excellent yields and ee’s.17 Arai et al. have similarly reported a

procedure employing a chiral sulfonyldiamine-CuCl catalyst system with stoichiometric

amounts of pyridine to successfully catalyze the Henry reaction of aromatic and aliphatic

aldehydes in generally excellent yields and good to excellent and ee’s.18 Inspired by the

success with copper catalyzed Henry reactions and because of the drawbacks mentioned previously for the bisoxazolidine catalyzed Henry reaction, we decided to explore the

possibility of a dimethylzinc-free variant.

4.2.1 Henry reaction optimization and substrate scope determination

Initial screening of a variety of metal salts revealed that copper acetate complexes afford the most promising results (Table 4.1). The reaction catalyzed by Cu(I) acetate proceeded significantly faster than in the presence of Cu(II) acetate. Because we were able to obtain 2-nitro-1-phenylethanol in 96% yield and 68% ee in 1.5 hours at room temperature, we decided to use this as a starting point to optimize the reaction.

Table 4.1. Screening of the bisoxazolidine catalyzed Henry reaction

O 1 (10 mol%) OH metal salt (9 mol%) * H + MeNO2 EtOH NO2 R 25oC R R = OMe, H

Entry Substrate Metal Salt Time (h) Yield (%) ee (%)

1 H Cu(COOCF3)2 24 0% N/A O

2 H Zn(OAc)2 24 <10% N/A O

3 H Mg(OAc)2 24 <10% N/A O

4 H Cu(OAc)2 24 50% 69% O

O 5 H CuCl + pyridine (20 mol %) 20 75% 16%

O 6 H CuOAc 1.5 96% 68%

Catalyst loading, solvents, additives, temperatures, and concentrations were screened using benzaldehyde as the model substrate. The best results were obtained with 10 mol %

of 1 and 9 mol % of CuOAc in ethanol at -15 oC. Under these conditions, we obtained 2-

nitro-1-phenylethanol, in 93% yield and 89% ee after 16 hours (Scheme 4.5).

H O N NHO

(10 mol %) O OH CuOAc (9 mol %) H + MeNO2 o EtOH, -15 C, 16 h NO2 93%, 89% ee

Scheme 4.5. Bisoxazolidine – CuOAc catalyzed Henry reaction

We then decided to explore the substrate scope of aromatic aldehydes (Table 4.2). We were pleased to find that electron-withdrawing substituents on the aromatic rings are well 70

tolerated and furnished the corresponding β-hydroxy nitroalkanes in up to 95% yield and

86% ee within 24 hours. For example, the formation of 2-nitro-1-(4-bromophenyl)ethanol was accomplished within 16 hours with 93% yield and 86% ee (Table 4.2, entry 5). Less reactive aldehydes such as 4-methoxybenzaldehyde required longer reaction times with diminished yields, but the product was still formed in 84% ee.

Table 4.2. Enantioselective Henry reaction of aromatic aldehydes

H O N NHO (10 mol %) O OH CuOAc (9 mol %) R H + MeNO2 R EtOH NO2

Temp. Time Yield Entry Substrate Product ee (%)c, d (oC) (h) (%)b

1 OH CHO -15 16 93% 89% (S)

NO 2

OH 2 CHO -15 16 91% 88% (S)

NO 2

OH 3 CHO -10 24 95% 84% (S)

F NO2 F

OH 4 CHO -15 6 90% 78% (S)

NC NO2 NC

OH 5 CHO -15 16 93% 86% (S)

Br NO2 Br

OH CHO 6 -10 24 88% 74% (S)

O2N NO2

O2N

OH 7 CHO -10 48 67% 84% (S)

MeO NO2 MeO

a All reactions were performed on a 1 mmol scale using 10 mol % of 1 as catalyst, 9 mol

% CuOAc, four 4 Å molecular sieves, and 10 equivalents of nitromethane in 2.4 mL

EtOH. b Isolated yields. c Determined by HPLC on Chiralcel OD and Chiralpak AD d The absolute configuration of the major enantiomer was determined by chiral HPLC analysis using Chiralcel OD and Chiralpak AD as described in the literature. 13c,21- 24

We then decided to examine the suitability of this procedure for aliphatic aldehydes (Table 4.3). We were pleased to discover that the bisoxazolidine – Cu(I)

catalyzed nitroaldol reaction provided the corresponding β-hydroxy nitroalkanes in up to

97% yield and 97% ee. Importantly, sterically hindered aldehydes are well tolerated, and

we were able to obtain (S)-3,3-dimethyl-1-nitrobutan-2-ol in 85% yield and 92% ee

(Table 4.3, entry 7). The reaction procedure was also compatible with α,β-unsaturated

aldehydes, and (S)-1-nitro-4-phenyl-but-3-en-2-ol was produced in 90% yield and 88% ee (Table 4.3, entry 1).

Table 4.3. Enantioselective Henry reaction of aliphatic aldehydes

H O N NHO (10 mol %) O OH CuOAc (9 mol%) R H + MeNO2 R EtOH NO2

Temp. Time Entry Substrate Product Yield (%)b ee (%) c, d (oC) (h)

OH 1 CHO -15 24 90% 88% (S)

NO 2

OH 2 CHO -10 24 87% 93% (S)

NO2

OH 3 CHO -10 24 85% 91% (S)

NO2

O OH 4 -10 48 91% 93% (S)e

4 4 NO 2

O OH 5 -10 48 92% 93% (S)

7 7

NO2

OH 6 O -10 48 91% 93% (S)

NO2

OH 7 O 0 48 85% 92% (S)

NO2

O OH 8 0 48 97% 97% (S)

NO 2

a All reactions were performed on a 1 mmol scale using 10 mol % of 1 as catalyst, 9 mol

% CuOAc, four 4 Å molecular sieves, and 10 equivalents of nitromethane in 2.4 mL

4.2.2 Metal-controlled reversal of enantioselectivity

In recent years, the concept of completely reversing the enantioselectivity of a reaction while maintaining a single chiral catalyst has received increasing attention.25

Often, if the chiral ligand is derived from a natural product that is only readily available

as a single enantiomer, it is advantageous to simply change reaction conditions to obtain

the opposite product configuration. Mosher first explored this concept in the 1970’s. He found that the absolute configuration of secondary alcohols obtained by asymmetric reduction of ketones can be determined by the amount of time the components of the chiral reagent ((+)-(2S,3R)-4-dimethylamino-l,2-diphenyl-3-methyl-2-butanol and lithium aluminum hydride) were mixed prior to the introduction of the substrate.26,27 Du et al.

have shown that a tridentate bisoxazoline ligand can switch the enantioselectivity of the

product obtained by the Henry reaction of α-ketoesters depending on whether Cu(OTf)2

28 or Et2Zn is used. We have observed a similar metal enantioselectivity switch with our

bisoxazolidine catalyst. In a previous paper, it was shown that the use of bisoxazolidine 1

4 and Me2Zn gives (R)-β-hydroxy nitroalkanes, while with CuOAc the (S)-enantiomer is predominantly produced (Scheme 4.6).

OH 1 O 1 OH Me2Zn CuOAc H + MeNO2 NO2 NO2 (R)-2-nitro-1- (S)-2-nitro-1- phenylethanol phenylethanol

Scheme 4.6. Enantioselectivity switch with bisoxazoline catalyst 1

For the CuOAc controlled reaction, we propose the following mechanism accounting for a Re-face attack on the aldehyde (Scheme 4.7):

H O R R H H OH O2N O N OH Cu * N O O O

R H H H O N O N Cu Cu * * O O N O O O (1 + CuOAc)

key intermediate

MeNO2 O OH H OH O N Cu * RCHO N O O O

Scheme 4.7. CuOAc promoted Henry reaction with bisoxazolidine catalyst 1

Attempts to calculate the structure of the key intermediate dictating the

asymmetric induction in the bisoxazolidine–copper(I) Henry reaction by molecular modeling were unsuccessful because of the complexity and large number of atoms in the presumed complex. The asymmetric induction was therefore rationalized based on the reported crystal structure of the ligand.2 We assume that the steric hindrance imposed by the C2-symmetric bisoxazolidine ligand favors an orientation of the benzaldehyde in

which the phenyl ring is pointing away from the fused benzene ring of the ligand’s 77

indanol moiety (Figure 4.1). This orientation correctly predicts the Re-face attack on

benzaldehyde resulting in the observed (S)-configuration of the nitroaldol product. If the benzaldehyde coordinates to the copper center in the opposite manner such that the (R)- enantiomer is produced, it is expected to experience steric repulsion with one of the indanol units (Figure 4.2).

Figure 4.1. Illustration of the favored intermediate in the bisoxazolidine-copper(I)

catalyzed Henry reaction2

Figure 4.2. Illustration of the disfavored intermediate in the bisoxazolidine-copper(I) catalyzed Henry reaction2

In order to better understand the opposite sense of asymmetric induction observed

with the copper(I) and zinc(II) complexes, we attempted to analyze the zinc(II) Henry

reaction. We propose the following mechanism accounting for Si-face attack on the

aldehyde (Scheme 4.8):

H R N * Me Me2Zn H R H O2N O Zn O O ZnMe O N O

H R N * Me H Me N H O Zn O Zn * O Me O N (1 + Me2Zn) O key intermediate

MeNO2 H Me N Zn * CH4 RCHO N O O O

Scheme 4.8. Me2Zn promoted Henry reaction with bisoxazolidine catalyst 1

The catalytic cycle begins similarly to the CuOAc reaction with a tetrahedral bisoxazolidine derived zinc complex. Reaction with nitromethane generates one equivalent of methane and the activated nitronate. Upon coordination of the aldehyde, the complex cannot maintain a tetrahedral geometry as is predicted when CuOAc is used because the zinc center still carries a methyl group. Zinc metalloenzymes are known to adopt trigonal bipyramidal geometries.29 Specifically, the crystal structure of FucA, a

zinc metalloaldolase isolated from E. coli, shows a trigonal bipyramidal catalytic zinc ion complex with three histidine residues and a bidentate ene-ol hydroxamate ligand.30 We propose that the bisoxazolidine-zinc(II) catalytic species reorganizes into a similar

arrangement.31 The asymmetric induction was rationalized based on the reported crystal

structure of the ligand.2 The ligand and the methyl group dictate that the phenyl ring of the aldehyde occupies the least crowded space of the complex, which causes the nitronate to attack the Si-face of the substrate, resulting in the formation of the (R)-enantiomer of the nitroaldol product (Figure 4.3). If the substrate coordinates to the zinc center in the opposite orientation such that the (S)-enantiomer of the product is formed, the phenyl ring of benzaldehyde will undergo steric repulsion with one of the indanol moieties (Figure

4.4). Accordingly, the key intermediate resulting in Si-face attack should be favored.

Figure 4.3. Illustration of the favored intermediate in the bisoxazolidine-zinc(II)

catalyzed Henry reaction2

Figure 4.4. Illustration of the disfavored intermediate in the bisoxazolidine-zinc(II) catalyzed Henry reaction2

4.2.4. Application of the Henry reaction in the synthesis of alkaloid precursors

Finally, we decided to evaluate the general usefulness of our asymmetric

nitroaldol reaction procedure with the bifunctional aldehyde, methyl 4-oxobutanoate. An

enantioselective synthesis of (S)-methyl 4-hydroxy-5-nitropentanoate, which provides access to important alkaloid precursors, 5-hydroxypiperidin-2-one and 5-

(aminomethyl)dihydrofuran-2(3H)-one as well as other multifunctional chiral structures, has not been described. We envisioned that the bisoxazolidine catalyzed Henry reaction between methyl 4-oxobutanoate and nitromethane followed by sequential reduction and lactamization should give the important alkaloid precursors in high yields and ee’s

(Scheme 4.9).32 To date, the most efficient syntheses of (S)-5-hydroxypiperidin-2-one and (S)-5-(aminomethyl)dihydrofuran-2(3H)-one start from (S)-glutamic acid and require

5 steps with 24% overall yield and 6 steps with 19% yield, respectively.33 We were able to prepare the nitroaldol product in 85% and 89% ee. Hydrogenation followed by spontaneous cyclization then gave the lactam in 85% yield and 98% ee after one recrystallization. Notably, this lactam can be converted to lactone with 78% yield.34 We have thus introduced a much more efficient synthetic approach towards these important building blocks.

1, CuOAc O MeNO O NO2 H 2 O 85%, 89% ee O O OH (S)-methyl 4-hydroxy-5-nitropentanoate

O NH H2, Pd/C NH Ref. 34 2 O O 85%, 98% ee 78% OH (S)-5-hydroxypiperidin- (S)-5-(aminomethyl) 2-one dihydrofuran- 2(3H)-one

Scheme 4.9. Synthesis of (S)-5-hydroxypiperidin-2-one

4.3 Conclusions

In conclusion, we have developed the first general procedure for employing a bisoxazolidine-copper(I) complex in the asymmetric Henry reaction. A range of aromatic 83

nitroaldol compounds has been prepared in up to 95% yield and up to 89% ee using 10

mol % of the bisoxazolidine catalyst prepared from aminoindanol and cyclohexadione.

The reaction of aliphatic substrates proved more successful, and the corresponding

nitroaldol products were obtained in up to 97% yield and 97% ee. We also discovered an

interesting switch in enantioselectivity using the same chiral ligand in combination with

either copper(I) acetate or dimethylzinc which may be attributed to the formation of four-

and five-coordinate transition states, respectively. The general usefulness and potential of

this nitroaldol reaction procedure was also demonstrated. Employing methyl 4-

oxobutanoate, we were able to prepare (S)-5-hydroxypiperidin-2-one in 72% overall yield

and 98% ee within two steps which compares favorably with previously reported

methods.

4.4 Experimental details

4.4.1 Synthetic procedures

All commercially available ligands, reagents, and solvents were used without further

purification. NMR spectra were obtained at 400 MHz (1H NMR) and 100 MHz (13C

NMR). Chemical shifts are reported in ppm relative to TMS. Reaction products were purified by column chromatography on silica gel (particle size 32-63 μm).

General Henry Reaction Procedure:

The bisoxazolidine ligand (37 mg, 0.10 mmol) and CuOAc (11 mg, 0.09 mmol) were

suspended in anhydrous EtOH (2.4 mL) under nitrogen at room temperature. After 30

minutes, nitromethane (610 mg, 10 mmol) was added, and the mixture stirred for an

additional 30 minutes. Upon the addition of molecular sieves (4 Å), the solution was

cooled to the prescribed reaction temperature and the aldehyde (1 mmol) added. After

completion, the reaction was cooled to -20 oC, and solvents were removed under reduced

pressure. The crude residue was loaded directly onto a silica gel column and purified by

flash chromatography as described below.

4.4.2 Characterization of nitroaldol products

(S)-2-Nitro-1-phenylethanol21

Chromatographic purification (CH2Cl2) gave 155 mg (0.93 mmol, 93%, 89% ee) of a

1 white solid. H NMR (400 MHz, CDCl3) δ = 2.85 (bs, 1 H), 4.51 (dd, J = 3.0 Hz, 13.3

Hz, 1 H), 4.61 (dd, J = 9.5 Hz, 13.3 Hz, 1 H), 5.46 (m, 1 H), 7.34-7.43 (m, 5 H). 13C

NMR (100 MHz, CDCl3) δ = 71.0, 81.2, 125.9, 128.9, 129.0, 138.1. The ee was

determined by HPLC on Chiralcel OD using hexanes:IPA (90:10) as the mobile phase, t1

(minor) = 11.9 min, t2 (major) = 13.3 min, α = 1.18.

(S)-2-Nitro-1-(2-naphthyl)ethanol22

Chromatographic purification (CH2Cl2) gave 197 mg (0.91 mmol, 91%, 88% ee) of a

1 white solid. H NMR (400 MHz, CDCl3) δ = 3.02 (bs, 1 H), 4.56 (dd, J = 3.0 Hz, 13.3

Hz, 1 H), 4.66 (dd, J = 9.5 Hz, 13.3 Hz, 1 H), 5.59 (dd, J = 3.0 Hz, 9.5 Hz, 1 H), 7.43

(dd, J = 1.4 Hz, 8.6 Hz, 1 H), 7.49-7.53 (m, 2 H), 7.82-7.87 (m, 4 H). 13C NMR (100

MHz, CDCl3) δ = 71.1, 81.1, 123.2, 152.2, 126.6, 126.7, 127.7, 128.0, 129.0, 133.1,

133.4, 135.3. The ee was determined by HPLC on Chiralcel OD using hexanes:IPA

(85:15) as the mobile phase, t1 (minor) = 30.1 min, t2 (major) = 42.0 min, α = 1.46.

(S)-2-Nitro-1-(4-fluorophenyl)ethanol13c

Chromatographic purification (CH2Cl2) gave 176 mg (0.95 mmol, 95%, 84% ee) of a

1 colorless oil. H NMR (400 MHz, CDCl3) δ = 2.88 (bs, 1 H), 4.50 (dd, J = 3.1 Hz, 13.4

Hz, 1 H), 4.59 (dd, J = 9.4 Hz, 13.4 Hz, 1 H), 5.46 (dd, J = 3.1 Hz, 9.4 Hz, 1 H), 7.07-

13 7.13 (m, 2 H), 7.38-7.42 (m, 2 H). C NMR (100 MHz, CDCl3) δ = 70.3, 81.1, 116.0 (d,

JC-F = 21.7 Hz), 127.8 (d, JC-F = 8.4 Hz), 133.8 (d, JC-F = 3.3 Hz), 162.9 (d, JC-F = 248.1

Hz). The ee was determined by HPLC on Chiralcel OD using hexanes:IPA (90:10) as the

mobile phase, t1 (minor) = 13.7 min, t2 (major) = 15.9 min, α = 1.23.

(S)-2-Nitro-1-(4-cyanophenyl)ethanol23

Chromatographic purification (CH2Cl2) gave 173 mg (0.90 mmol, 90%, 78% ee) of a

1 white powder. H NMR (400 MHz, CDCl3) δ = 3.31 (d, J = 4.1 Hz, 1 H), 4.52-4.62 (m, 2

H), 5.55 (ddd, J = 4.1 Hz, 4.2 Hz, 8.5 Hz, 1 H), 7.57 (d, J = 8.3 Hz, 1 H), 7.70 (d, J = 8.3

13 Hz, 1 H). C NMR (100 MHz, CDCl3) δ = 70.1, 80.6, 112.9, 118.1, 126.7, 132.8, 143.0.

The ee was determined by HPLC on Chiralcel OD using hexanes:IPA (90:10) as the

mobile phase, t1 (minor) = 32.3 min, t2 (major) = 38.7 min, α = 1.23.

(S)-2-Nitro-1-(4-bromophenyl)ethanol22

Chromatographic purification (CH2Cl2) gave 229 mg (0.93 mmol, 93%, 86% ee) of a

1 white powder. H NMR (400 MHz, CDCl3) δ = 2.84 (d, J = 3.7 Hz, 1 H), 4.49 (dd, J =

2.7 Hz, 13.5 Hz, 1 H), 4.57 (dd, J = 9.3 Hz, 13.5 Hz, 1 H), 5.44 (ddd, J = 2.7 Hz, 3.7 Hz,

9.3 Hz, 1 H), 7.29 (d, J = 8.5 Hz, 1 H), 7.54 (d, J = 8.5 Hz, 2 H). 13C NMR (100 MHz,

CDCl3) δ = 70.3, 80.9, 123.0, 127.6, 132.2, 137.0. The ee was determined by HPLC on

Chiralcel OD using hexanes:IPA (85:15) as the mobile phase, t1 (minor) = 12.4 min, t2

(major) = 15.7 min, α = 1.39.

(S)-2-Nitro-1-(4-nitrophenyl)ethanol21

Chromatographic purification (CH2Cl2) gave 187 mg (0.88 mmol, 88%, 74% ee) of a

1 white solid. H NMR (400 MHz, CDCl3) δ = 3.18 (d, J = 4.1 Hz, 1 H), 4.55-4.65 (m, 2

H), 5.62 (ddd, J = 4.0 Hz, 4.1 Hz, 8.1 Hz, 1 H), 7.63 (d, J = 8.7 Hz, 2 H), 8.27 (d, J = 8.7

13 Hz, 2 H). C NMR (100 MHz, CDCl3) δ = 69.9, 80.6, 124.2, 126.9, 144.9, 148.2. The ee

was determined by HPLC on Chiralcel OD using hexanes:IPA (90:10) as the mobile

phase, t1 (minor) = 34.2 min, t2 (major) = 38.9 min, α = 1.16.

(S)-2-Nitro-1-(4-methoxyphenyl)ethanol21

Chromatographic purification (3:1 hexanes:ethyl acetate) gave 132 mg (0.67 mmol, 67%,

1 70% ee) of a yellow oil. H NMR (400 MHz, CDCl3) δ = 2.76 (bs, 1 H), 3.81 (s, 3 H),

4.48 (dd, J = 2.9 Hz, 13.2 Hz, 1 H), 4.60 (dd, J = 9.6 Hz, 13.2 Hz, 1 H), 5.40 (ddd, J =

2.9 Hz, 4.2 Hz, 9.6 Hz, 1 H), 6.92 (d, J = 8.7 Hz, 2 H), 7.32 (d, J = 8.7 Hz, 2 H). 13C

NMR (100 MHz, CDCl3) δ = 69.9, 80.6, 124.2, 126.9, 144.9, 148.2. The ee was

determined by HPLC on Chiralcel OD using hexanes:IPA (90:10) as the mobile phase, t1

(minor) = 22.1 min, t2 (major) = 27.4 min, α = 1.20.

(S)-1-Nitro-4-phenyl-but-3-en-2-ol24

Chromatographic purification (90:10 CH2Cl2:hexanes) gave 173 mg (0.90 mmol, 90%,

1 88% ee) of a yellow solid. H NMR (400 MHz, CDCl3) δ = 2.58 (s, 1 H), 4.48-4.56 (m, 2

H), 5.06 (m, 1 H), 6.15 (dd, J = 6.2 Hz, 15.9 Hz, 1 H), 6.80 (d, J = 15.9 Hz, 1 H), 7.27-

13 7.40 (m, 5 H). C NMR (100 MHz, CDCl3) δ = 69.6, 79.8, 124.8, 126.7, 128.5, 128.7,

133.7, 135.4. The ee was determined by HPLC on Chiralpak AD using hexanes:IPA

(95:5) as the mobile phase, t1 (minor) = 32.1 min, t2 (major) = 33.3 min, α = 1.04.

(S)-1-Cyclohexyl-2-nitroethanol13c

Chromatographic purification (CH2Cl2) gave 151 mg (0.87 mmol, 87%, 93% ee) of a

1 colorless oil. H NMR (400 MHz, CDCl3) δ = 1.04-1.32 (m, 5 H), 1.48 (m, 1 H), 1.66-

1.71 (m, 2 H), 1.76-1.85 (m, 3 H), 4.42 (dd, J = 8.9 Hz, 13.1 Hz, 1 H), 4.49 (dd, J = 2.9

13 Hz, 13.1 Hz, 1 H). C NMR (100 MHz, CDCl3) δ = 25.7, 25.9, 26.1, 28.0, 28.8, 41.4,

72.8, 79.3. The ee was determined by HPLC on Chiralpak AD using hexanes:IPA (97:3)

as the mobile phase, t1 (minor) = 33.3 min, t2 (major) = 34.7 min, α = 1.05.

(S)-3-Methyl-1-nitro-2-butanol13c

Chromatographic purification (CH2Cl2) gave 113 mg (0.85 mmol, 85%, 91% ee) of a

1 colorless oil. H NMR (400 MHz, CDCl3) δ = 0.99 (d, J = 5.6 Hz, 3 H), 1.01 (d, J = 5.6

Hz, 3 H), 1.81 (m, 1 H), 2.43 (d, J = 4.9 Hz, 1 H), 4.11 (m, 1 H), 4.41 (dd, J = 8.9 Hz,

13 13.1 Hz, 1 H), 4.48 (dd, J = 2.8 Hz, 13.1 Hz, 1 H). C NMR (100 MHz, CDCl3) δ =

17.4, 18.4, 31.7, 73.3, 79.2. The ee was determined by HPLC on Chiralcel OD using

hexanes:IPA (98:2) as the mobile phase, t1 (minor) = 27.5 min, t2 (major) = 29.9 min, α =

1.10.

(S)-1-Nitro-2-heptanol17

Chromatographic purification (CH2Cl2) gave 147 mg (0.91 mmol, 91%, 93% ee) of a

1 colorless oil. H NMR (400 MHz, CDCl3) δ = 0.90 (t, J = 6.8 Hz, 3 H), 1.25-1.59 (m, 8

H), 2.74 (d, J = 4.9 Hz, 1 H), 4.30 (m, 1 H), 4.38 (dd, J = 8.3 Hz, 12.8 Hz, 1 H), 4.44

13 (dd, J = 2.9 Hz, 12.8 Hz, 1 H). C NMR (100 MHz, CDCl3) δ = 13.9, 24.4, 24.8, 31.4,

33.7, 68.7, 80.6. The ee was determined by HPLC on Chiralpak AD using hexanes:IPA

(98:2) as the mobile phase, t1 (minor) = 30.7 min, t2 (major) = 41.4 min, α = 1.60.

(S)-1-Nitro-2-undecanol24

Chromatographic purification (CHCl3) gave 200 mg (0.92 mmol, 92%, 93% ee) of a

1 colorless oil. H NMR (400 MHz, CDCl3) δ = 0.88 (t, J = 6.9 Hz, 3 H), 1.27-1.60 (m, 16

H), 2.49 (d, J = 4.3 Hz, 1 H), 4.29-4.40 (m, 2 H), 4.44 (dd, J = 2.7 Hz, 12.8 Hz, 1 H). 13C

NMR (100 MHz, CDCl3) δ = 14.1, 22.7, 25.2, 29.3, 29.3, 29.4, 29.5, 31.8, 33.7, 68.7,

80.6. The ee was determined by HPLC on Chiralpak AD using hexanes:IPA (95:5) as the

mobile phase, t1 (minor) = 10.9 min, t2 (major) = 15.0 min, α = 1.60.

(S)-4-Methyl-1-nitropentan-2-ol24

Chromatographic purification (CHCl3) gave 134 mg (0.91 mmol, 91%, 93% ee) of a

1 colorless oil. H NMR (400 MHz, CDCl3) δ = 0.96 (d, J = 6.2 Hz, 3 H), 0.97 (d, J = 6.2

Hz, 3 H), 1.23 (m, 1 H), 1.51 (m, 1 H), 1.84 (m, 1 H), 2.49 (d, J = 3.6 Hz, 1 H), 4.33-4.45

13 (m, 3 H). C NMR (100 MHz, CDCl3) δ = 21.7, 23.2, 24.3, 42.4, 66.9, 80.9. The ee was

determined by HPLC on Chiralpak AD using hexanes:IPA (95:5) as the mobile phase, t1

(minor) = 11.3 min, t2 (major) = 14.7 min, α = 1.48.

(S)-3,3-Dimethyl-1-nitrobutan-2-ol13c

Chromatographic purification (CHCl3) gave 125 mg (0.85 mmol, 85%, 92% ee) of a

1 colorless oil. H NMR (400 MHz, CDCl3) δ = 0.98 (s, 1 H), 2.41 (d, J = 4.3 Hz, 1 H),

4.04 (ddd, J = 2.0 Hz, 4.3 Hz, 10.1 Hz, 1 H), 4.37 (dd, J = 10.1 Hz, 13.0 Hz, 1 H), 4.53

13 (dd, J = 2.0 Hz, 13.0 Hz, 1 H). C NMR (100 MHz, CDCl3) δ = 25.6, 34.3, 76.2, 78.2.

The ee was determined by HPLC on Chiralcel OD using hexanes:IPA (98:2) as the

mobile phase, t1 (minor) = 21.6 min, t2 (major) = 24.9 min, α = 1.19.

(S)-1-Nitro-4-phenyl-2-butanol23

Chromatographic purification (CH2Cl2) gave 189 mg (0.97 mmol, 97%, 97% ee) of a

1 white solid. H NMR (400 MHz, CDCl3) δ = 1.75-1.92 (m, 2 H), 2.60 (d, J = 4.6 Hz, 1

H), 2.75 (m, 1 H), 2.87 (m, 1 H), 4.27-4.43 (m, 3 H), 7.20-7.32 (m, 5 H). 13C NMR (100

MHz, CDCl3) δ = 31.3, 35.1, 67.7, 80.5, 126.3, 128.4, 128.6, 140.6. The ee was

determined by HPLC on Chiralpak AD using hexanes:IPA (90:10) as the mobile phase, t1

(minor) = 11.5 min, t2 (major) = 13.9 min, α = 1.3

4.4.3 Synthesis and characterization of methyl 4-hydroxy-4-nitropentanoate

The bisoxazolidine ligand (22 mg, 0.06 mmol) and CuOAc (6.5 mg, 0.05 mmol) were suspended in anhydrous EtOH (0.5 mL) under nitrogen at room temperature. After 30 minutes, nitromethane (240 mg, 3.39 mmol) was added, and the mixture stirred for an additional 30 minutes. Upon the addition of molecular sieves (4 Å), the solution was cooled to -10 oC and methyl 4-oxobutanoate (46 mg, 0.39 mmol) was added in anhydrous

EtOH (0.5 mL). The reaction stirred for 66 hours, and after completion, the reaction was

cooled to -20 oC, and solvents were removed under reduced pressure. The crude residue

was loaded directly onto a silica gel column and purified by flash chromatography.

(S)-Methyl 4-hydroxy-5-nitropentanoate

Chromatographic purification (90:10 dichloromethane:ethyl acetate) gave 59 mg (0.33

1 mmol, 85%, 89% ee) of a white solid. H NMR (400 MHz, CDCl3) δ = 1.75-1.92 (m,

2H), 2.55 (t, J = 7.0 Hz, 2H), 3.26 (bs, 1H), 3.70 (s, 3H), 4.35-4.49 (m, 3H). 13C NMR

(100 MHz, CDCl3) δ = 28.4, 29.7, 52.0, 67.7, 80.3, 173.8. Anal. Calcd. C6H11NO5: C,

40.68; H, 6.26; N, 7.91. Found: C, 41.16; H, 6.54; N, 7.79.The ee was determined by

HPLC on Chiralpak AD using hexanes:EtOH (90:10) as the mobile phase, t1 (major) =

26.7 min, t2 (minor) = 32.1 min, α = 1.24.

4.4.4 Synthesis and characterization of 5-hydroxypiperidin-2-one

Methyl 4-hydroxy-5-nitropentanoate (56 mg, 0.32 mmol) in anhydrous MeOH (2 mL) was added to the glass vessel of a Parr hydrogenation apparatus containing 10 wt. % Pd/C

(34 mg, 0.032 mmol) in anhydrous MeOH (8 mL). The apparatus was pressurized with

o H2 (50 psi) and heated to 60 C for 4 hours. The crude reaction material was filtered

through celite and the solvents removed by rotoevaporation. The solid material was

washed with dichloromethane and the pure product isolated by filtration.

(S)-5-Hydroxypiperidin-2-one35

Washing with dichloromethane gave 31 mg (0.273 mmol, 85%, 98% ee) of a white solid.

1 H NMR (400 MHz, CD3OD) δ = 1.84-1.99 (m, 2H), 2.30 (ddd, J = 18.0 Hz, 6.9 Hz, 6.9

Hz, 1H), 2.50 (ddd, J = 18.0 Hz, 6.9 Hz, 6.9 Hz, 1H), 3.18 (dd, J = 12.7 Hz, 4.8 Hz, 1H),

13 3.41 (dd, J = 12.7 Hz, 3.8 Hz, 1H), 4.06 (m, 1H). C NMR (100 MHz, CDCl3) δ = 28.1,

28.8, 49.3, 63.8, 174.5. The ee was determined by HPLC on Chiralpak AS using

hexanes:EtOH (90:10) as the mobile phase, t1 (major) = 10.0 min, t2 (minor) = 13.9 min,

23 o α = 1.66. [α]D = -8.75 (c 0.4, CH3OH).

4.5 References

1 For a recent review, see: Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006,

106, 3561-3651.

2 Wolf, C.; Liu, S. J. Am. Chem. Soc. 2006, 128, 10996-10997.

3 Liu, S.; Wolf, C. Org. Lett. 2007, 9, 2965-2968.

4 Liu, S.; Wolf, C. Org. Lett. 2008, 10, 1831-1834.

5 For a recent review on the asymmetric Henry reaction: Palomo, C.; Oiarbide, M.; Laso,

A. Eur. J. Org. Chem. 2007, 2561-2574.

6 Trost, B. M.; Yeh, V. S. C.; Ito, H.; Bremeyer, N. Org. Lett. 2002, 4, 2621-2623.

7 Ono, N. The Nitro Group in Organic Synthesis, Wiley-VCH: New York, 2001.

8 Bandini, M.; Piccinelli, F.; Tommasi, S.; Umani-Ronchi, A.; Ventrici, C. Chem.

Commun. 2007, 616–618.

9 a) Sasai, J.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1992, 114,

4418-4420. b) Sasai, J.; Suzuki, T.; Itoh, N.; Shibasaki, M. Tetrahedron Lett. 1993, 34,

851-854. c) Sasai, H.; Zuzuki, N.; Itoh, K.; Tanaka, T.; Date, K.; Okamura, K.; Shibasaki,

M. J. Am. Chem. Soc. 1993, 115, 10372-10373.

10 a) Kogami, Y.; Nakajima, T.; Ashizawa, T.; Kezuka, S.; Ikeno, T.; Yamada, T. Chem.

Lett. 2004, 614-615. b) Kogami, Y.; Nakajima, T.; Ikeno, T.; Yamada, T. Synthesis 2004,

1947-1950.

11 Choudary, B.M.; Ranganath, K. V. S.; Pal, U.; Kantam, M. L.; Sreedhar, B. J. Am.

Chem. Soc. 2005, 127, 13167-13171.

12 a) Trost, B. M.; Yeh, V. S. C. Angew. Chem. Int. Ed. 2002, 41, 861-863. b) Trost, B.

M.; Yeh, V. S. C.; Ito, H.; Bremeyer, N. Org. Lett. 2002, 4, 2621-2623.

13 a) Christensen, C.; Juhl, K.; Jørgensen, K. A. Chem. Commun. 2001, 2222-2223. b)

Christensen, C.; Juhl, K.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 4875-

4881. c) Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W.

J. Am. Chem. Soc. 2003, 125, 12692-12693. 94

14 Maheswaran, H.; Prasant, K. L.; Krishna, G. G.; Ravikumar, B.; Sridhar, B.; Kantam,

M. L. Chem. Commun. 2006, 4066-4068.

15 Arai, T.; Watanabe, M.; Yanagisawa, A. Org. Lett. 2007, 9, 3595-3597.

16 Quin, B.; Xiao, X.; Liu, X.; Huang, J.; Wen, Y.; Feng, X. J. Org. Chem. 2007, 72,

9323-9328.

17 Xiong, Y.; Wang, F.; Huang, X.; Wen, Y.; Feng, X. Chem. Eur. J. 2007, 13, 829-833.

18 Arai, T.; Takashita, R.; Endo, Y.; Watanabe, M.; Yanagisawa, A. J. Org. Chem. 2008,

73, 4903-4906.

19 Arai, T.; Watanabe, M.; Fujiwara, A.; Yokoyama, N.; Yanagisawa, A. Angew. Chem.

Int. Ed. 2006, 45, 5978-5981.

20 Jiang, J.-J.; Shi, M. Tetrahedron: Asymmetry 2007, 18, 1376-1382.

21 Blay, G.; Climent, E.; Fernández, I.; Hernández-Olmos, V.; Pedro, J. Tetrahedron:

Asymmetry 2007, 18, 1603-1612.

22 Bulut, A.; Aslan, A.; Dogan, O. J. Org. Chem. 2008, 73, 7373-7375.

23 Saá, J. M.; Tur, F.; González, J.; Vega, M. Tetrahedron: Asymmetry 2006, 17, 99-106.

24 Blay, G.; Domingo, L. R.; Hernández-Olmos, V.; Pedro, J. R. Chem. Eur. J. 2008, 14,

4725-4730.

25 For a recent review on reversing enantioselectivity: Tanaka, T.; Hayashi, M. Synthesis

2008, 3361-3376.

26 Yamaguchi, S.; Mosher, H. S.; Pohland, A. J. Am. Chem. Soc. 1972, 94, 9254-9255.

27 Yamaguchi, S.; Mosher, H. S. J. Org. Chem. 1973, 38, 1870-1877. 95

28 Du, D.-M.; Lu, S.-F.; Fang, T.; Xu, J. J. Org. Chem. 2005, 70, 3712-3715.

29 a) Sideraki, V.; Wilson, D. K.; Kurz, L. C.; Quiocho, F. A.; Rudolph, F. B.

Biochemistry 1996, 35, 15019-15028. b) Lebioda, L.; Stec, B.; Brewer, J. M.; Tykarska,

E. Biochemistry 1991, 30, 2823-2827.

30 Joerger, A. C.; Gosse, C.; Fessner, W-. D.; Schulz, G. E. Biochemistry 2000, 39, 6033-

6041.

31 For examples of trigonal bipyramidal Zn(II) complexes see: a) Kimura, E.; Koike, T.;

Toriumi, K. Inorg. Chem. 1988, 27, 3687-3688. b) Seitz, M.; Stempfhuber, S.; Zabel, M.;

Schütz, M.; Resier, O. Angew. Chem. Int. Ed. 2005, 44, 242-245. c) Rivas, J. C. M.;

Salvagni, E.; de Rosales, R. T. M.; Parsons, S. Dalton Trans. 2003, 3339-3349. d)

Kimura, E.; Koike, T.; Shionoya, M.; Shiro, M. Chem. Lett. 1992, 787-790.

32 a) Gagnon, A.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2002, 41, 1581-1584. b)

Fenster, M. D. B.; Dake, G. R. Org. Lett. 2003, 5, 4313-4316. (c) Fan, G.-J.; Wang, Z.;

Wee, A. G. H. Chem. Commun. 2006, 3732-3734. d) Morgan, I. R.; Yazici, A.; Pyne, S.

G. Tetrahedron 2008, 64, 1409-1419.

33 a) Fabiano, E.; Golding, B. T.; Sadeghi, M. M. Synthesis 1987, 190-192. b) Olsen, R.

K.; Bhat, K. L.; Wardle, R. B. J. Org. Chem. 1985, 50, 896-899. c) Humphries M. E.;

Murphy, J.; Phillips, A. J; Abell, A. D. J. Org. Chem. 2003, 68, 2432-6243. d) Andres, J.

M.; Pedrosa, R.; Perez-Encabo, A. Tetrahedron Lett. 2006, 47, 5317-5320. e) Feng, C.-

G.; Chen, J.; Ye, J.-L.; Ruan, Y.-P.; Zheng, X.; Huang, P.-Q. Tetrahedron 2006, 62,

7459-7465.

34 Herdeis, C. Synthesis 1986, 232-233.

35 Huh, N.; Thompson, C. M. Tetrahedron 1995, 51, 5935-5950.

V. Asymmetric catalysis and enantioselective sensing with a sterically congested N,N’ -dioxide

5.1 Introduction

In 1933, Kuhn introduced the term “atropisomerism” to describe stereoisomers

that exist due to restricted rotation about a single bond such that separation of the isomers

is possible at room temperature. 1 Because Kuhn’s separation criteria are vague in that no free energy barrier to rotation is defined, the term is generally used to refer to compounds that have hindered rotation around a single bond (Figure 5.1).2

NO2 NO2

CO2H CO2H CO2H CO2H

Enantiomers resolvable at Enantiomers not resolvable room temperature due to fast racemization at room temperature

Figure 5.1 . Conformationally stable 4,4’,6,6’-tetranitrobiphenyl-2,2’-dicarboxylic acid and conformationally unstable biphenyl-2,2’-dicarboxylic acid 3

While the structure and stereodynamics of biaryls have been investigated extensively, 2 1,8-diarylnaphthalenes remained relatively unexplored until a report

published by Clough and Roberts in 1976. They described the synthesis of atropisomeric

1,8-di(2’-methyl-1’-phenyl)naphthalene, 1, by the coupling of o-toluyl magnesium with

1,8-diiodonaphthalene in the presence of a nickel acetylacetonate catalyst to produce

three isomers: two chiral anti -enantiomers and a meso syn -compound (Scheme 5.1). 4

Rotation of one aryl group about the pivotal biaryl bond results in syn /anti -

diastereomerization of the compound which impedes isolation and long term storage of a

single enantiomer.

MgI [Ni(acac)2]3 + + + I I

anti-1a anti-1b syn-1

Scheme 5.1 . Synthesis of 1,8-di(2-methyl-1’-phenyl)naphthalene, 1

In contrast to the meta-substituted conformationally unstable 1,8-bis(2’-phenyl-4’-

pyridyl)naphthalene, 2,2 the di-ortho -substituted atropisomers, 1, could be separated by column chromatography at room temperature on alumina, but interconversion between the syn - and anti -isomers was found to have a half-life of approximately 1 day in solution

(Scheme 5.2). NMR studies were conducted with compounds 1 and 2 and energy barriers to isomerization were determined as 100 kJ/mol and 74.8 kJ/mol, respectively. This

illustrates that rotational barriers to diasteromerization of 1,8-disubstituted naphthalenes

increase as the steric bulk in close proximity to the chiral axis increases.

∆G = ∆G = 100 kJ/mol 74.8 kJ/mol

N N N N

anti-1 syn-1 anti-2 syn-2

Scheme 5.2 . Rotational energy barriers between anti - and syn -isomers of 1,8- disubstituted naphthalenes

For atropisomers to be useful as non-interconverting, enantiomerically pure chiral sensors or catalysts, the barrier to rotation must be further increased to establish sufficient stereochemical stability. Many efforts have been directed to the introduction of more sterically demanding groups in the peri-positions of naphthalene, but in most cases only trace amounts of the desired compounds were obtained.5 However, Wolf et al. have

developed a synthetic route that produces highly sterically congested and

conformationally stable 1,8-diquinolyl- and 1,8-diacridylnaphthalenes in good yields

(Figure 5.2).6

100

R N N R R N N R R N N R O O

R = Me, i-Pr, Ph R = 3,5-dimethylphenyl, R = 3,5-dimethylphenyl, t-butyl t-butyl

Figure 5.2 . Sterically congested and confomationally stable 1,8-diquinolyl- and 1,8- diacridylnaphthalenes developed by Wolf et al.

The 1,8-diquinolylnapthalene derivatives were found to have energy barriers to rotation between 110-125 kJ/mol and syn /anti-interconversion occurs only upon heating.6c

Additional conformational stability was gained by the introduction of the diacridyl groups. The 3,5-dimethyl substituted 1,8-diacridylnaphthalene was found to have a free energy activation barrier to rotation greater than 180 kJ/mol. After heating to 180 oC for

24 hours, no syn /anti -interconversion was observed. Due to the increased stability of the

diacridyl derivatives, their inherent rigid C 2-symmetric bidentate scaffold, and their UV

and fluorescence properties, this unique class of compounds affords ideal candidates for

asymmetric sensing and catalysis applications.

The diacridyl derivatives were first employed as effective chiral fluorosensors for

a variety of carboxylic acids, amino acids, and amines. 6a,6f,7 Selectivities as high as 4.5

were observed for the enantioselective sensing of camphanic acid with 1,8-bis(3’-(3,5-

dimethylphenyl)-9’-acridyl)naphthalene. Furthermore, the N,N’-dioxide of this 101

compound was also very successfully used for enantioselective recognition of chiral

hydrogen bond donating analytes. 8 Scandium complexes of the diacridyl N,N’-dioxides

proved excellent enantioselective sensors for a variety of amino acids, amines, amino

alcohols, and carboxylic acids. 6d,9 Because the sensors had proven to be very effective

and are reminiscent of broadly useful chiral catalysts such as BINOL and TADDOL (all

possessing the qualities of being C2-symmetric, rigid, and bidentate), we decided to scale up the synthesis and develop a more efficient enantiomer separation protocol for 1,8- bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene N,N’ -dioxide. It was expected that this would produce sufficient amounts of this ligand to develop new sensing applications and to investigate its use in asymmetric catalysis.

5.2 Synthesis of 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene N,N’ -dioxide

The goal was to synthesize a gram of 1,8-bis(3’-(3,5-dimethylphenyl)-9’- acridyl)naphthalene N,N’ -dioxide, 5. Following the synthetic procedure developed by

Wolf et al., microwave-assisted Suzuki coupling of 2-chloro-4-bromobenzoic acid and

3,5-dimethylphenyl boronic acid gave 4-(3’,5’-dimethylphenyl)-2-chlorobenzoic acid in

77% yield (Scheme 5.3). This acid was then coupled to aniline by copper catalyzed amination to form 4-(3’,5’-dimethylphenyl)-2-(N-phenylamino)benzoic acid in 80%

yield. Upon reaction with phosphorous oxybromide and subsequent ring-closure, 9-

bromo-3-(3’,5’-dimethylphenyl)acridine was formed in 80% yield. Lithium-halogen

102

exchange followed by reaction with tributyltin chloride provided 3-(3’,5’-

dimethylphenyl)-9-tributylstannylacridine for the Stille reaction in 82% yield. The

palladium catalyzed Stille reaction was then completed to form 1,8-bis(3’-(3,5-

dimethylphenyl)-9’-acridyl)naphthalene in 89% yield, a marked improvement over the

previously reported 66% yield. 6f Prior to oxidation, the diastereomers of the 1,8- diacridylnaphthalene were separated by flash chromatography on silica gel. Finally, the anti -diacridylnaphthalene was oxidized to the corresponding N,N’ -dioxide 5 in 65%

yield. We were thus able to produce 1 gram of pure anti-1,8-bis(3’-(3,5-dimethylphenyl)-

9’-acridyl)naphthalene N,N’ -dioxide.

103

B(OH) 2 Pd(PPh3)4, TBAB COOH COOH H2O, Na2CO3 + Br Cl MW, 130 oC, 20 min Cl

77%

COOH Br Cu/Cu O, aniline POBr 2 NH 3 2-ethoxyethanol, 100 oC N 130 oC 80% 80%

Br Br

o 1. BuLi, -78 C, SnBu3 2. Bu3SnCl

N Pd(PPh3)4 1:1 Et2O:THF N N DMF, 130 oC 82% 89%

m-CPBA N N O O

56% 5

Scheme 5.3. Synthesis of 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene N,N’ -

dioxide, 5

Because 5 was synthesized in racemic form, an effective chiral separation procedure needed to be developed to allow isolation of enantiopure N,N’ -dioxide in the 104

amounts necessary for optimization of sensing and catalysis applications. Several

methods can be employed to separate the enantiomers of atropisomeric compounds, such

as crystallization through the formation of diastereomeric salts. 3 However, we decided to use chiral HPLC to separate the enantiomers. An efficient HPLC procedure allows one to inject large amounts of sample while maintaining baseline separation of peaks in a short amount of time. The low solubility of the N,N’-dioxide in common organic solvents

limited mobile phase combinations traditionally used in chiral separations. Furthermore,

many chiral columns such as the polysaccharide Daicel columns are not tolerant of a

wide range of solvents and are usually limited to hexanes / alcohol combinations. The

Whelk-O 1 column developed by the Pirkle group 10 is very tolerant of a variety of mobile phases and compatible with chlorinated solvents in which the N,N’ -dioxide was highly soluble. Therefore, employing a preparative Whelk-O 1 column (10 mm x 250 mm) and a mobile phase of dichloromethane : ethanol (90 : 10), 20 mg of sample could be injected into a 1 mL sample loop for each HPLC cycle (Figure 5.3). This method is fast, as the enantiomers have retention times of 3.5 and 6.0 minutes. Because an extremely small impurity in the racemic ligand mixture is revealed when injecting preparative volumes of the ligand solution, the material eluting between the two enantiomeric peaks was not collected. With this efficient protocol, 200 mg of the atropisomer were separated in a single day.

105

Analytical injection

190

170

a 150 b s 130 o r 110 b a 90 n c 70 e 50

-10 0 2 4 6 8 10 Time (min)

Preparative injection

4500

4000

3500

a 3000 b s 2500 o r 2000 b a 1500 n c e 1000 500

0 0 1 2 3 4 5 6 7 -500 Time (min)

Figure 5.3. HPLC chromatograms for the separation of the enantiomers of 1,8-bis(3’-

(3,5-dimethylphenyl)-9’-acridyl)naphthalene N,N’ -dioxide

106

5.3 Applications of 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene N,N’ - dioxide in asymmetric catalysis

5.3.1 Introduction

Chiral pyridine N-oxides have been used as catalysts in many asymmetric reactions including cyanation of α,β-unsaturated imides, 11 allylation of aldehydes, 12

addition of propargylic and allylic chlorosilane to aldehydes, 13 Michael additions of β- keto esters to methylvinyl ketone, 14 and cyanosilylation of ketones. 15 Further, Reinhardt and Wolf have employed 2 mol% of a 1,1’-biisoquinoline N,N’ -dioxide in the allylation

of benzaldehyde with allylchlorosilane to produce 1-phenylbut-3-en-1-ol in 75% yield. 16

This result indicates the suitability of C 2-symmetric N,N’ -dioxides for Lewis base

catalysis. It was initially envisioned that N,N’ -dioxide 5 could be used either for Lewis acid or Lewis base catalysis. For example, N-oxides have a high affinity for silicon which

can be exploited to generate hypervalent silicates with allylsilanes for the asymmetric

allylation of aldehydes (Scheme 5.4). 17 Chiral bidentate N,N’ -dioxides can also form

stable Lewis acids by coordination to a metal ion. Coordination of a bidentate dienophile

to such a chiral Lewis acid could be exploited for stereoselective Diels-Alder reactions.

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Lewis base catalysis:

+ O anti-5 H OH N O H + SiCl O R H 3 Si R N O Cl R Cl

Lewis acid catalysis:

O anti-5 O O Cu(II) N O O O + N Cu N N N O O

Scheme 5.4 . Lewis base catalysis using 5 in the asymmetric allylation of aldehydes and

Lewis acid catalysis using 5 in a stereoselective Diels-Alder reaction

The crystal structure of N,N’ -dioxide 5 shows a nitrogen-nitrogen distance of 3.84

Å and an oxygen-oxygen distance of 4.32 Å. 18 This structure is reminiscent of highly

108

successful asymmetric ligands such as bisoxazolines and BINOL derivatives. Based on

the high affinity for silicon, it is likely that 5 would be a suitable chiral Lewis base for asymmetric activation of silicon reagents (SiCl 4, trimethylsilylcyanide, allytrichlorosilanes, etc.). Upon coordination, these reagents would be embedded deeply in the C 2-symmetric environment of the ligand.

5.3.2 Applications of 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene N,N’ - dioxide as a chiral catalyst for reactions utilizing silicon compounds

The allylation of aldehydes by allyltrichlorosilane is generally regarded as a good enantioselective reaction to evaluate the potential of a new N,N’ -dioxide catalyst.

Nakijima et al. have used 3,3’-dimethyl-2,2’-biquinoline N,N’ -dioxide in the allylation of

benzaldehyde in the presence of N,N-diispropylethyl amine (DIEA) and obtained 1-

phenylbut-3-en-1-ol in 85% yield and 88% ee (Scheme 5.5).19

N N O O O (10 mol %) OH + SiCl3 DIEA -78 oC, 6 h 85%, 88% ee

Scheme 5.5 . The asymmetric allylation of benzaldehyde

109

We were able to allylate p-anisaldehyde with racemic 2,2’-biquinoline N,N’ -dioxide

under conditions similar to those employed by Nakijima. But even after several

optimization attempts, we were not able to produce the allyl alcohol in greater than 10%

yield using enantiopure 5. Initial screening of other reactions involving silicon reagents, including the cyanation of imines with trimethylsilylcyanide in conjunction with

Cu(OTf) 2 (90% conversion to product, 4% ee), also showed low conversion or formation

of essentially racemic product.

We then turned our attention to the desymmetrization of meso -epoxides through nucleophilic attack of a chloride ion generated from silicon tetrachloride. This reaction is synthetically relevant as the corresponding vicinal halohydrin products are important synthetic intermediates of biologically significant compounds such as halogenated marine natural products, 20 and also because the reaction simultaneously installs two chiral centers. 21 The use of N-oxides for this transformation has been somewhat explored, and

Fu et al. have shown that they were able to desymmetrize cis -stilbene oxide with

tetrachlorosilane in 88% yield and 84% ee using planarly chiral ferrocene derived N-

oxides.22 Using 5 mol % of enantiopure 5 and DIEA, we were able to successfully desymmetrize cis -stilbene oxide with tetrachlorosilane in 90% yield and 60% ee at -78 oC

(Scheme 5.6). This finding represents the first example of effective asymmetric catalysis

with a 1,8-diacridylnaphthalene N,N’ -dioxide. It also provides a unique entry to integrate both catalysis and reaction analysis. The ultimate efficiency of an asymmetric reaction would be achieved if a catalyst could report the completion of the reaction and the

110

stereochemical outcome. Throughout the course of the epoxide opening reaction, color

changes were observed. Upon addition of SiCl 4 to a solution of 5, diisopropylethyl

amine, and cis -stilbene oxide, the initially red-orange solution turned dark green. After 1 hour the solution had become orange, and then after 4 hours the solution was yellow. We believe that the color changes observed during this reaction are promising for future enantioselective sensing applications.

N N O O (enantiopure) 5 O HO Cl SiCl4 o DIEA, CH2Cl2, -78 C, 6 h

90%, 60% ee

Scheme 5.6 . 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene N,N’ -dioxide

catalyzed desymmetrization of cis -stilbene oxide by silicon tetrachloride

5.4 Applications of 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene N,N’ - dioxide as a Brønsted acid sensor

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5.4.1 Introduction

Enantioselective optical spectroscopy provides an effective means to quantify enantiomeric excess while offering high sensitivity, inexpensive instrumentation, waste reduction, and the capability to perform real-time analyses of enantiomeric mixtures. 6d

Several sensing systems have utilized hydrogen-bond donation from the sensor to

effectively discriminate between different enantiomers of analytes. In particular, BINOL,

BINOL derived dendrimers, helicene diols, and thioureas have been used for this type of

enantioselective sensing. 23-26

Enantioselective sensing with Brønsted acids has been decidedly less explored.

Kubo et al. have developed a chiral calyx[4]crown sensor that contains a chiral 1,1’- binaphthyl unit (Figure 5.4). 27 This sensor was shown to be capable of differentiation between the enantiomers of phenylglycinol using UV-vis spectroscopy. Upon addition of

(R)-phenylglycinol to the sensor derived from ( S)-BINOL, the original band of the

sensor alone shifted from 515 nm to 538 nm and a new band appeared at 652 nm.

However, when ( S)-phenylglycinol was added to the sensor, there were no changes in the

UV-vis spectrum. The sensing ability of this highly enantioselective sensor was

attributed to selective deprotonation of the weakly acidic phenol units of the calixarene.

112

O O O N OH X HO N O X = O O

Figure 5.4 . Calix[4]crown employed by Kubo et al. in the enantioselective sensing of

amino alcohols and amino acids

As mentioned previously, the atropisomeric 1,8-diacridylnaphthalenes developed

by Wolf et al. have proven to be effective chiral sensors as either the free diacridines,

N,N’ -dioxides, or as N,N’ -dioxide – scandium complexes. A remaining application to be

investigated was the use of this class of compounds as strong Brønsted acid sensors. pKa

Values for protonated pyridine N-oxides in dimethyl sulfoxide have been calculated and depending upon the aryl ring substitution, usually range between 1 and 3 (Figure 5.5). 28 It

was rationalized that 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene N,N’ -

dioxide could be protonated by a very strong acid thus generating the first strong

Brønsted acid sensor.

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N N N OH OH OH

pKa = 1.63 pKa = 2.43 pKa = 2.01

Figure 5.5 . p Ka values of selected substituted pyridine N-oxides

5.4.2 Synthesis and applications of a strong Brønsted acid sensor

We decided to explore the possibility of protonating our N,N’ -dioxide, 5, with hydrochloric acid while carefully monitoring this reaction by UV-vis spectroscopy. The

N,N’ -dioxide was dissolved in anhydrous acetonitrile at a concentration of 1x10 -4 M and titrated with a 2x10 -2 M HCl in acetonitrile solution. We were delighted to discover that addition of the HCl solution resulted in a new, large absorption signal at 410 nm.

Moreover, maximum absorbance was achieved at two equivalents of HCl to the sensor

(Figure 5.6). We then titrated the protonated sensor with a triethylamine solution, and the original UV-vis spectrum of the free N,N’ -dioxide reappeared upon addition of two equivalents of base (Figure 5.7). These data suggest that we are able to form a well- defined diprotic N,N’ -dioxide with potential use in enantioselective sensing applications.

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4 3.5 3 0 eq. HCl 0.5 eq. HCl 2.5 1 eq. HCl 2 1.5 eq. HCl 1.5 Absorbance 2 eq. HCl 1 2.5 eq. HCl 0.5 5 eq. HCl 0 10 eq. HCl 200 300 400 500 600 700 800 Wavelength (nm)

Figure 5.6 . Titration of 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene N,N’ - dioxide with HCl

3.5

3 0 eq. Et3N 2.5 0.5 eq. Et3N 1 eq. Et3N 2 1.5 eq. Et3N 1.5 Absorbance 2 eq. Et3N 1 2.5 eq. Et3N 0.5 5 eq. Et3N

0 10 eq. Et3N 200 300 400 500 600 700 800 Wavelength (nm)

Figure 5.7. Titration of diprotic 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene

N,N’ -dioxide with Et 3N

115

Once the protonation of 5 was established, we decided to explore potential

sensing applications. Due to variability in the stated molarity of purchased HCl solutions,

it was necessary to ensure that all sensing solutions contained the fully protonated sensor.

This was accomplished by isolating the diprotic sensor. HCl in ether was added in ten

times excess to the N,N’ -dioxide dissolved in dichloromethane. Excess solvent and HCl

were removed under nitrogen flow followed by drying on a vacuum pump. Titration with

triethylamine confirmed that the solutions contained only the diprotic sensor and no

excess of HCl.

Employing this reproducible protonation protocol, we attempted to screen various substrates to see if an acid – base reaction could be monitored by UV-vis spectroscopy.

As anticipated, stoichiometric amounts of amines and amino alcohols showed quantitative deprotonation of the sensor (Figures 5.8 and 5.9).

N HO H OH OH O NH2 N quinine threoninol

Figure 5.8 . Structures of selected aminoalcohols screened

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1.2

0.8

0.6

I/Io at I/Io410 nm 0.4

0.2

0 0 0.5 1 1.5 2 2.5 3 3.5 Equiv. threoninol

Figure 5.9 . Titration of diprotic 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene

N,N’ -dioxide with threoninol

We had envisioned that very weak bases may be protonated by strongly acidic 5 in

analogy to the mechanism of acid catalyzed aldol reactions or S N1 reactions. Therefore,

substrates containing ketone, ester, carboxylic acid, and alcohol functionalities were

tested (Figure 5.10).

117

OH O CH OH OH 3 OH OH HO O

1-phenylbutanol BINOL 2-butanol 2-methylsuccinic acid

O O O O O O OH OO OH

2-isopropylidene-5- dimethyl-2,3-O- mandelic acid methylcyclohexanone isopropylidene tartrate

Figure 5.10 . Structures of alcohols, ketones, esters, and carboxylic acids screened

Unfortunately, these compounds did not induce any change in the spectrum of the fully

protonated N,N’ -dioxide, even in the presence of up to 1000 equivalents of the analyte.

To probe the sensing of analytes with p Ka values in between those of amines and the alcohols, ketones, esters, and carboxylic acids, we decided to study carboxylates. Using stoichiometric amounts of triethylamine and a carboxylic acid, triethylammonium salts of the carboxylate were prepared. But even the carboxylates proved to be too strongly basic and deprotonation of the sensor occurred quantitatively and without enantioselectivity

(Figures 5.11 and 5.12). The findings listed above indicate that the low p Ka of the

Brønsted acid of 5 may not allow enantioselective sensing applications of common

functionalities. But it points towards interesting future applications including Brønsted

118

acid catalysis and chiral recognition of sulfonic, phosphonic, and phosphinic acid

derivatives.

O O O O

Et3NH Et3NH triethylammonium salt of maleic acid dicarboxylate

Figure 5.11 . Structure of maleic acid triethylammonium dicarboxylate

1.2

0.8

0.6

I/Io at I/Io410 nm 0.4

0.2

0 0 0.5 1 1.5 2 2.5 3 Equiv. maelic acid dicarboxylate

Figure 5.12. Titration of diprotic 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene

N,N’ -dioxide with the triethylammonium dicarboxylate of maleic acid

119

5.5 Conclusions

In conclusion, we have made progress on the utilization of 1,8-bis(3’-(3,5-

dimethylphenyl)-9’-acridyl)naphthalene N,N’ -dioxide in new asymmetric catalysis and

enantioselective sensing applications. The synthesis of the ligand was successfully

scaled-up, and 1 gram of material was prepared. A chiral separation procedure was

developed that allows isolation of preparative amounts of the enantiomers of this ligand.

The use of the N,N’ -dioxide as an asymmetric catalyst for the desymmetrization of meso -

epoxides is promising from both a synthetic method development and enantioselective

sensing standpoint. We have also shown that both N-oxide groups in the ligand can be

protonated by a strong acid, and the protonation shows a significant UV-vis response that

demonstrates potential for the development of a Brønsted acid sensor.

5.6 Experimental details

All commercially available ligands, reagents, and solvents were used without

further purification. NMR spectra were obtained at 300 MHz ( 1H NMR) and 75 MHz

(13 C NMR). Chemical shifts are reported in ppm relative to TMS. Reaction products were

purified by column chromatography on silica gel (particle size 32-63 µm).

120

4-(3 ’, 5’-Dimethylphenyl)-2-chlorobenzoic acid 6f

To 2-chloro-4-bromobenzoic acid (3.76 g, 16.0 mmol), 3,5-dimethylphenylboronic acid

(2.40 g, 16.0 mmol), tetrabutylammonium bromide (5.2 g, 16.0 mmol), sodium carbonate (6.44 g, 60.8 mmol), and palladium tetrakis (184 mg, 0.0160 mmol) in an 80 mL microwave vessel was added 16 mL deionized water. The vessel was carefully purged with nitrogen for 10 minutes and the mixture heated to 130 oC (130 W) for 50

minutes using a continuous focused microwave power delivery system. Nitrogen was

bubbled through the water for 10 minutes. The crude reaction material was acidified to

pH 2 with 3 M HCl and extracted with dichloromethane. Following the initial extraction,

the organic residue was redissolved in dichloromethane and extracted with 6 M HCl to

remove any lingering tetrabutylammonium bromide. Solvents were removed by

rotoevaporation and the material recrystallized in ethyl acetate to yield pure product (3.22

1 g, 77%). H-NMR (300 MHz, CDCl 3) δ = 2.40 (s, 6 H), 7.07 (s, 1 H), 7.22 (s, 2 H), 7.57

(dd, J = 2.0 Hz, 8.3 Hz, 1 H), 7.71 (d, J = 2.0 Hz, 1 H), 8.10 (d, J = 8.3 Hz, 1 H). 13 C-

NMR (75 MHz, CDCl 3) δ = 11.1, 114.8, 115.0, 116.0, 119.6, 120.1, 122.7, 124.9, 128.0,

128.4, 136.7, 159.5.

4-(3 ’, 5’-Dimethylphenyl)-2-(N-phenylamino)benzoic acid 6f

To dimethylphenyl chlorobenzoic acid (1 g, 3.8 mmol), Cu (22 mg, 0.34 mmol), Cu(I)

oxide (22 mg, 0.34 mmol), and potassium carbonate (527 mg, 3.8 mmol) in a 3-neck

vessel under nitrogen was added 4 mL of 2-ethoxyethanol and aniline (712 mg, 7.6

121 mmol). The reaction was allowed to proceed with good stirring at 130 oC for 36 hours. To

the slightly cooled reaction material was added 5 mL of a sodium carbonate solution and

a small amount of charcoal. The mixture was filtered through a celite pad and the filtrate

acidified to pH 2 by 3M HCl. The mixture was then cooled to 0 oC for 3 hours and then the precipitate was isolated by filtration and recrystallized in ethyl acetate to yield pure

1 product (0.95 g, 80%). H-NMR (300 MHz, CDCl 3) δ = 2.35 (s, 6 H), 6.90 (dd, J = 1.5

Hz, 8.5 Hz, 1 H), 7.00 (s, 1 H), 7.13 (s, 2H), 7.30-7.44 (m, 6 H), 8.07 (d, J = 8.6 Hz, 1

13 H), 9.40 (bs, 1 H). C-NMR (75 MHz, CDCl 3) δ = 22.1, 110.0, 113.1, 117.4, 123.5,

124.6, 125.8, 130.2, 130.6, 133.7, 139.0, 141.0, 141.2, 149.0, 149.6, 173.6.

9-Bromo-3-(3 ’, 5’-dimethylphenyl)acridine 6f

To phosphorous oxybromide (6.76 g, 23.6 mmol) in a 3-neck vessel shielded by foil was added 4-(3’,5’-Dimethylphenyl)-2-(N-phenylamino)benzoic acid (676 mg, 2.13 mmol).

The reaction was heated to 100oC for 2 hours, cooled to room temperature, and then quenched with 30 mL of ice water. The solution was basified with aqueous ammonium hydroxide and the precipitate collected by filtration. The precipitate was then dissolved in dichloromethane, dried with magnesium sulfate, and solvents removed by rotoevaporation. The crude material was purified by silica gel chromatography

(dichloromethane mobile phase) and the product freeze dried (617 mg, 80%). 1H-NMR

(300 MHz, CDCl 3) δ = 2.44 (s, 6 H), 7.09 (s, 1 H), 7.46 (s, 2 H), 7.63 (ddd, J = 1.1 Hz,

6.6 Hz, 8.8 Hz, 1 H), 7.82 (dd, J = 6.9 Hz, 8.5 Hz, 1 H), 7.94 (dd, J = 1.6 Hz, 9.1 Hz, 1

122

13 H), 8.27 (d, J = 8.8 Hz, 1 H), 8.39-8.47 (m, 3 H). C-NMR (75 MHz, CDCl 3) δ = 22.0,

125.3, 125.5, 126.0, 126.7, 127.0, 127.2, 127.5, 127.8, 129.9, 130.2, 130.4, 135.4, 138.6,

139.3, 142.8, 149.2, 149.2.

3-(3 ’, 5’-Dimethylphenyl)-9-trimethylstannylacridine 6f

All glassware was flame dried under vacuum. The purified bromoacridine derivative (395 mg, 1.09 mmol) was dissolved in an anhydrous 1:1 diethylether:THF solution (6 mL) at -

78 oC under inert atmosphere. To this solution was added dropwise (over 15 minutes) a

1.6 M butyllithium solution in hexanes (1.03 mL, 1.64 mmol). Upon addition, the solution became very dark. A second portion of butyllithium was added after 20 minutes

(0.34 mL, 0.53 mmol). Directly after, tributyltin chloride (1.11 mL, 4.12 mmol in 1 mL anhydrous Et 2O) was added in one portion. The ice bath was removed immediately and the solution allowed to stir at room temperature for 18 hours. Solvents were removed by rotoevaporation and the crude material purified by column chromatography (98:2 dichloromethane : triethylamine mobile phase) to yield pure product (513 mg, 82%). 1H-

NMR (300 MHz, CDCl 3) δ = 0.87 (t, J = 7.1 Hz, 7.3 Hz, 9 H), 1.30-1.70 (m, 18 H), 2.41

(s, 6 H), 7.04 (s, 1 H), 7.50-7.54 (m, 3 H), 7.71-7.77 (m, 1H), 7.86 (dd, J = 2.0 Hz, 9.0

Hz, 1 H), 8.09 (d, J = 8.5 Hz, 1 H), 8.15 (d, J = 9.0 Hz, 1 H), 8.26 (d, J = 8.5 Hz, 1 H),

13 8.49 (d, J = 1.7 Hz, 1 H). C-NMR (75 MHz, CDCl 3) δ = 14.1, 14.2, 22.1, 27.9, 29.7,

125.7, 125.9, 126.0, 128.1, 130.2, 130.3, 131.0, 131.1, 131.3, 133.9, 134.6. 139.1, 140.5,

142.6, 148.7, 148.8, 158.9.

123

1,8-Bis(3-(3 ’, 5’-dimethylphenyl)-9-acridyl)naphthalene 6f

1,8-Dibromonaphthalene (84 mg, 0.293 mmol), copper(II)oxide (47 mg, 0.585 mmol), and palladium tetrakis triphenylphophine (121 mg, 0.11 mmol) were combined under nitrogen in anhydrous DMF (3 mL). The reaction was heated to 130 oC, stirred for 5

minutes, and then 3-(3’,5’-Dimethylphenyl)-9-trimethylstannylacridine (670 mg, 1.17

mmol) in 3 mL of anhydrous DMF was added in one portion. The reaction proceeded for

40 hours at 130 oC, was quenched with saturated sodium bicarbonate water, extracted with

dichloromethane, and solvents removed under reduced pressure. The crude material was

purified by silica gel column chromatography (2:2:1:1% dichloromethane : hexanes :

ethyl acetate : triethylamine mobile phase) to yield pure product (202 mg, 89%). anti-

1 Isomer: H-NMR (300 MHz, CDCl 3) δ = 2.45 (s, 12 H), 6.62-6.68 (m, 2 H), 6.83-6.86

(m, 4 H), 7.00-7.03 (m, 2 H), 7.07 (s, 2 H), 7.31-7.39 (m, 8 H), 7.67 (d, J = 9.1 Hz, 2 H),

13 7.73-7.78 (m, 2 H), 7.91 (s, 2 H). 8.31 (d, J = 8.2 Hz, 2 H). C-NMR (75 MHz, CDCl 3) δ

= 22.3, 124.8, 125.4, 125.5, 125.6, 125.9, 126.2, 126.3, 126.6, 127.0, 129.3, 129.8, 130.1,

130.5, 131.2, 134.2, 134.6, 135.5, 139.0, 140.8, 141.9, 146.1, 147.5, 147.6. syn -Isomer:

1 H-NMR (300 MHz, CDCl 3) δ = 2.26 (s, 12 H), 6.65-6.70 (m, 2 H), 6.75-6.78 (m, 2 H),

6.85-6.88 (m, 2 H), 6.96-6.99 (m, 4 H), 7.12 (s, 4 H), 7.28-7.31 (m, 2 H), 7.36-7.42 (m, 2

H), 7.69-7.75 (m, 4 H), 7.91 (d, J = 1.7 Hz, 2 H), 8.27 (dd, J = 1.1 Hz, 8.4 Hz, 2 H). 13 C-

NMR (75 MHz, CDCl 3) δ = 22.0, 124.8, 125.3, 125.4, 125.5, 125.8, 126.1, 126.3, 126.4,

124

126.9, 129.4, 129.7, 130.1, 130.4, 131.1, 134.2, 134.7, 135.5, 138.8, 140.7, 142.1, 146.1,

147.4, 147.5.

1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene N,N’ -dioxide 29

To anti -1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene (800 mg, 1.16 mmol) in

50 mL anhydrous dichloromethane under nitrogen at 0oC was added dropwise MCPBA

(77% purity, 571 mg, 2.55 mmol) in 20 mL dichloromethane. The reaction was slowly

warmed to room temperature, stirred for 1 hour, and then quenched with a 2 M NaOH

solution. The product was extracted with dichloromethane and solvents removed by

rotoevaporation. The crude reaction material was purified by recrystallization (96:2:2

dichloromethane : ethyl acetate : ethanol) to yield pure product (471 mg, 56%). The

enantiomers were separated by HPLC using UV detection at 254 nm on a preparative

Whelk-O 1 column (10 mm x 250 mm) using dichloromethane:EtOH (90:10) as the

mobile phase, t 1 = 3.5 min, t 2 = 6.0 min. 1 mL of a 0.03 M solution of the ligand in dichloromethane:EtOH (90:10) was injected into a 1 mL sample loop for each injection, and the enantiomers were collected separately following elution off the column. Solvents were removed by rotoevaporation, and the enantiomeric purity of each enantiomer was confirmed to be >99% by reinjection on the HPLC using the same separation conditions.

1 H-NMR (300 MHz, CDCl 3) δ = 2.45 (s, 12H), 6.63-6.69 (m, 2H), 6.81 (d, J = 9.1 Hz,

2H), 6.87 (d, J = 8.0 Hz, 2H), 7.09-7.14 (m, 4H), 7.34-7.41 (m, 8H), 7.77 (dd, J = 7.2 Hz,

8.2 Hz, 2H), 8.32 (dd, J = 1.1 Hz, 8.2 Hz 2H), 8.47 (d, J = 9.1 Hz 2H). 8.69 (d, J = 1.7

125

13 Hz, 2H). C-NMR (75 MHz, CDCl 3) δ = 22.3, 117.6, 120.5, 126.1, 126.5, 126.5, 126.6,

126.7, 126.3, 126.9, 127.5, 130.0, 130.7, 131.0, 132.2, 133.4, 134.1, 135.1, 135.9, 138.6,

138.6, 139.2, 140.2, 143.0.

2-Chloro-1,2-diphenylethanol 30 cis -Stilbene oxide (50 mg, 0.255 mmol), enantiopure 1,8-bis(3’-(3,5-dimethylphenyl)-9’- acridyl)naphthalene N,N’ -dioxide (9 mg, 0.1275 mmol), and DIEA (50 mg, 0.383 mmol)

were dissolved in anhydrous dichloromethane under nitrogen. This solution was cooled to

-78 oC and then silicon tetrachloride that had been prepared in a dry box (1 M solution in

o CH 2Cl 2, 0.50 mL, 0.51 mmol) was added via syringe. After stirring for 6 hours at -78 C,

the reaction was quenched with a saturated sodium bicarbonate solution. The aqueous

layer was then treated with a 1:1 solution of KF/NaH 2PO 4 (~1 g of each in 10 mL of

water). This mixture was then extracted with dichloromethane. Solvents were removed

by rotoevaporation. Enantiomeric excess was determined by HPLC analysis using a

1 Chiralcel OD column (95 : 5 hexanes : IPA). H-NMR (300 MHz, CDCl3) δ = 3.05 (bs, 1

H), 4.95 (d, J = 8.3 Hz, 1 H), 5.0 (d, J = 8.3 Hz, 1 H), 7.08-7.12 (m, 2 H), 7.16-7.32 (m, 8

H).

UV-Vis measurements

All UV-vis absorption spectra were collected under air atmosphere using a 4.5 x 10 -5 M

diprotic 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene N,N’ -dioxide solution in

126 anhydrous acetonitrile. For measurements of the UV spectrum of 5 in the presence of 0.5-

200 equivalents of analyte, solutions of the analytes (8.98 x 10 -2 M) were added. For 400-

1000 equivalents to the sensor, the analytes were added in neat (as either a solid or a

liquid). To obtain the triethylammonium carboxylates, equimolar amounts of the

carboxylic acid and triethylamine were combined and then diluted with anhydrous

acetonitrile to obtain 8.98 x 10 -2 M solutions. Analytes were added to a cuvette

containing 2 mL of the sensor solution and then mixed by inversion of the cuvette for 10

seconds.

5.7 References

1 Kuhn, R. In: Freudenberg, K. (ed.) Stereochemie Deuticke: Leipzig, 1933, pp. 803, 810.

2 Wolf, C. Dynamic Stereochemistry of Chiral Compounds The Royal Society of

Chemistry: Cambridge, 2008.

3 Christie, G. H.; Kenner, J. J. Chem. Soc. 1922 , 121 , 614-620.

4 Clough, R. L.; Roberts, J. D. J. Am. Chem. Soc. 1976 , 98 , 1018-1020.

5 a) Yin, J.; Rainka, M. P.; Zhang, X-. X.; Buchwald, S. L. J. Am. Chem. Soc. 2002 , 124 ,

1162-1163. b) Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002 , 124 , 6343-

6348. c) Su, W.; Urgaonka, S.; McLaughlin, P. A.; Verkade, J. G. J. Am. Chem. Soc.

2004 , 126 , 16433-16439. d) Dufkov, L.; Kotora, M.; Cisarov, I. Eur. J. Org. Chem.

2005 , 2491-2499 . 127

6 a) Wolf, C.; Mei, X. J. Am. Chem. Soc. 2003 , 125 , 10651-10658. b) Wolf, C.;

Tumambac, G. E. J. Phys. Chem. A 2003 , 107 , 815-817. c) Tumambac, G. E.; Mei, X.;

Wolf, C. Eur. J. Org. Chem. 2004 , 3850-3856. d) Mei, X.; Wolf, C. J. Am. Chem. Soc.

2004 , 126 , 14736-14737. e) Tumambac, G. E.; Wolf, C. J. Org. Chem. 2004 , 69 , 2048-

2055. f) Mei, X.; Martin, R. M.; Wolf, C. J. Org. Chem. 2006 , 71 , 2854-2861.

7 Wolf, C.; Liu, S.; Reinhardt, B. C. Chem. Commun . 2006 , 4242-4244.

8 Mei, X.; Wolf, C. Chem. Commun. 2004 , 2078-2079.

9 Liu, S.; Pestano, J.P.; Wolf, C. J. Org. Chem. 2008 , 4267-4270.

10 Pirkle, W. H.; Welch, C. J.; Lamm, B. J. Org. Chem . 1992 , 57 , 3854-3860.

11 Sammis, G.; Jacobsen, E. J. Am. Chem. Soc. 2003 , 125 , 4442-4443.

12 Malkov, A. V.; Dufkova, L.; Farrugia, L.; Kocovsky, P. Angew. Chem. Int. Ed. 2003 ,

42 , 3674-3677.

13 Nakajima, M.; Saito, M.; Hashimoto, S. Tetrahedron: Asymmetry 2002 , 13 , 2449-2452.

14 a) Krause, N.; Hoffmann-Roeder, A. Synthesis 2001 , 171-196. b) Christoffer, J. Eur. J.

Org. Chem. 1998 , 1259-1266. c) Leonard, J.; Diez-Barra, E.; Merino, S. Eur. J. Org.

Chem. 1998 , 2051-2061. d) Rossiter, B.; Swingle, N. Chem. Rev. 1992 , 92 , 771-806. e) Shibasaki, M.; Sasai, A. T. Angew. Chem. Int. Ed. 1997 , 36 , 1236-1256.

15 Chen, F.-X.; Qin, B.; Feng, X.; Zhang, G.; Jiang, Y. Tetrahedron 2004 , 60 , 10449-

10460.

16 Reinhardt, B. Synthesis of highly congested, axially chiral 1,8-bis(3,3'-t-butyl-9,9'-

acridyl)naphthalene; Masters Thesis. Georgetown University, Washington, DC, 2004. 128

17 Chelucci, G.; Murineddu, G.; Pinna, G. A. Tetrahedron: Asymmetry 2004 , 15 , 1373-

1389.

18 Mei, X. Synthesis, Properties, and Applications of 1,8-Diacridylnaphthalenes; Ph.D.

Thesis. Georgetown University, Washington, DC, 2006.

19 Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J. Am. Chem. Soc. 1998 , 120 , 6419-

6420.

20 Martín, J. D.; Pérez, C.; Ravelo, J. L. J. Am. Chem. Soc. 1986 , 108 , 7801-7811.

21 Nakijima, M; Saito, M.; Uemura, M.; Hashimoto, S. Tetrahedron Lett . 2002 , 43 , 8827-

8829.

22 Tao, B.; Lo, M. M. –C.; Fu, G. C. J. Amer. Chem. Soc. 2001 , 123 , 353-354.

23 Pu, L. Chem. Rev. 2004 , 104 , 1687-1716.

24 Bell, T. W.; Hext, N. M. Chem. Soc. Rev . 2004 , 33 , 598-598.

25 Willener, Y.; Joly, K. M.; Moody, C. J.; Tucker, J. G. R. J. Org. Chem. 2008 , 73 ,

1225-1233.

26 Hu, C.; He, Y.; Chen, Z.; Huang, X. Tetrahedron: Asymmetry 2009 , 20 , 104-110.

27 Kubo, Y.; Maeda, S.; Tokita, S.; Kubo, M. Nature 1996 , 382 , 522-524.

28 Chmurzy ński, L.; Warnke, Z. Aust. J. Chem. 1993 , 46 , 185-194.

29 Mei, X.; Wolf, C. J. Am. Chem. Soc. 2006 , 128 , 13326-13327.

30 Denmark, S. E.; Barsanti, P. A.; Wong, K. -T.; Stavenger, R. A. J. Org. Chem. 1998 ,

63 , 2428-2429.

129

VI. The development of heme-targeted antimalarials i,ii

6.1 Introduction

Malaria remains the among world’s most widespread and devastating infectious diseases, with between 350 and 500 million annual cases and more than 1 million casualties.1 Among the protozoan parasites of the genus Plasmodium causing malaria in humans, Plasmodium falciparum is the most lethal species. Since the discovery of the antimalarial potency of quinine and other cinchona alkaloids, a variety of agents exhibiting a 4-substituted quinoline pharmacophore has been introduced. In particular, chloroquine (CQ), mefloquine, sontoquine, and amodiaquine have proved to be among the most effective antimalarial drugs (Figure 6.1).2-4

i Reproduced in part with permission from the American Chemical Society, Washington, DC, USA. a)

Yearick, K.; Ekoue-Kovi, K.; Iwaniuk, D. P.; Natarajan, J. K.; Alumasa, J.; de Dios, A. C.; Roepe, P. D.;

K.; Alumasa, J. N.; Yearick, K.; Ekoue-Kovi, K. A.; Casabianca, L. B.; de Dios, A. C.; Wolf, C.; Roepe, P.

Yearick, K.; Iwaniuk, D. P.; Natarajan, J. K.; Alumasa, J.; de Dios, A. C.; Roepe, P. D.; Wolf, C. Bioorg.

130

HN HO HO N N HN OMe F3C N N N Cl CF3 quinine chloroquine mefloquine

OH N N HN HN

N Cl N Cl sontoquine amodiaquine

Figure 6.1 . 4-Substituted quinoline derivatives used as antimalarial drugs

Aminoquinolines are known to form a complex with ferriprotoporphyrin IX

(FPIX), which is generated in the food vacuole of the intraerythrocytic malaria parasite as

a result of proteolysis of host hemoglobin (Hb). Free FPIX is cytotoxic to Plasmodium which therefore has developed a strategy to limit the amount of free FPIX by converting it into insoluble crystalline hemozoin. 5 It is commonly believed that drug-FPIX interactions inhibit conversion of hematin to hemozoin and hence its detoxification via crystallization, and the accumulation of significant concentrations of toxic FPIX-drug adducts is believed to be ultimately responsible for killing the parasite. 6-10 It is widely accepted that the 4-aminoquinoline pharmacophore plays a crucial role in the complexation to FPIX resulting in inhibition of hemozoin formation and parasite 131

growth, 11 while the presence of a basic amino group in the side chain is generally

considered essential for trapping high concentrations of the drug in the acidic food

vacuole of the parasite. 12

Unfortunately, widespread use of CQ in the 1960’s with the intent to eradicate malaria most likely contributed to an increasing incidence of CQ resistant strains of parasites. 13 The mechanism of CQ resistance is not yet fully understood. As stated previously, FPIX is released from proteolyzed red blood cell Hb within the parasite digestive vacuole (DV) as the parasite very rapidly grows within the human red blood cell. As such, the principle target (heme made by the host) cannot be mutated or alternatively expressed by the parasite in order to confer resistance. Mounting evidence shows that an integral membrane protein of the DV, Pfcrt, participates in the active efflux of CQ (Figure 6.2). 13-15 Moreover, there is some evidence that the pH of the DV differs

between chloroquine sensitive (CQS) and chloroquine resistant (CQR) strains of

malaria. 16 The CQR mechanism is therefore unique, complex, and has taken decades to

appear on a large scale even in the face of massive CQ use.15

132

H+

+ rt H f c Cl P N N Fe N N

H+

HO O O OH N HN Digestive Vacuole H+ N Cl

Figure 6.2 . Representation of the acidic parasitic DV containing FPIX with Pfcrt membrane transport protein participating in active CQ efflux

The problem of CQR malaria can be addressed in multiple ways. One approach is to synthesize novel antimalarials that differ significantly in structure to CQ. Promising

CQR reversal agents 17,18 and new therapeutics 19 including artemisinin and other endoperoxides have been introduced. 20-25 However, the latter are less affordable in the most plagued tropical and subtropical regions and resistance to endoperoxide-derived antimalarials has already been reported. 26 Another approach is to modify proven antimalarial drugs that are effective towards CQS strains but ineffective towards CQR strains in an attempt to enhance activity against the CQR strains. Arguably, quinine, 133

chloroquine and mefloquine are among the most successful antimalarial drugs ever used,

and additional lead compounds with improved activity against CQR strains have been

discovered via synthetic modifications of these structures. 27-29 Importantly, 4-

aminoquinolines carrying an aliphatic side chain are often well tolerated and afford

excellent activity-toxicity profiles. 30 The evident need for safe, effective and inexpensive antimalarials that are equally active against multiple species of Plasmodia , e.g. P. falciparum and P. vivax , has therefore directed increasing efforts to the design of new CQ analogs.

Since modification of the 7-chloroquinoline ring, i.e. incorporation of other electron-withdrawing or electron-donating substituents such as amino and methoxy groups into the various positions in the quinoline ring, have generally proved detrimental to the antimalarial activity, 12,31 a systematic variation of the side chain structure and

basicity seems to be more promising. Although few comprehensive and methodical

modifications of the CQ side chain have been reported to date, it has been established that

both shortening and lengthening of the separation of the two aliphatic amino groups to

either 2-3 or 10-12 carbon atoms as well as the incorporation of a phenol moiety can lead

to increased activity against CQR strains. 29,32-34 Additionally, several studies revealed that introduction of a branched dialkylamino motif at the side chain N-terminus of CQ, e.g. replacement of the ethyl by isopropyl or tert -butyl groups, can furnish metabolically more stable antimalarials with enhanced life-time and retained activity against drug resistant strains of P. falciparum .35,36

134

We envisioned that altering the structure of CQ through the incorporation of an

increasing number of basic amino groups along with systematic structural variations

(length and branching) of the aliphatic side chain attached to the potent 4-amino-7-

chloroquinoline pharmacophore would provide new candidates that overcome

antimalarial drug resistance. The introduction of a highly branched tether between the

two amino functions in CQ as well as the replacement of the metabolically unstable

terminal diethylamino group by an isopropyl analog were expected to enhance the life-

time of CQ analogs that could thus retain activity against CQR strains. Because there is

some evidence that the pH of the DV differs between CQS and CQR strains of malaria,16 fine tuning both the basicity of the quinolyl nitrogen by changing the heteroatom in the 4- position of the quinolyl ring to oxygen and simultaneously altering the length of the CQ side chain, may also optimize the interactions with FPIX (Figure 6.3). Additionally, we considered changing the heteroatom in the 4-position because recent solid state NMR studies have shown that CQ may form a dative bond with monomeric FPIX (via a heme

Fe – quinoline nitrogen bond 10 ) under acidic conditions that mimic those of the parasite

DV. Thus, assuming other structural features remain constant, altering the nucleophilicity

of the quinolyl nitrogen (as predicted for a 4O substitution) would influence reactivity of the drug vs. monomeric heme. Lastly, sulfonamides including the protease inhibitor and antiretroviral fosamprenavir, the nonsteroidal anti-inflammatory drug celecoxib, and sumatriptan, which has been used to treat migraine headaches, have found widespread use as pharmaceuticals. Among the few examples of antimalarial sulfonamides reported

135

to date, some exhibit remarkable potency. 37-40 We therefore decided to synthesize additional CQ analogs that incorporate sulfonamide groups containing titratable amines on the nitrogen terminus of the CQ pharmacophore.

Structural modification of the side chain (length and branching) Modification of N-terminus (alkyl NR2 group modifications, sulfonamide HN incorporation)

N Cl

Variation of the basicity of the quinolyl nitrogen by changing the heteroatom in position 4

Figure 6.3. Important functional sites of the CQ structure

By systematic modification of the CQ scaffold, we envisioned to uncover new structure-activity relationships of this important antimalarial, to find new entries to novel drugs active against CQR strains, and to better understand the mechanism of drug resistance.

136

6.2 Synthesis of antimalarial drug candidates

6.2.1 Synthesis of 4-aminoquinolines with symmetrically branched side chains

The synthesis of the symmetrically branched compounds, N-(7-chloro-4- quinolyl)-1,9-bis(diethylamino)-5-aminononane and N-(7-chloro-4-quinolyl)-1,9- bis(diisopropylamino)-5-aminononane required optimization of various coupling conditions for diamide bond formation (Scheme 6.1).41 The screening of a range of

coupling agents revealed that benzotriazol-1-yl-oxytripyrrolidinophosphonium

hexafluorophosphate (Pybop) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) allow

efficient α,ω -diamide formation with 5-oxoazelaic acid and diethylamine and

diisopropylamine, respectively, to produce 1,9-bis(diethylamido)nonan-5-one in 62%

yield and 1,9-bis(diisopropylamido)nonan-5-one in 82% yield. Reductive amination of

the ketone group using ammonium acetate and sodium cyanoborohydride furnished 1,9-

bis(diethylamido)-5-aminononane and 1,9-bis(diisopropylamido)-5-aminononane in 58%

and 50% yield, respectively. Subsequent reduction of the terminal amides with lithium

aluminium hydride gave 1,9-bis(diethylamino)-5-aminononane and 1,9-bis(diisopropyl)-

5-aminononane in good yields. These amines were then employed in a carefully

optimized nucleophilic aromatic substitution procedure using excess of 4,7-

dichloroquinoline at high temperatures in a closed vessel to produce the branched amino

CQ derivatives.

137

O R=Et O Pybop, DIEA R N NR HO OH + R NH 2 2 n n 2 n n R=i-Pr O O O n=2 O CDMT, NMM n=2, R=Et, 62% n=2, R=i-Pr, 82%

NH2 NH2 NaCNBH R2N NR2 LiAlH R2N NR2 3 n n 4 n n NH OAc O O 4 n=2, R=Et, 80% n=2, R=Et, 58% n=2, R=i-Pr, 85% n=2, R=i-Pr, 50%

Cl R2N n n NR2 HN Cl N ∆ Cl N

n=2, R=Et, 47% n=2, R=i-Pr, 30%

Scheme 6.1 . Synthesis of symmetrically branched N-(7-chloro-4-quinolyl)-1,9- bis(diethylamino)-5-aminononane and N-(7-chloro-4-quinolyl)-1,9- bis(diisopropylamino)-5-aminononane

6.2.2 Synthesis of 4-oxoquinolines with linear and branched side chains

Linear 4-oxoquinoline CQ derivatives were synthesized from 4,7- dichloroquinoline and α,ω− alkanediols via consecutive nucleophilic displacements

138

(Scheme 6.2). 42 In the first step, diols of varying alkyl chain lengths were coupled to 4,7-

dichloroquinoline by nucleophilic aromatic substitution promoted by potassium tert -

butoxide in tert -butanol ( t-BuOK / t-BuOH) in good to excellent yields. The final linear oxo-compounds were obtained by activating the terminal oxygen with methanesulfonyl chloride (MsCl) and subsequent SN2 reaction with diethylamine.

OH O Cl t-BuOK/ n t-BuOH OH + HO n ∆ N Cl N Cl n = 1, 94% n = 2, 99% n = 3, 64% n = 4, 99% n = 5, 92%

N 1. MsCl O n 2. Et2NH

N Cl n = 1, 61% n = 2, 62% n = 3, 99% n = 4, 96% n = 5, 83%

Scheme 6.2 . Synthesis of linear 4-oxosubstituted quinolines

Branched 4-oxoquinoline CQ derivatives were synthesized in a similar manner to

the branched 4-aminoquinoline CQ derivatives. 1,9-Bis(diethylamido)nonan-5-one and

1,9-bis(diethylamido)heptan-5-one were directly submitted to lithium aluminum hydride

reduction to yield the corresponding α,ω -bis(diethylamino)alkanols (Scheme 6.3).

139

Deprotonation with t-BuOK / t-BuOH and subsequent nucleophilic aromatic substitution at position 4 of 4,7-dichloroquinoline then yielded 7-chloro-4-(1’,7’-bis(diethylamino)-

4’-heptoxy)quinoline and 7-chloro-4-(1’,9’-bis(diethylamino)-5’-nonoxy)quinoline, respectively.

O PyBop O HO OH + Et2NH N N n n DIEA n n O O O O n = 1, 98% n = 2, 62%

N Cl N N t-BuOK/ n n LiAlH4 OH t-BuOH O N N n n ∆ N Cl n = 1, 85% n = 1, 54% n = 2, 90% n = 2, 35%

Scheme 6.3 . Synthesis of branched 4-oxosubstituted quinolines

6.2.3 Synthesis of sulfonamide derived CQ derivatives

Following a literature procedure, N-(7-chloro-4-quinolyl)-1,3-diaminopropane

was prepared from 4,7-dichloroquinoline and 1,3-diaminopropane.42 The sulfonamide

CQ derivatives were then synthesized in one step by coupling of the corresponding

140

sulfonyl chlorides with the terminal amino function of the CQ analogs in the presence of

triethylamine (Scheme 6.4).43

O Ar S HN NH2 HN N ArSO2Cl H O

Et3N N Cl N Cl

N Ar = O N

20% 40% 30%

Scheme 6.4 . Synthesis of sulfonamide derived CQ derivatives

6.3 Antimalarial activity of synthesized CQ analogs

The activity of these compounds versus two CQS and two CQR strains were

measured by Dr. Paul Roepe’s group at Georgetown University using a standardized

assay based on SYBR Green I intercalation that has recently been adopted and validated

44-46 by a number of laboratories. IC 50 values were obtained from an average of two

separate measurements each repeated in triplicate and compared to CQ. Each compound

was tested against CQS strains (HB3 and/or GCO3) and CQR strains (Dd2 and/or FCB).

141

6.3.1 Antimalarial activity of 4-aminoquinolines with symmetrically branched side

chains

We initially synthesized the branched 4-aminoquinolines with an additional titratable amine, as compared to CQ, to capitalize on the pH gradient towards the DV which would favor migration into the food vacuole. The substitution of the terminal diethyl amino groups with diisopropyl amino groups and the branching of the side chain were expected to improve biostability and thus increase antiplasmodial activity.

Unfortunately, the relatively high IC 50 values of N-(7-chloro-4-quinolyl)-1,9- bis(diethylamino)-5-aminononane and N-(7-chloro-4-quinolyl)-1,9- bis(diisopropylamino)-5-aminononane reveal that basicity and structure of the side chain could not be optimized independently (Table 6.1, entries 4 and 5). The potency of these symmetrically branched compounds can be increased by decreasing the side chain length

(Table 6.1, entries 2 and 3).41 Chloroquine analogs exhibiting a linear side chain with similar basicity were found to afford superior antimalarial activity as compared to the symmetrically branched compounds. For example, CQ derivatives carrying a linear dibasic side chain of varying length exhibit significantly lower IC 50 values than the

symmetrically branched analogs (Table 6.1, entries 4-5 and 6-10). Notably, the

symmetrically branched CQ analogs show a superior selectivity index (SI, ratio of the

IC 50 for the resistant versus the sensitive strain) compared to CQ.

142

Table 6.1 . Antiplasmodial activity of the symmetrically branched 4-aminoquinolines

Experimental IC (nM) Entry Compound 50 HB3 Dd2 SI GCO3 FCB SI

NEt HN 2 1 14 140 10.4 16 170 10.6

N Cl

Et2N n n NEt2 HN 2 187 128 0.7 97 186 1.9 n = 1 Cl N

i-Pr2N n n Ni-Pr2 HN 3 44 100 2.3 42 104 2.5 n = 1 Cl N

Et2N n n NEt2 HN 4 716 882 1.2 517 1060 2.1 n = 2

Cl N

i-Pr2N n n Ni-Pr2 HN 5 1314 2550 2.0 1512 2225 1.5 n = 2

Cl N

143

HN nN NEt2 6 27 31 1.1 38 53 1.4 n = 2 Cl N

HN nN NEt2 7 21 28 1.3 28 49 1.8 n = 3 Cl N

HN nN NEt2 8 24 85 3.5 87 156 1.8 n = 4 Cl N

HN nN NEt2 9 16 43 2.8 55 67 1.2 n = 5 Cl N

HN nN NEt2 10 63 274 4.4 175 263 1.5 n = 6 Cl N

144

6.3.2 Antimalarial activity of 4-oxoquinolines with linear and branched side chains

The 4 O linear compounds were synthesized to study the significance of the

basicity of the quinolyl nitrogen. The IC 50 values of these compounds were found to be

significantly higher than that of CQ for both CQS and CQR strains. However, the SI

values of these compounds were exceptionally better than that of CQ (Table 6.2). While

the IC 50 values of these compounds illustrate that the structure has not yet been optimized, the significantly lower SIs demonstrate the therapeutic potential of 4-O substituted 7-chloroquinolines.

Table 6.2. Antiplasmodial activity of 4-oxoquinolines with linear and branched side chains

Experimental IC (nM) Compound 50 HB3 Dd2 SI GCO3 FCB SI

NEt HN 2 11 116 10.5 10 15.7 151

N Cl

N O n 5800 4570 0.8 5290 5080 1.0

Cl N n = 1

145

N O n 5100 2800 0.5 2340 2330 1.0

Cl N

n = 2

N O n 2920 1180 0.4 1660 1100 0.7

Cl N n = 3

N O n 1870 1010 0.5 1490 930 0.6

Cl N n = 4

N O n 3060 4160 1.4 2270 1190 0.5

Cl N n = 5

N N n O n 94 409 4.4 74 352 4.8 N Cl n = 1

146

N N n O n 73 316 4.3 45 604 13.4 N Cl n = 2

Because the 4O linear compounds will exist effectively as monoprotic weak bases,42 the concentration of the compounds in the DV will then be linearly related to the net pH gradient. 47 Thus, one possible explanation for the reduced activity of these compounds is a lowered ability to concentrate within the DV (site of hemoglobin digestion and release of free heme). Additionally, the activity of the compounds increases up to n = 4 chain length, and then decreases thereafter, suggesting that this may be an optimal chain length for these CQ derivatives.

Since the accumulation of the linear 4 O drugs may be decreased due to the lack of

an additional titratable nitrogen, it was anticipated that the presence of another amino

group in the corresponding 4 O branched derivatives would increase potency while

maintaining the low SIs observed for the linear compounds. We were pleased to find that

introduction of an additional amino group to the side chain of 4 O CQ derivatives

improves antimalarial activity versus both CQS and CQR strains, but unfortunately SIs

were somewhat compromised.

147

6.3.3 Antimalarial activity of sulfonamide derived CQ derivatives

Because of the well known therapeutic value of the sulfonamide pharmacophore and several reports of promising antimalarials exhibiting this functionality, several CQ derived sulfonamides containing a basic side chain were introduced.37-40 Unfortunately, these compounds showed limited activity against CQS and CQR strains of malaria (Table

6.3).

Table 6.3. Antiplasmodial activity of sulfonamide derived CQ derivatives

Experimental IC (nM) Compound 50 HB3 Dd2 SI

NEt HN 2 10 127 12.7

N Cl

N O S HN N 754 966 1.3 H O

N Cl

O S HN N H O N 453 607 1.3

N Cl

148

O O N S HN N >1000 >1000 N/A H O

N Cl

The basic tertiary amino function in the side chain is commonly believed to be crucial for the accumulation of the drug within the acidic food DV. The pH of DV for CQS strains is

16 estimated to be 5.7, and the pH for the CQR strains is estimated to be 5.2. The p Ka

41 values for CQ have been measured as pKa1 = 9.8 and a p Ka2 = 8.6. At the pH of either

the CQS or CQR DV’s, the drug should exist in a diprotic form after crossing the DV

membrane, thereby trapping it. However, for the sulfonamide compounds, the first

titratable amino function is replaced by a sulfonamide linkage. The appended

sulfonamide groups have basic functionalities with p Ka values similar to the pH of the

DV. Consequently, the sulfonamide compounds have less diprotic character than the terminal amino derivatives in the DV. It is therefore not surprising that the IC 50 values of

these synthesized sulfonamides increased into the micromolar range.

149

6.4 Conclusions

In conclusion, 12 new heme-targeted antimalarials have been prepared by systematically varying side chain lengths, N-terminal branching and substitutions, and

heteroatom substitution of the 4-position of quinoline. This study reveals that methodical

variation of the side chain of chloroquine provides a promising entry towards affordable

heme-targeted antimalarials that may overcome the ever-increasing problem of

worldwide drug resistance.

6.5 Experimental Details

1,9-Bis(diethylamido)nonan-5-one

To a mixture of 5-oxoazelaic acid (2.5 g, 12.4 mmol) and PyBop (15.4 g, 29.7 mmol) in

anhydrous CH 3CN (18.0 mL) under inert atmosphere was added diethylamine (5.11 mL,

49.9 mmol) and N,N -diisopropylethylamine (6.0 mL, 34.2 mmol). The reaction proceeded with good stirring at 35 oC for 64 h and then solvents were removed in vacuo .

The residue was dissolved in CH 2Cl 2, washed with a 2M HCl, dried over anhydrous

MgSO 4, and concentrated in vacuo to produce a yellow oil (2.39 g, 7.7 mmol, 62%

1 yield). H NMR (300 MHz, CDCl 3) δ = 1.08 (t, J = 7.1 Hz, 6 H), 1.16 (t, J = 7.2 Hz, 6

H), 1.65-1.90 (m, 4 H), 2.33 (t, J = 7.5 Hz, 4 H), 2.50 (t, J = 7.1 Hz, 4 H), 3.10-3.30 (m, 8

13 H); C NMR (75 MHz, CDCl 3) δ = 14.9, 14.1, 19.3, 31.8, 40.0, 41.6, 41.9, 171.6, 210.5.

150

1,9-Bis(diethylamido)-5-aminononane

To a mixture of 1,9-bis(diethylamido)nonan-5-one (2.39 g, 7.7 mmol) in 24 mL of

anhydrous MeOH under inert atmosphere was added ammonium acetate (15.4 g, 46.0

mmol) and sodium cyanoborohydride (1.2 g, 19.2 mmol). The reaction mixture was

stirred at room temperature for 4 days. The solvents were removed under reduced

pressure and the residue was dissolved in CH 2Cl 2 and extracted with 6M HCl. The aqueous layer was basified using a concentrated NaOH solution, extracted with CH 2Cl 2,

dried over anhydrous MgSO 4, and concentrated in vacuo to give 1.39 g of a yellow oil

1 (4.4 mmol, 58% yield). H NMR (300 MHz, CDCl 3) δ = 0.97 (t, J = 7.2 Hz, 6 H), 1.04 (t,

J = 7.2 Hz, 6 H), 1.27-1.64 (m, 8 H), 2.21 (t, J = 7.2 Hz, 4 H), 2.70-2.81 (m, 1 H), 3.20-

13 3.51 (m, 8 H), 3.83 (bs, 2 H); C NMR (75 MHz, CDCl 3) δ = 13.1, 14.3, 21.8, 32.9,

37.4, 40.0, 41.9, 50.8, 171.8.

1,9-Bis(diethylamino)-5-aminononane

To a mixture of 1,9-bis(diethylamido)-5-aminononane (0.2 g, 0.64 mmol) in 1.5 mL of anhydrous toluene under inert atmosphere was added dropwise lithium aluminum hydride as a 2M THF solution (1.4 mL, 3.8 mmol). The reaction mixture was stirred for 24 h at

110 °C. Then, 10 mL of a 4M NaOH was added and the mixture was extracted with

CH 2Cl 2, dried over anhydrous MgSO 4, and concentrated in vacuo to give 0.15 g of a

1 yellow oil (0.51 mmol, 80% yield). H NMR (300 MHz, CDCl 3) δ = 0.95 (t, J = 7.1 Hz,

151

12 H), 1.17-1.48 (m, 12 H), 2.31-2.33 (m, 2 H), 2.35 (t, J = 7.7 Hz, 4 H), 2.45 (q, J = 7.1

13 Hz, 8 H), 2.59-2.62 (m, 1 H); C NMR (75 MHz, CDCl 3) δ = 11.9, 24.5, 27.4, 38.36,

47.1, 51.3, 53.1.

N-(7-Chloro-4-quinolyl)-1,9-bis(diethylamino)-5-aminononane

A mixture of 4,7-dichloroquinoline (0.75 g, 3.8 mmol) and 1,9-bis(diethylamino)-5- aminononane (0.07 g, 0.25 mmol) was heated to 120 oC for 72 h in a closed vessel.

Saturated NaHCO 3 solution was added to the cooled reaction mixture, which was then

extracted with CH 2Cl 2, dried over anhydrous MgSO 4, and concentrated in vacuo . The

crude product was purified by flash chromatography using EtOAc:EtOH:Et 3N (1:1:0.01)

as the mobile phase to give a yellow oil (0.05 g, 0.11 mmol, 47% yield). 1H NMR (300

MHz, CDCl 3) δ = 0.99 (t, J = 7.2 Hz, 12 H), 1.29-1.74 (m, 12 H), 2.39 (t, J = 7.4 Hz, 4

H), 2.48 (q, J = 7.2 Hz, 8 H), 3.6 (m, 1 H), 4.83 (d, J = 8.1 Hz, 1 H), 6.40 (d, J = 5.4 Hz,

1 H), 7.34 (dd, J = 9.0 Hz, 2.4 Hz, 1 H), 7.37 (d, J = 9.0 Hz, 1 H), 7.94 (d, J = 2.4 Hz, 1

13 H), 8.49 (d, J = 5.4 Hz, 1 H); C NMR (75 MHz, CDCl 3) δ = 11.8, 24.2, 27.3, 34.8, 47.1,

52.9, 53.0, 99.3, 121.1, 125.3, 129.2, 135.1, 149.6, 149.7, 152.3; MS (ESI) m/z calcd for

+ C26 H43 ClN 4 446.3. Found (M + H) : 447.3.

1,9-Bis(diisopropylamido)nonan-5-one

To a mixture of 5-oxoazelaic acid (1.0 g, 5.0 mmol) and 2-chloro-4,6-dimethoxy-1,3,5- triazine (2.0 g, 11.4 mmol) in anhydrous CH 3CN (18.0 mL) under inert atmosphere was

152

added N-methyl morpholine (2.5 g, 24.7 mmol) and diisopropylamine (1.0 g, 9.9 mmol).

The mixture was stirred at room temperature for 48 h and then the solvents were removed in vacuo . The residue was dissolved in CH 2Cl 2, extracted with 2M HCl, dried over anhydrous MgSO 4, and concentrated in vacuo to give a yellow oil (1.5 g, 4.1 mmol, 82%

1 yield). H NMR (300 MHz, CDCl 3) δ = 1.17 (d, J = 6.6 Hz, 12 H), 1.34 (d, J = 6.9 Hz, 12

H), 1.85 (m, 4 H), 2.30 (t, J = 7.2 Hz, 4 H), 2.48 (t, J = 6.9 Hz, 4 H), 3.37-3.59 (m, 2 H),

13 3.86-3.95 (m, 2 H); C NMR (75 MHz, CDCl 3) δ = 19.7, 20.9, 21.2, 34.5, 42.1, 45.9,

48.6, 171.7, 210.8.

1,9-Bis(diisopropylamido)-5-aminononane

To a mixture of 1,9-bis(diisopropylamido)nonan-5-one (0.73 g, 2.0 mmol) in 4 mL of

anhydrous MeOH under inert atmosphere was added ammonium acetate (1.25 g, 16.2

mmol) and sodium cyanoborohydride (0.43 g, 6.8 mmol). The reaction mixture was

stirred at room temperature for 3 days. Solvents were removed under reduced pressure

and the residue was dissolved in CH 2Cl 2 and extracted with 6M HCl. The aqueous layer was basified using a concentrated NaOH solution, extracted with CH 2Cl 2, dried over anhydrous MgSO 4, and concentrated in vacuo to a yellow oil (0.37 g, 1.0 mmol, 50%

1 yield). H NMR (300 MHz, CDCl 3) δ = 1.17 (d, J = 6.6 Hz, 12 H), 1.34 (d, J = 6.9 Hz, 12

H), 1.40-1.77 (m, 6 H), 2.30 (t, J = 7.2 Hz, 4 H), 2.35-2.50 (m, 2 H), 2.75-2.82 (m, 1 H),

13 3.40-3.59 (m, 2 H), 3.90-4.00 (m, 2 H); C NMR (75 MHz, CDCl 3) δ = 20.9, 21.4, 21.6,

34.9, 35.6, 42.6, 46.3, 51.8, 172.3.

153

1,9-Bis(diisopropylamino)-5-aminononane

To a mixture of 1,9-bis(diisopropylamido)-5-aminononane (0.18 g, 0.5 mmol) in 1.5 mL

of anhydrous toluene under inert atmosphere was added dropwise lithium aluminum

hydride as a 2M THF solution (1.4 mL, 3.8 mmol). The reaction mixture was stirred for

24 h at 110 °C. Then, 10 mL of 4M NaOH was added and the mixture was extracted with

CH 2Cl 2, dried over anhydrous MgSO 4, and concentrated in vacuo to a yellow oil (0.15 g,

1 0.42 mmol, 85% yield). H NMR (300 MHz, CDCl 3) δ = 1.02 (d, J = 6.6 Hz, 24H), 1.24-

1.46 (m, 12 H), 2.40 (t, J = 7.4 Hz, 4 H), 2.62-2.69 (m, 1 H), 3.02 (sept, J = 6.6 Hz, 4 H);

13 C NMR (75 MHz, CDCl 3) δ = 20.9, 24.2, 31.9, 38.3, 45.5, 48.7, 51.5.

N-(7-Chloro-4-quinolyl)-1,9-bis(diisopropylamino)-5-aminononane

A mixture of 4,7-dichloroquinoline (0.75 g, 3.8 mmol) and 1,9-

bis(diisopropylamino)nonan-5-amine (0.07 g, 0.21 mmol) was heated to 120 oC for 72 h under nitrogen in a closed vessel. After cooling to room temperature, aqueous NaHCO 3 was added and the mixture was extracted with CH 2Cl 2, dried over anhydrous MgSO 4, and concentrated in vacuo . The crude product was purified by flash column chromatography

using CH 2Cl 2:EtOH:Et 3N (2:1:0.04) as the mobile phase and a yellow oil (0.03 g, 0.06

1 mmol, 30% yield) was obtained. H NMR (300 MHz, CDCl 3) δ = 0.96 (d, J = 6.6 Hz,

24H), 1.25-1.70 (m, 12 H), 2.35 (t, J = 7.1 Hz, 4 H), 2.97 (sep, J = 6.6 Hz, 4 H), 3.50-

3.70 (m, 1 H), 4.73 (d, J = 8.6 Hz, 1 H), 6.41 (d, J = 5.5 Hz, 1 H), 7.35 (dd, J = 9.0, 2.0

154

Hz, 1 H), 7.65 (d, J = 9.0 Hz, 1 H), 7.95 (d, J = 2.0 Hz, 1 H), 8.50 (d, J = 5.5 Hz, 1 H);

+ MS (ESI) m/z calcd for C 30 H51 ClN 4 502.4. Found (M + H) : 503.3.

1,9-Bis(diethylamino)nonan-5-ol

1,9-Bis(diethylamido)nonan-5-one (0.1 g, 0.32 mmol) and lithium aluminum hydride in

1M THF (2.1 ml, 2.1 mmol, 6.6 equiv.) were dissolved in 3 mL of anhydrous toluene and refluxed at 110 ºC for 48 h. The reaction was quenched with 4M NaOH and extracted with CH 2Cl 2. The combined organic layers were dried over anhydrous MgSO 4 and evaporated under reduced pressure to 0.08 g (0.29 mmol, 90% yield) of a brown oil. 1H

NMR (300 MHz, CDCl 3) δ = 1.03 (t, J = 6.9 Hz, 12 H), 1.32-1.55 (m, 12 H), 2.41 (t, J =

13 6.6 Hz, 4 H), 2.55 (q, J = 6.9 Hz, 8 H), 3.51-3.61 (m, 1 H); C NMR (75 MHz, CDCl 3)

δ = 11.6, 23.3, 26.9, 37.5, 46.9, 53.0, 71.2.

7-Chloro-4-(1’,9’-bis(diethylamino)-5’-nonoxy)quinoline

A mixture of 4,7-dichloroquinoline (0.21 g, 1.05 mmol, 3 equiv.), 1,9- bis(diethylamino)nonan-5-ol (0.1 g, 0.35 mmol, 1 equiv.), and a 1.0 M solution of t-

BuOK in t-BuOH (0.70 mL, 0.7 mmol, 2 equiv.) was heated under inert atmosphere to

o 120 C for 72 h in a closed vessel. Saturated NaHCO 3 solution was added to the cooled reaction mixture, which was extracted with CH 2Cl 2, dried over anhydrous MgSO 4, and concentrated in vacuo . Purification by flash chromatography using CH 2Cl 2:EtOH:Et 3N

(2:1:0.02) as the mobile phase gave 0.06 g (0.12 mmol, 35% yield, NMR yield >95%) of

155

1 a yellow oil. H NMR (300 MHz, CDCl 3) δ = 0.98 (t, J = 7.2 Hz, 12 H), 1.43-1.95 (m, 12

H), 2.40-2.59 (m, 8 H), 4.55-4.70 (m, 1 H), 6.69 (d, J = 5.3 Hz, 1 H), 7.41 (dd, J = 1.8

Hz, 9.8 Hz, 1 H), 8.00 (d, J = 1.8 Hz, 1 H), 8.15 (d, J = 9.8 Hz, 1 H), 8.70 (d, J = 5.3 Hz,

13 1 H); C NMR (75 MHz, CDCl 3) δ = 11.9, 23.6, 27.4, 33.8, 47.1, 53.0, 78.9, 101.7,

120.7, 123.9, 126.5, 128.1, 135.9, 150.3, 152.7, 161.5; GC-MS (CI) m/z calcd for

+ C26 H42 ClN 3O 447.3. Found (M + H) : 448.2.

Representative procedure for the synthesis of α,α,α,ωα, ωωω-(7-chloro-4-quinolyl)alkanediols:

To a solution of 4,7-dichloroquinoline (0.2 g, 1.0 mmol, 1 equiv.) in ethylene glycol (2.0 mL, 35.9 mmol, 35.5 equiv.) under inert atmosphere was added a 1.0 M solution of potassium t-butoxide in t-butyl alcohol (1.5 mL, 1.5 mmol, 1.5 equiv.). The reaction proceeded with good stirring at 80 o C for 18 h and was then quenched with saturated

NaHCO 3. The mixture was extracted with CH 2Cl 2, dried over anhydrous MgSO 4, concentrated in vacuo , and purified by recrystallization from CHCl 3 to yield 0.21 g of white crystals (0.95 mmol, 94% yield).

O-(7-Chloro-4-quinolyl)ethylene glycol

1 H NMR (300 MHz, CDCl 3) δ = 2.17 (bs, 1 H), 4.16 (bt, 2 H), 4.33 (t, J = 4.5 Hz, 2 H),

6.74 (d, J = 5.1 Hz, 1 H), 7.45 (dd, J = 2.2 Hz, 8.9 Hz, 1 H), 8.03 (d, J = 2.2 Hz, 1 H),

13 8.15 (d, J = 8.9 Hz, 1 H), 8.74 (d, J = 5.1 Hz, 1 H); C NMR (75 MHz, CDCl 3) δ = 61.4,

70.8, 101.6, 120.2, 124.0, 127.1, 128.1, 136.5, 150.0, 152.9, 162.1. 156

O-(7-Chloro-4-quinolyl)-1,3-propanediol

Employing 0.2 g (1.0 mmol) of 4,7-dichloroquinoline in the procedure described above

1 and recrystallization from CHCl 3 gave 0.25 g (1.0 mmol, 99% yield) of white crystals. H

NMR (300 MHz, CDCl 3) δ = 2.18 (m, 2 H), 3.03 (bs, 1 H), 3.98 (t, J = 5.9 Hz, 2 H), 5.27

(t, J = 5.9 Hz, 2 H), 6.55 (d, J = 5.5 Hz, 1 H), 7.36 (dd, J = 2.1 Hz, 8.7 Hz, 1 H), 7.96 (d,

J = 2.1 Hz, 1 H), 7.97 (d, J = 8.7 Hz, 1 H), 8.59 (d, J = 5.5 Hz, 1 H); 13 C NMR (75 MHz,

CDCl 3) δ = 31.7, 57.8, 64.8, 100.5, 119.3, 123.1, 126.2, 126.8, 135.7, 148.7, 151.8,

161.3.

O-(7-Chloro-4-quinolyl)-1,4-butanediol

Employing 0.2 g (1.0 mmol) of 4,7-dichloroquinoline in the procedure described above and recrystallization from CHCl 3 gave 0.17 g (0.67 mmol, 66% yield) of white

1 crystals. H NMR (300 MHz, CDCl 3) δ = 1.64 (bs, 1 H), 1.80 (m, 2 H), 2.06 (m, 2 H),

3.79 (t, J = 6.7 Hz, 2 H), 4.24 (t, J = 6.6 Hz, 2 H), 6.72 (d, J = 5.3 Hz, 1 H), 7.44 (dd, J =

2.0, 8.9 Hz, 1 H), 8.02 (d, J = 2.0 Hz, 1 H,), 8.14 (d, J = 8.9 Hz, 1 H), 8.7 (d, J = 5.3 Hz,

13 1 H); C NMR (75 MHz, CDCl 3) δ = 25.8, 29.4, 62.5, 68.5, 100.9, 119.8, 123.3, 126.3,

127.8, 135.5, 149.5, 152.5, 161.6.

157

O-(7-Chloro-4-quinolyl)-1,5-pentanediol

Employing 0.2 g (1.0 mmol) of 4,7-dichloroquinoline in the procedure described above

1 and recrystallization from CHCl 3 gave 0.3 g (1.1 mmol, 99% yield) of white crystals. H

NMR (300 MHz, CDCl 3) δ = 1.50 (bs, 1 H), 1.68 (m, 4 H), 1.99 (m, 2 H), 3.73 (bt, 2 H),

4.20 (t, J = 6.8 Hz, 2 H), 6.70 (d, J = 5.3 Hz, 1 H), 7.44 (dd, J = 2.1, 9.0 Hz, 1 H), 8.01

(d, J = 2.1 Hz, 1 H), 8.14 (d, J = 9.0 Hz, 1 H), 8.72 (d, J = 5.3 Hz, 1 H); 13 C NMR (75

MHz, CDCl 3) δ = 22.4, 28.5, 32.3, 62.2, 68.4, 100.8, 119.7, 123.4, 126.3, 127.4, 135.6,

149.3, 152.3, 161.6.

O-(7-Chloro-4-quinolyl)-1,6-hexanediol

Employing 0.2 g (1.0 mmol) of 4,7-dichloroquinoline in the procedure described above

1 and recrystallization from CHCl 3 gave 0.34 g (1.2 mmol, 92% yield) of white crystals. H

NMR (300 MHz, CDCl 3) δ = 1.40-1.69 (m, 6 H), 1.99 (m, 2 H), 3.68 (m, 3 H), 4.24 (t, J

= 5.8 Hz, 2 H), 6.71 (d, J = 5.3 Hz, 1 H), 7.44 (dd, J = 2.1, 8.9 Hz, 1 H), 8.01 (d, J = 2.1

13 Hz, 1 H), 8.14 (d, J = 8.9 Hz, 1 H), 8.72 (d, J = 5.3 Hz, 1 H); C NMR (75 MHz, CDCl 3)

δ = 25.5, 25.8, 28.7, 32.5, 62.5, 68.5, 100.8, 119.8, 123.4, 126.3, 127.6, 135.6, 149.5,

152.4, 161.6.

158

Representative procedure for the synthesis of O-(7-chloro-4-quinolyl)-N,N - diethylaminoalkanols:

To a solution of O-(7-chloro-4-quinolyl) -1,4-butanediol (0.78 g, 3.1 mmol, 1 equiv.) and

Et 3N (0.94 g, 9.3 mmol, 3 equiv.) in 20 mL of anhydrous THF at room temperature was added dropwise methansulfonyl chloride (1.07 g, 9.3 mmol, 3 equiv.). The reaction proceeded with good stirring for 10 minutes and was then quenched with saturated

NaHCO 3. The mixture was extracted with CH 2Cl 2, dried over anhydrous MgSO 4, and

concentrated in vacuo . The residue was dissolved in anhydrous CH 3CN (15.0 mL) under inert atomosphere and N,N -diisopropylethylamine (2.0 g, 15.5 mmol, 5 equiv.) and

diethylamine (4.53 g, 62.0 mmol, 20 equiv.) were added. The reaction mixture was

o stirred at 40 C for 48 h and was quenched with saturated NaHCO 3. The mixture was extracted with CH 2Cl 2, dried over anhydrous MgSO 4, and concentrated in vacuo . The

product was purified by flash column chromatography using CH 2Cl 2:EtOH:Et 3N

(5:1:0.005) as the mobile phase to give a light yellow oil (0.78 g, 2.5 mmol, 61% yield).

O-(7-Chloro-4-quinolyl)-2-(N,N -diethylamino)ethanol 48,49

Employing 0.07 g (0.3 mmol) of O-(7-chloro-4-quinolyl)ethylene glycol in the procedure

described above and purification by flash chromatography using CH 2Cl 2:EtOH (5:1)

containing 0.5% Et 3N as the mobile phase gave 0.07 g (0.27 mmol, 61% yield) of the

1 desired product as a light yellow oil . H NMR (300 MHz, CDCl 3) δ = 1.10 (t, J = 7.1 Hz,

6 H), 2.67 (q, J = 7.1 Hz, 4 H), 3.03 (t, J = 5.9 Hz, 2 H), 4.25 (t, J = 5.9 Hz, 2 H), 6.71 (d,

159

J = 5.1 Hz, 1 H), 7.41 (dd, J = 2.2 Hz, 8.9 Hz, 1 H), 7.99 (d, J = 2.2 Hz. 1H), 8.10 (d, J =

13 8.9 Hz, 1 H), 8.71 (d, J = 5.1 Hz, 1 H); C NMR (75 MHz, CDCl 3) δ = 12.6, 48.7, 51.9,

68.2, 101.7, 120.5, 124.1, 127.1, 128.5, 136.3, 150.4, 153.2, 162.2.

O-(7-Chloro-4-quinolyl)-3-(N,N -diethylamino)propanol

Employing 0.06 g (0.27 mmol) of O-(7-chloro-4-quinolyl)-1,3-propanediol in the procedure described above and purification by flash chromatography using CH 2Cl 2:EtOH

(5:1) containing 0.5% Et 3N as the mobile phase gave 0.05 g (0.17 mmol, 69% yield) of a

1 light yellow oil . H NMR (300 MHz, CDCl3) δ = 1.06 (t, J = 7.2 Hz, 6 H), 2.11 (m, 2 H),

2.61 (q, J = 7.2 Hz, 4 H), 2.72 (t, J = 6.8 Hz, 2 H), 4.27 (t, J = 6.2 Hz, 2 H), 6.74 (d, J =

5.3 Hz, 1 H), 7.45 (dd, J = 2.2 Hz, 8.8 Hz, 1 H), 8.02 (d, J = 2.2 Hz. 1H), 8.13 (d, J = 8.8

13 Hz, 1 H), 8.73 (d, J = 5.3 Hz, 1 H); C NMR (75 MHz, CDCl 3) δ = 11.7, 26.8, 47.0,

49.1, 66.9, 100.9, 119.8, 123.3, 126.3, 127.8, 135.5, 149.5, 152.5, 161.6; MS (ESI) m/z

+ calcd for C 16 H21 ClN 2O 292.1. Found (M + H) : 293.1.

O-(7-Chloro-4-quinolyl)-4-(N,N -diethylamino)butanol

1 H NMR (300 MHz, CDCl 3) δ = 1.03 (t, J = 7.2 Hz, 6 H), 1.85 (m, 2 H), 2.06 (m, 2 H),

2.55 (m, 6 H), 4.17 (t, J = 6.8 Hz, 2 H), 6.72 (d, J = 5.4 Hz, 1 H), 7.44 (dd, J = 2.1 Hz,

9.0 Hz, 1 H), 8.01 (d, J = 2.1 Hz, 1 H), 8.15 (d, J = 9.0 Hz, 1 H), 8.72 (d, J = 5.4 Hz, 1

13 H); C NMR (75 MHz, CDCl 3) δ = 11.5, 23.7, 26.8, 46.7, 52.4, 68.4, 100.8, 119.8,

160

123.4, 126.3, 127.7, 135.5, 149.6, 152.4, 161.5; MS (ESI) m/z calcd for C 17 H23 ClN 2O

306.2. Found (M + H) +: 307.2.

O-(7-Chloro-4-quinolyl)-5-(N,N -diethylamino)pentanol

Employing 0.09 g (0.35 mmol) of O-(7-chloro-4-quinolyl)-1,5-pentanediol in the procedure described above and purification by flash chromatography using CH 2Cl 2:EtOH

(5:1) containing 0.5% Et 3N as the mobile phase gave 0.11 g (0.34 mmol, 96% yield) of a

1 light yellow oil. H NMR (300 MHz, CDCl 3) δ = 1.03 (t, J = 7.1 Hz, 6 H), 1.56 (m, 4 H),

1.96 (m, 2 H), 2.55 (m, 6 H), 4.24 (t, J = 6.4 Hz, 2 H), 6.70 (d, J = 5.3 Hz, 1 H), 7.44 (dd,

J = 2.1 Hz, 9.0 Hz, 1 H), 8.01 (d, J = 2.1 Hz, 1 H), 8.15 (d, J = 9.0 Hz, 1 H), 8.72 (d, J =

13 5.3 Hz, 1 H); C NMR (75 MHz, CDCl 3) δ = 11.2, 24.1, 26.4, 28.7, 46.7, 52.6, 68.4,

100.9, 119.9, 123.4, 126.4, 127.8, 135.6, 149.7, 152.5, 161.6; MS (ESI) m/z calcd for

+ C18 H25ClN 2O 320.2. Found (M + H) : 321.1.

O-(7-Chloro-4-quinolyl)-6-(N,N -diethylamino)hexanol

Employing 0.07 g (0.25 mmol) of O-(7-chloro-4-quinolyl)-1,6-hexanediol in the procedure described above and purification by flash chromatography using CH 2Cl 2:EtOH

(5:1) containing 0.5% Et 3N as the mobile phase gave 0.07 g (0.21 mmol, 83% yield) of a

1 light yellow oil . H NMR (300 MHz, CDCl 3) δ = 2.41 (t, J = 7.2 Hz, 6 H), 1.35-1.60 (m,

6 H), 1.92 (m, 2 H), 2.41 (t, J = 7.5 Hz, 2 H), 2.51 (q, J = 7.2 Hz, 4 H), 4.15 (t, J = 6.9

Hz, 2 H), 6.67 (d, J = 5.3 Hz, 1 H), 7.41 (dd, J = 2.0 Hz, 9.0 Hz, 1 H), 7.99 (d, J = 2.0

161

13 Hz, 1 H), 8.12 (d, J = 9.0 Hz, 1 H), 8.69 (d, J = 5.3 Hz, 1 H); C NMR (75 MHz, CDCl 3)

δ = 11.5, 26.0, 26.9, 27.34, 28.7, 46.8, 52.7, 68.5, 100.8, 119.8, 123.4, 126.3, 127.8,

135.5, 149.6, 152.4, 161.6; GC-MS (CI) m/z calcd for C 19 H27 ClN 2O 334.2. Found (M +

H) +: 335.3.

1,7-Bis(diethylamido)heptan-4-one

To a solution of 4-ketopimelic acid (0.2 g, 1.2 mmol) in CH 3CN was added

diisopropylamine (0.5 mL, 2.9 mmol, 2.4 equiv.), PyBop (1.19 g, 2.3 mmol, 1.9 equiv.)

and N,N -diisopropylethylamine (0.5 mL, 3.2 mmol, 2.7 equiv.). The reaction was

refluxed at 80 oC for 48 h. The solvents were removed in vacuo and the residue was dissolved in CH 2Cl 2 and washed with 2M HCl and water. The organic layer was dried

over anhydrous MgSO 4 and evaporated under reduced pressure to give 0.31 g (1.1 mmol,

1 98% yield) of a brown oil. H NMR (300 MHz, CDCl 3) δ = 1.07 (t, J = 7.2 Hz, 6 H), 1.15

(t, J = 7.2 Hz, 6 H), 2.56 (t, J = 6.6 Hz, 4 H), 2.82 (t, J = 6.6 Hz, 4 H), 3.25-3.44 (m, 8

13 H); C NMR (75 MHz, CDCl 3) δ = 13.2, 14.3, 27.1, 37.7, 40.4, 42.0, 171.0, 211.5.

1,7-Bis(diethylamino)heptan-4-ol

1,7-Bis(diethylamido)heptan-4-one (0.1 g, 0.35 mmol) and lithium aluminum hydride

(2.1 ml of a 1M solution in THF, 2.1 mmol, 6 equiv.) in 3 mL of anhydrous toluene were refluxed at 110 ºC for 48 h. The reaction was quenched with 4M NaOH and extracted with CH 2Cl 2. The combined organic layers were dried over anhydrous MgSO 4 and

162

evaporated under reduced pressure to afford 0.08 g (0.31 mmol, 85% yield) of a brown

1 oil. H NMR (300 MHz, CDCl 3) δ = 1.01 (t, J = 7.2 Hz, 12 H), 1.32-1.44 (m, 2 H), 1.51-

13 1.64 (m, 6 H), 2.36-2.65 (m, 12 H), 3.51-3.60 (m, 1 H); C NMR (75 MHz, CDCl 3) δ =

11.3, 24.3, 37.0, 46.6, 53.5, 71.4.

7-Chloro-4-(1’,7’-bis(diethylamino)-4’-heptoxy)quinoline

A mixture of 4,7-dichloroquinoline (0.23 g, 1.2 mmol, 3 equiv.), 1,7- bis(diethylamino)heptan-4-ol (0.1 g, 0.39 mmol, 1 equiv.), and a 1.0 M solution of t-

BuOK in t-BuOH (0.78 mL, 0.78 mmol, 2 equiv.) was heated under inert atmosphere to

o 120 C for 72 h with good stirring in a closed vessel. Saturated NaHCO 3 was added to the

cooled reaction mixture, which was extracted with CH 2Cl 2, dried over anhydrous MgSO 4, and concentrated in vacuo . Purification by flash chromatography using

CH 2Cl 2:EtOH:Et 3N (2:1:0.02,) as the mobile phase gave a yellow oil (0.09 g, 0.21 mmol,

1 54% yield, NMR yield >95%). H NMR (300 MHz, CDCl 3) δ = 0.96 (t, J = 7.1 Hz, 12

H), 1.37-1.59 (m, 4 H), 1.56-1.86 (m, 4 H), 2.42-2.54 (overlapping t and q, 12 H), 4.60

(sep, J = 5.7 Hz, 1 H), 6.77 (d, J = 5.4 Hz, 1 H), 7.40 (dd, J = 1.9 Hz, 8.8 Hz, 1 H), 7.98

(d, J = 8.8 Hz, 1 H), 8.12 (d, J = 1.9 Hz, 1 H), 8.69 (d, J = 5.4 Hz, 1 H); 13 C NMR (75

MHz, CDCl 3) δ = 11.6, 23.0, 47.0, 52.8, 78.6, 101.9, 120.7, 123.9, 126.6, 128.2, 135.9,

+ 150.3, 152.7, 161.3; MS (ESI) m/z calcd for C 24 H38 ClN 3O 419.3. Found (M + H) : 420.2.

163

N-(7-Chloro-4-quinolyl)-1,3-diaminopropane 29

4,7-dichloroquinoline (20 g, 101 mmol) and 1,3-diaminopropane (50 mL, 606 mmol)

were combined under nitrogen and heated to 110 0C for 2 hours with good stirring. The

reaction was quenched with saturated sodium bicarbonate water, extracted with

dichloromethane, and solvents removed by rotoevaporation. Some of the desired product

precipitated during the extraction and was filtered off. Excess 1,3-diaminopropane

remaining in the desired product was removed by suspending the material in deionized

water and sonication. The mixture was then filtered in a large Hirsch funnel to give 24 g

1 (>99% yield) of pale yellow crystals. H NMR (300 MHz, CDCl 3) δ = 1.48 (bs, 2 H),

1.84-1.96 (m, 2 H), 3.00-3.10 (m, 2 H), 3.38-3.48 (m, 2 H), 6.33 (d, J = 5.4 Hz, 1 H),

7.30 (dd, J = 2.1 Hz, 9.0 Hz, 1 H), 7.72 (d, J = 9.0 Hz, 1 H), 7.92 (d, J = 2.1 Hz, 1 H),

13 8.50 (d, J = 5.4 Hz, 1 H); C NMR (75 MHz, CDCl 3) δ = 29.5, 40.8, 42.8, 97.8, 117.1,

122.0, 124.2, 127.6, 133.9, 148.6, 150.0, 151.5.

Representative procedure for the synthesis of sulfonamide analogs:

To a mixture of N-(7-chloro-4-quinolyl)-1,3-diaminopropane (0.15 g, 0.64 mmol) in 4.5 mL of anhydrous THF under nitrogen at room temperature was added triethylamine

(0.084 g, 0.83 mmol) and dansyl chloride (0.21 g, 0.76 mmol). After stirring for 36 hours at room temperature, the mixture was quenched with water and extracted with dichloromethane. The combined organic layers were dried over anhydrous MgSO 4,

164

concentrated in vacuo , and purified by recrystallization from chloroform to give a white solid (0.06 g, 0.13 mmol, 20% yield).

N-(N’ -3-(7-chloro-4-quinolyl)aminopropyl)-5-dimethylaminonaphthalene-1- sulfonamide

1 H NMR (300 MHz, DMSO-d6) δ = 1.69 (tt, J = 6.6 Hz, J = 6.6 Hz, 2 H), 2.80 (s, 6 H),

2.94 (dt, J = 6.6 Hz, J = 6.1 Hz, 2 H), 3.10 (dt, J = 6.6 Hz, J = 5.8 Hz, 2 H), 6.16 (d, J =

7.3 Hz, 1 H), 7.15 (t, J = 5.8 Hz, 1 H), 7.23 (d, J = 7.9 Hz, 1 H), 7.41 (dd, J = 2.2 Hz, J

= 8.5 Hz, 1 H), 7.54 (d, J = 7.9 Hz, 1 H), 7.59 (d, J = 8.5 Hz, 1 H), 7.76 (d, J = 2.2 Hz, 1

H), 7.99 (t, J = 6.1 Hz, 1 H), 8.09 (dd, J = 1.0 Hz, J = 7.3 Hz, 1 H), 8.15 (d, J = 7.3 Hz,

13 1 H), 8.30 (m, 2 H), 8.41 (d, J = 7.3 Hz, 1 H); C NMR (75 MHz, DMSO-d6) δ = 27.8,

45.0, 98.4, 115.0, 117.3, 118.9, 123.43, 123.9, 127.3, 127.8, 128.3, 129.0, 129.3, 133.3,

135.8, 148.8, 149.80, 151.3, 151.6

N-(N’ -3-(7-chloro-4-quinolyl)aminopropyl)-8-quinolinesulfonamide

Employing 0.19 g (0.82 mmol) of N-(7-chloro-4-quinolyl)-1,3-diaminopropane and 8- quinolinesulfonyl chloride (0.22 g, 0.98 mmol) in the procedure described above gave

1 0.14 g (0.33 mmol, 40% yield) of white crystals. H NMR (300 MHz, DMSO-d6) δ =

1.71 (tt, J = 6.5 Hz, J = 6.5 Hz, 2 H), 2.95 (dt, J = 6.5 Hz, J = 5.8 Hz, 2 H), 3.15 (dt, J =

6.5 Hz, J = 6.2 Hz, 2 H), 6.23 (d, J = 5.5 Hz, 1 H), 7.17 (t, J = 5.8 Hz, 1 H), 7.35 (t, J =

6.2 Hz, 1 H), 7.42 (dd, J = 2.2 Hz, J = 9.0 Hz, 1 H), 7.65-7.74 (m, 2 H), 7.76 (d, J = 2.2

165

Hz, 1 H), 8.12 (d, J = 9.1 Hz, 1 H), 8.24 (dd, J = 1.3 Hz, J = 8.3 Hz, 1 H), 8.30-8.34 (m,

2 H), 8.49 (dd, J = 1.8 Hz, J = 8.4 Hz, 1 H), 9.03 (dd, J = 1.8 Hz, J = 4.2 Hz, 1 H); 13 C

NMR (75 MHz, DMSO-d6) δ = 27.6, 39.6, 40.7, 98.4, 117.2, 122.4, 124.0, 125.6, 127.1,

128.4, 130.6, 133.4, 133.5, 136.2, 136.9, 142.6, 148.6, 149.9, 151.2, 151.5.

N-(N’ -3-(7-chloro-4-quinolyl)aminopropyl)-2-phenoxy-5-pyridinesulfonamide

Employing 0.15 g (0.64 mmol) of N-(7-chloro-4-quinolyl)-1,3-diaminopropane and 6- phenoxy-3-pyridinesulfonyl chloride (0.2 g, 0.76 mmol) in the procedure described above

1 gave 0.038 g (0.081 mmol, 13% yield) of white crystals. H NMR (300 MHz, CDCl 3) δ =

1.94 (tt, J = 6.2 Hz, J = 6.2 Hz, 2 H), 3.16 (t, J = 6.2 Hz, 2 H), 3.54 (dt, J = 6.2 Hz, 2

H), 5.57 (bs, 1 H), 6.32 (d, J = 5.7 Hz, 1 H), 7.00 (d, J = 8.4 Hz, 1 H), 7.13 (d, J = 8.4

Hz, 2 H), 7.28 (d, J = 8.4 Hz, 1 H), 7.36 (dd, J = 2.0 Hz, J = 8.9 Hz, 1 H), 7.41-7.46 (m,

2 H), 7.70 (d, J = 8.9 Hz, 1 H), 7.90 (d, J = 1.9 Hz, 1 H), 8.08 (dd, J = 2.7 Hz, J = 8.6

Hz, 1 H), 8.46 (d, J = 5.7 Hz, 1 H), 8.64 (d, J = 2.7 Hz, 1 H); 13 C NMR (75 MHz,

DMSO-d6) δ = 28.5, 41.2, 99.4, 112.4, 118.1, 122.3, 124.8, 126.1, 128.1, 130.6, 132.4,

134.1, 139.4, 147.1, 149.6, 150.7, 152.5, 153.6, 165.8.

166

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