new asymmetric transformations and catalysis brem

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Novel Cinchona derived organocatalysts: new asymmetric transformations and catalysis

Breman, A.C.

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Citation for published version (APA):Breman, A. C. (2014). Novel Cinchona derived organocatalysts: new asymmetric transformations and catalysis.

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Novel Cinchona DerivedOrganocatalysts

New Asymmetric Transformations and Catalysis

Arjen C. Breman

Novel C

inch

on

a Derived

Org

ano

catalysts Arjen

C. B

reman

Novel Cinchona Derived Organocatalysts


Novel Cinchona Derived Organocatalysts


ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctor

aan de Universiteit van Amsterdam

op gezag van de Rector Magnificus

prof. dr. D. C. van den Boom

ten overstaan van een door het college voor promoties

ingestelde commissie,

in het openbaar te verdedigen in de Agnietenkapel

op dinsdag 30 september 2014, te 14:00 uur

door

Arjen Christiaan Breman

geboren te Zaanstad

Promotiecommissie:

Promotor: Prof. dr. H. Hiemstra

Copromotor: Dr. S. Ingemann Jorgensen

Overige leden: Prof. dr. J. N. H. Reek

Prof. dr. A. M. Brouwer

Dr. J. H. van Maarseveen

Prof. dr. P. Timmerman

Prof. dr. ir. R. V. A. Orru

Prof. dr. F. P. J. T. Rutjes

Prof. dr. S. Connon

Faculteit der Natuurwetenschappen, Wiskunde en Informatica (FNWI)

This research has been financially supported by the National Research School Combination Catalysis (NRSC–C)

Cover design: R. R. Dumpel.

Then I met you

Table of Contents

List of Abbreviations 11 Chapter 1: General Introduction: Asymmetric Organoc atalysis, New Strategies to Chiral Non–Racemic Compounds 13 1.1 Asymmetric catalysis with small organic molecules 14

1.1.1 Asymmetric catalysis in nature 14 1.1.2 Covalent activation 15 1.1.3 Non–covalent activation 18

1.2 Cinchona alkaloids 20 1.2.1 Isolation and characterization 20 1.2.2 Total synthesis 21

1.3 Applications of Cinchona alkaloids in synthesis 23 1.3.1 Chiral bases for enantiomer separation 23 1.3.2 Chiral ligands in metal–promoted reactions 24 1.3.3 Chiral organocatalysts 26 1.3.4 Mechanism of non–covalent bifunctional catalysis 28 1.3.5 Applications of Cinchona alkaloid catalyzed reactions 31

1.4 Outline of this thesis 32 1.5 References 33 Chapter 2: Enantioselective Organocatalytic Thiol A ddition to α,β–Unsaturated α–Amino Acid Derivatives 37 2.1 Introduction 38

2.1.1 Conjugate additions of thiols 38 2.1.2 α,β–Dehydro–α–amino acids 39 2.1.3 β–Functionalized cysteines 40

2.2 Substrate synthesis 41 2.3 Catalyst screening 44 2.4 Substrate scope 45 2.5 Mechanism of the conjugate addition 47 2.6 Follow–up chemistry 48 2.7 Conclusion 49 2.8 Acknowledgments 49 2.9 Experimental section 49 2.10 References 60

Chapter 3: Optimization of the Thiol Addition to α,β–Unsaturated α–Amino Acid Derivatives and Applications in Peptide Chemistry 63 3.1 Introduction 64

3.1.1 Types of hydrogen bond donors 64 3.1.2 Sulfur protecting groups 67

3.2 Substrate synthesis 68 3.3 Catalyst synthesis 68 3.4 Catalyst screening 72 3.5 Scope of the addition reaction 74 3.7 Mechanism of the thiol addition 75 3.8 Follow up chemistry 76 3.9 Conclusion 79 3.10 Acknowledgments 79 3.11 Experimental section 79 3.12 References 93 Chapter 4: Studies on the Role of the Quinuclidine Ring System in Asymmetric Organocatalysis 95 4.1 Introduction 96 4.2 Analogue synthesis 97

4.2.1 Synthesis of the [1.2.2]–series 98 4.2.2 Synthesis of the [3.2.2]–series 101

4.3 Catalysis 105 4.3.1 Reference catalysts 105 4.3.2 Screening of the catalysts 106 4.3.3 Catalyst activity 109

4.4 pKAH determination 110 4.5 Conclusion 112 4.6 Acknowledgments 113 4.7 Experimental section 113 4.8 References 136 Chapter 5: Synthesis of Quinuclidines by Intramolec ular Silver–Catalyzed Hydroamination of Alkynes 139 5.1 Introduction 140

5.1.1 2–Alkylidenequinuclidines 140 5.1.2 Hydroamination 141

5.2 Substrate synthesis 142 5.3 Catalyst screening 144 5.4 Reaction scope 146 5.5 Follow up chemistry 148

5.6 Conclusion 148 5.7 Acknowledgments 149 5.8 Experimental section 149 5.9 References 165 Summary 167 Samenvatting 171 Dankwoord 175

11

List of Abbreviations Ac acetyl Ac2O acetic anhydride AD asymmetric

dihydroxylation AIBN 2,2′–

azobis(isobutyronitrile) All allyl APT attached proton test Ar aryl ax axial BINAP (2,2'–bis(diphenyl–

phosphino)–1,1'–binaphthyl)

BINOL 1,1’–binaphthalene 2,2’–diol

Bn benzyl Boc tert–butoxycarbonyl (Boc)2O di–tert–butyl

dicarbonate br broad (in NMR) Bu butyl cat catalyst CLIPS chemical linkage of peptides onto scaffolds COD 1,5–cyclooctadiene conv conversion d doublet (in NMR) DABCO 1,4–diazabicyclo

[2.2.2]octane DBU 1,8–diazabicyclo

[5.4.0]undec–7–ene DCE 1,2–dichloroethane dd double doublet (in NMR) DIPEA N,N–di–isopropyl ethylamine DFT density functional theory (DHQ)2PHAL dihydroquinine 1,4– phthalazinediyl diether (DHQD)2PHAL dihydroquinidine 1,4–

phthalazinediyl diether dig digonal

DMAP 4–(dimethylamino) pyridine DMF N,N–dimethyl– formamide DMSO dimethylsulfoxide DPM diphenylmethane dppp 1,3–bis(diphenyl–

phosphino)propane dr diastereomeric ratio dt double triplet (in NMR) ee enantiomeric excess EDC 1–ethyl–3–(3–dimethyl– aminopropyl) carbodiimide e.g. exempli gratia eq equatorial equiv equivalent ESI electrospray ionization et al. et alia Et ethyl EtOAc ethyl acetate EWG electron withdrawing

group FAB fast atom bombardment Fmoc 9–fluorenyl– methyloxycarbonyl Fmoc–Osu 9–fluorenylmethyl N–succinimidyl carbonate GABA γ–aminobutyric acid h hour HATU (1–[bis(dimethylamino)–

methylene]–1H–1,2,3–triazolo[4,5–b]pyridinium–3–oxid–hexafluorophosphate

HOAt 1–hydroxy–7–azabenzotriazole

HOBt hydroxybenzotriazole HPLC high performance liquid

chromatography HRMS high resolution mass spectrometry

12

HSQC heteronuclear single quantum coherence I luminous intensity i inductive effect Im imidazole i–Pr iso–propyl IR infrared J coupling constant (in NMR) kcal kilocalorie LCMS liquid chromatography

mass spectrometry LDA lithium diisopropylamide LiHMDS lithium

bis(trimethylsilyl)amide M molar m multiplet (in NMR) Me methyl min minute(s) mp melting point MS mass spectrometry Ms methanesulfonyl NaHMDS sodium

bis(trimethylsilyl)amide n–BuLi n–butyllithium nd not determined NMR nuclear magnetic

resonance NMP N–methyl–2–

pyrrolidone NOE nuclear Overhauser effect Nu nucleophile PE petroleum ether pKa –log10(Ka) pKAH –log10(Ka) of the

protonated base PG protecting group PGl2 prostacyclin

Ph phenyl ppm parts per million PPTS pyridinium p–toluenesulfonate Pr propyl q quartet (in NMR) rac racemic RDS rate determining step rt room temperature s singlet (in NMR) SEM 2–(trimethylsilyl) ethoxymethyl SPINOL 1,1′–spirobiindane–

7,7′–diol t–Bu tert–butyl T temperature t triplet (in NMR) TCEP tris(2–carboxyethyl)

phosphine hydrochloride

tet tetrahedral Teoc trimethylsilyl– ethoxycarbonyl Tf trifluoromethylsulfonyl TFA trifluoroacetic acid TFAA trifluoroacetic anhydride TIS tri–isopropylsilane TLC thin layer chromatography THF tetrahydrofuran TMS trimethylsilyl trig trigonal TSDPEN N–(2–amino–1,2–

diphenylethyl)–4–methylbenzenesulfon–amide

VAPOL 2,2′–Diphenyl–(4–biphenanthrol

General Introduction

13

CHAPTER 1

General Introduction: Asymmetric Organocatalysis, N ew Strategies to

Chiral Non–Racemic Compounds

Abstract: The synthesis of enantiomerically enriched compounds can be catalyzed by different classes of catalysts. A relative new class are small organic molecules and this type of catalysis is referred to as asymmetric organocatalysis. This class of catalysts is divided according to the two modes of activation: covalent and non–covalent catalysis. Cinchona alkaloids play an important role in the field of asymmetric organocatalysis, due to proper functional groups and the availability of two pseudoenantiomeric forms. Therefore, many organic reactions have been catalyzed by these alkaloids with high levels of enantioselectivity. However, the mechanisms of these reactions are far from understood and only a limited number of reports have appeared in which the enantiomerically enriched products have been further applied.

CHAPTER 1

14

1.1 Asymmetric catalysis with small organic molecul es

1.1.1 Asymmetric catalysis in nature

Nature performs stereocontrolled synthesis of chiral compounds from achiral starting materials with the use of enzymes. Most enzymes are proteins and responsible for thousands of metabolic processes.1 Due to inter– and intra–electrostatic interactions, enzymes adopt specific three–dimensional structures. Each enzyme has an ‘active site’ where the stereocontrolled synthesis takes place; substrates bind in a controlled way in the chiral pocket and undergo asymmetric transformations. In the last 30 years an increase in the use of enzymes to produce fine chemicals has been seen. The advantages of enzymes are that they are chemo–, regio– and stereoselective and function under conditions that are mild and environmentally friendly. Based on this researchers have been trying to imitate the active site of enzymes in order to apply the mimics in asymmetric catalysis. Extensive attention has been given to mimic the active site of enzymes with an active metal center. The field of asymmetric (transition) metal catalysis started in 1968 when Knowles and coworkers incorporated chiral phosphine ligands in a rhodium–based catalyst and used this complex for the asymmetric hydrogenation of alkenes.2 In the first experiment the ee did not exceed 15%. Nevertheless, this result inspired many research groups to enter this field and in the following decades the field of asymmetric (transition) metal catalysis exploded. Nowadays many processes are known in which chiral metal complexes are used in order to prepare enantioenriched compounds.

The mimicking of enzymes without metals at the active site gained much more attention from the late 1990s and is now referred to as asymmetric organocatalysis.3 However, before that time some noteworthy results were published. In 1904 the first example of asymmetric catalysis was published by Mackwald.4 He used brucine, an alkaloid isolated from the Strychnos nux–vomica tree, for the decarboxylation of a malonate derivative in 10% ee. In addition, the use of Cinchona alkaloids5 (section 1.3.3) and N–heterocyclic carbenes (NHC’s)6 as chiral catalysts was investigated successfully prior to the late 1990s. Amino acids were introduced successfully as organocatalysts in 1971 by two groups reporting the use of proline as a chiral catalyst for the intramolecular aldol condensation of meso triketones (scheme 1).7

Scheme 1. Intramolecular aldol condensation reported by Wiechert and Hajos.7

The group of Wiechert was able to obtain the product with 71% ee.7a This result was improved by the group of Hajos by performing the reaction at lower temperature and subsequently dehydrate the cyclic product; this resulted in a quantitative yield and an ee of 93%.7b The activation of substrates by reaction with proline is now referred to as


15

covalent organocatalysis and is one of the most popular strategies in asymmetric organocatalysis.

This introductory chapter will further focus on Cinchona alkaloids and how they are applied in chemistry. Especially the use of Cinchona alkaloids as non–covalent bifunctional organocatalysts will be described. The main subject of this thesis is the use of novel Cinchona derived organocatalysts in asymmetric reactions activating the substrate through non–covalent interactions. First, in the next two paragraphs a short overview is given of key accomplishments in the field of organocatalysis since the late 1990s. The overview is separated according to the two distinct modes of activating the substrates: covalent and non–covalent activation.

1.1.2 Covalent activation

The pioneering work by Wiechert and Hajos was reinvestigated by List and coworkers in 2000.8 Proline catalyzed the intermolecular aldol reaction of acetone to aromatic and branched aldehydes giving ee‘s up to 96% (scheme 2).

Scheme 2. Intermolecular aldol reaction by List.8

Their protocol was insensitive to water and did not require initial formation of enolates as most metal catalyzed enantioselective aldol reactions. They proposed a mechanism in which proline acts as an “micro–aldolase”; that is, the secondary amine activates the nucleophile via enamine activation and the carboxylate facilitates the formation of the enamine and is responsible for the activation and orientation of the aldehyde.

In the same year the group of MacMillan and coworkers reported covalent activation of carbonyl compounds involving the formation of unsaturated iminium ions (scheme 3).9

Scheme 3. Diels–Alder reaction via iminium ion formation.

This strategy was applied successfully in the asymmetric Diels–Alder reaction. An imidazolidinone based catalyst derived from phenylalanine was introduced, now known as the MacMillan catalyst. The two reports8,9 led together with other results to an

CHAPTER 1

16

explosion of the field of covalent organocatalysis.10 Presently, many catalyst systems are known and have been applied successfully in conjugate additions and carbonyl or iminium addition reactions.11

Intensive research was performed in order to understand the mechanisms of these organocatalytic reactions. For example, the Michael addition of aldehydes to nitroalkenes catalyzed by diaryl prolinol ethers was studied by several groups (scheme 4).12 Experiments and calculations provided insight into the catalytic cycle by providing information about possible intermediates and the rate–determining step. A collaboration between Pápai and Pikho resulted in a detailed mechanism of the reaction between aldehydes and nitroalkenes. According to the results the protonation of the dihydrooxazine oxide III intermediate was the rate–determining step. This study shows that the mechanism of such reactions can be more complex than initially anticipated.

Scheme 4. Proposed mechanism by Pápai and Pihko.12

N–Heterocyclic carbenes (NHC’s) have witnessed a tremendous development in the past two decades not only as versatile ligands for transition metals, but also as (chiral) organocatalysts.13 The main difference with the mentioned activation mechanisms is that NHC’s can invert the reactivity of species (umpolung).13a In 1966 the first asymmetric reaction performed by an NHC was reported.6a It took until 2002 before ee’s above 90%


17

were obtained. The group of Enders used a bicyclic chiral triazolium salt as precatalyst for the asymmetric benzoin condensation (scheme 5).14

Scheme 5. Benzoin condensation reported by Enders.14

The Morita–Baylis–Hillman reaction is based on inverting the reactivity of an α,β–unsaturated system. The first asymmetric Morita–Baylis–Hillman reactions were developed in 1990’s.15 The group of Leahy used chiral auxiliaries based on camphorsulfonic acid and DABCO as a achiral catalyst for the synthesis of chiral 1,3–dioxan–4–ones.15a The group of Hatakeyama reported that the rigid modified Cinchona alkaloid, β–isocupreidine, efficiently catalyzes an enantioselective Morita–Baylis–Hillman reaction (scheme 6).15b

Scheme 6. Example of an asymmetric Morita–Baylis–Hillman reaction and the proposed mechanism.15b

Both the quinuclidine and the quinoline phenol (C6’–OH) were postulated to be involved in the stabilization of the transition state. Nucleophilic attack of the tertiary amine of the catalyst on the β–carbon results in the formation of an enolate, that subsequently attacks an aldehyde species, which was activated by the quinoline phenol (C6’–OH). After β–elimination of the catalyst the product is obtained. The desired adducts were obtained in high enantioselectivity but in moderate yield because of formation of a dioxanone byproduct. This principle has now been applied in several catalytic systems. Mostly

CHAPTER 1

18

tertiary amines or phosphines are used for the formation of a covalent bond between the catalyst and substrate, while hydrogen bond donors or Lewis acids are used to activate the electrophile.16

1.1.3 Non–covalent activation

Asymmetric organocatalysis involving activation of substrates via hydrogen bonding or electrostatic interactions is far from understood. A few reports have provided experimental insight in the mechanism of non–covalent activation. Jacobsen and coworkers reported in 1998 the use of a chiral thiourea catalyst for the asymmetric Strecker reaction giving the products in ee‘s up to 99% (scheme 7).17a In 2002 a more detailed study on the mechanism was reported by the same group.17b They showed with NMR in combination with calculations that the imine is activated by the thiourea via a dual H–bond interaction.

Scheme 7. Strecker reaction with dual H–bond activation by the thiourea.17

Subsequently, Takemoto and coworkers developed a so–called bifunctional non–covalent catalyst with the same chiral 1,2–diaminocyclohexane scaffold, in which one amine was modified with a thiourea function and the other amine was di–alkylated (scheme 8).18 This report gave an impulse to the field of asymmetric non–covalent bifunctional organocatalysis and since then many chiral scaffolds have been modified in a similar way.19 The catalyst developed by Takemoto catalyzed the addition of malonates to nitroalkenes. This reaction has been a benchmark in the field of non–covalent bifunctional catalysis.

Scheme 8. Malonate addition to nitrostyrene catalyzed by a bifunctional thiourea catalyst.18


19

In 2005, Takemoto and coworkers proposed that the malonate is deprotonated by the tertiary amine and the nitroalkenes is coordinated via a two hydrogen bonds to the thiourea (scheme 9).

Scheme 9. Proposed and calculated transition states.

They proposed that this transition state is responsible for the observed selectivity.18b One year later Pápai et al. proposed a different transition state based on DFT calculations.18c In their mechanism, the deprotonated nucleophile coordinates to the thiourea and the nitroalkene is activated by the protonated tertiary amine via a single hydrogen bond. In the calculations both transition states give the same direction of stereocontrol. Only the transition state proposed by Pápai is slightly more favored according to the calculations.

In 2004 the groups of Akiyama20a and Terada20b introduced chiral phosphoric acids based on BINOL as catalysts for the Mannich reaction (figure 1). Later other scaffolds like VAPOL and SPINOL have also been used as chiral backbones for phosphoric acids.21

Figure 1. Other types of non–covalent organocatalysts.

For example, the SPINOL derived phosphoric acid was applied successfully by Wang in the Friedel–Crafts reaction of indoles with imines.21c Another non–covalent pathway to activate substrates is through phase–transfer catalysis. At the end of the last century the groups of Lygo22a and Corey22b used quaternary ammonium salts obtained from Cinchona alkaloids for the asymmetric synthesis of a wide variety of unnatural amino acids, considerably improving the results reported by O’Donnel22c. Later, Maruoka used

CHAPTER 1

20

quaternary ammonium salts derived from BINOL for the asymmetric epoxidation of α,β–unsaturated systems.23

1.2 Cinchona alkaloids

1.2.1 Isolation and characterization

Cinchona alkaloids are found in the Cinchona and Remijia trees and the bark of these trees has been used as powerful medicine against malaria since the 16th century.24 In the beginning of 19th century the active compounds of these trees were isolated. At that time more than thirty compounds were isolated, where four compounds were found to be the major ones: quinine, quinidine, cinchonidine and cinchonine. The correct molecular formula (C20H24N2O2) of quinine was established by Strecker in 1854.25 After the elucidation of the molecular formula of quinine it took more than fifty years to elucidate its structure. Many prominent European chemist performed intense research on this topic over a period of twenty years. The methods to elucidate the atom connectivity were relative simple. For example, conventional acetylation followed by mild hydrolysis suggested the presence of a hydroxy group, which was confirmed by its conversion into the corresponding chloride with PCl5.26 Based on these types of experiments it was concluded that quinine has two tertiary nitrogen atoms, a hydroxyl group, a 6’–methoxyquinoline, a vinyl group and a bicyclic structure with a bridged nitrogen. These findings helped Rabe to suggest the correct connectivity of quinine in 1907.27 All stereochemical issues were correctly solved 37 years later by Prelog.28 The four major alkaloids found in the Cinchona bark are depicted in figure 2. All these alkaloids have five stereocenters with four stereocenters being carbon atoms (C3, C4, C8 and C9) atoms and one the nitrogen atom (N1) of the bicyclic system. The numbering is the one reported initially by Rabe.

Figure 2. Structure and atom numbering of the four major alkaloids found in the Cinchona bark.

In all these alkaloids the N1 atom and the C3 and C4 carbons have the same absolute stereochemistry. The other two stereocenters have opposite absolute configuration in quinine and quinidine (and the same relies to cinchonidine and cinchonine). Because these alkaloids have two stereocenters have the opposite configuration, these alkaloids are being considered pseudoenantiomers. The most basic nitrogen atom is the one (N1) in the bicyclic system. Several values of the pKAH are known ranging from 8 to 9.29 The amine (N1’) of the quinoline is less basic having a pKAH around 5. Because of the


21

relatively high complexity, the functional groups and the wide abundance of these relatively small molecules are frequently used in asymmetric catalysis (see section 1.3).

N H

H OH

N H

H OH

N H

HOH

N

MeO

N H

HOH

N

OMe

NN

MeO

OMe

4'98

4'

89

4'

98

4'

98

anti–closed syn–closed

anti–open syn–open

rotation about C9–C4'

rotation about C9–C4'

rotation aboutC8–C9

rotation aboutC8–C9

Figure 3. The four low–energy conformers of quinine.

In order to gain more insight in the behavior of these molecules in solution, conformational studies were performed with NMR and computational techniques.30 A collaboration between the groups of Wynberg and Sharpless in 1989 revealed that there are four low–energy conformers of the Cinchona alkaloids (figure 3). The calculations showed that quinine and quinidine preferentially adopt a syn–closed conformation in the gas phase and the anti–open conformation in apolar solvents.30 The rotations of the C8–C9 and C9–C4’ bonds determine the conformations of the alkaloids. Different solvents have an influence on the conformation. In chloroform–d1 the open conformations are preferred while in dichloromethane–d2 the closed conformations are preferred. More detailed studies on solvent effects by Baiker showed that polar solvents stabilize the two closed conformations.31 Modifying the alkaloids with esters or benzyl ethers at the C9, by protonation of the quinuclidine ring or complexation with OsO4 influences the conformation.30 Ester derivatives always have an anti–closed conformation, ether derivatives exhibit intermediate behavior between anti–closed and anti–open depending on the solvent. Upon protonation or complexation with OsO4 the anti–open conformation is preferred, irrespective the starting conformation and the solvent.

1.2.2 Total synthesis

The synthesis of quinine has intrigued chemist for more than 150 years. In the 1850s the first efforts towards the total synthesis of quinine were made.32 It took until 1918 before Rabe and Kindler reported the first partial synthesis of quinine and quinidine starting from a quinotoxine.33 Quinotoxine was discovered by Pasteur in 1853, by

CHAPTER 1

22

reacting the natural alkaloid with weak or dilute acids at elevated temperatures.34 Three steps were needed to convert quinotoxine into quinine and quinidine (scheme 10).33 First quinotoxine was oxidized by sodium hypobromite yielding N–bromoquinotoxine. In the present of sodium ethoxide the quinuclidine ring system was formed. Finally reduction of the carbonyl yielded, according to Rabe, quinine.

Scheme 10. The Woodward–Doering/Rabe–Kindler total synthesis of quinine.

During World War II the supply of quinine for the allied forces came to a hold. For this reason the US made it a vital goal to develop a synthetic route to quinine. A young chemist at Harvard University, R. B. Woodward, together with W. E. Doering took on the challenge. In 1944 they reported a synthetic route to quinotoxine,35 assuming the validity of Rabe’s claim that quinotoxine was converted to a stereoisomeric mixture of Cinchona alkaloids. Their synthesis required 17 steps in order to arrive at racemic quinotoxine. With the three additional steps, used by Rabe, twenty chemical steps were needed to synthesize the racemic Cinchona skeleton. The Woodward–Doering/Rabe–Kindler total synthesis of quinine has been a hot topic for discussion for more than 60 years. In 2001 Stork and co–workers referred to the total synthesis reported by Woodward–Doering as a “widely believed myth”,36 because Woodward and Doering relied on the results which were published by Rabe and Kindler. In 2007 Seeman concluded, after a comprehensive study, that the Woodward–Doering/Rabe–Kindler synthesis of quinine was a valid achievement.37 This was later confirmed by Smith and Williams in 2008, when they reproduced the procedure reported by Rabe and Kindler and were able to obtain the Cinchona alkaloids.38

Scheme 11. Uskokovic key synthon for the synthesis of quinine and quinidine.

In the 1970s Uskokovic and coworkers at Hoffmann–La Roche started investigations on the stereocontrolled total synthesis of quinine (scheme 11).39 They reported several papers concerning approaches to control the configuration at the C3 and C4 stereocenters. With their key synthon depicted in scheme 11 the group could prepare


23

the framework of the Cinchona alkaloids, but they were not able to control the stereochemistry at the C8–position. Thus, they always obtained mixtures of quinine and quinidine. It took two decades more before the first stereocontrolled synthesis of quinine was accomplished by the group of Stork in 2001 (scheme 12).40 Instead of making the quinuclidine framework via the N1–C8, they prepared the bicycle by forming the N1–C6 bond.

Scheme 12. First stereoselective total synthesis of quinine by Stork.40

After this milestone the total synthesis of Cinchona alkaloids remained a popular target for chemists. In 2004 and 2005 Jacobsen and Kobayashi reported the stereoselective synthesis of quinine and quinidine.41,42 Their synthesis relied again on the N1–C8 disconnection first reported by Rabe. The last steps in both syntheses were comparable and involved chiral epoxide formation via the asymmetric dihydroxylation/epoxide formation procedure developed by Sharpless, followed by a one pot deprotection/cyclization procedure (scheme 13). Both quinine and quinidine could be obtained depending on the nature of the stereocontrol during the asymmetric dihydroxylation.

Scheme 13. Key steps in the formation of the quinuclidine ring of quinidine by Jacobsen and Kobayashi.41,42

1.3 Applications of Cinchona alkaloids in synthesis

1.3.1 Chiral bases for enantiomer separation

Resolution of racemic mixtures using chiral resolving agents is based on the formation of two diastereomeric entities, usually salts which differ in solubility leading to preferential crystallization of one of them.43 Due to the highly basic nature of Cinchona alkaloids they can be used to resolve racemic acids and other chiral acidic compounds. Pasteur used derivatives of the Cinchona alkaloids (quinotoxine like structures) for the resolution of tartaric acid.34b,44 In the 1990s about 25% of all resolutions of racemic

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24

mixtures were carried out with the four major members of the Cinchona alkaloid family.45 Examples of industrial resolution processes with Cinchona are depicted in table 1.

Table 1. Examples of resolutions by Cinchona alkaloids.

entry compound function resolving agent ee (%) 1

MeO

CO2H

Me

nonsteroidal anti–inflammatory agents/analgesics

cinchonidine 99

2

nonsteroidal anti–inflammatory agents/analgesics

cinchonidine 99

3

precursor of PGI2 antiplatelet drug

quinine 99

4

precursor of (R)–aminoglutethimide

cinchonidine >90

5

GABA–antagonist precursor cinchonidine 46

The alkaloids have also been used for the resolution of various phosphoric and carboxylic acids, including axially chiral compounds, such as biaryl derivatives and allenic acids.46 Derivatives of Cinchona alkaloids have been only rarely used as resolving agents. For example, N–benzylcinchonidinium chloride can be used for efficient resolution of 1,1’–binaphthalene–2,2’–diol (BINOL) (scheme 14).47 Not only BINOL has been successfully resolved with N–benzylcinchonidinium chloride, also enantiomers of other weak acids have been successfully separated in this way.48

Scheme 14. Resolution of BINOL.

1.3.2 Chiral ligands in metal–promoted reactions

The first report on the use of Cinchona alkaloids as chiral ligands in asymmetric metal–promoted reactions was published by Cervinka in 1965.49 He described the reduction of aryl alkyl ketones by stoichiometric amounts of LiAlH4 complexed with Cinchona alkaloids giving ee’s up to 48%. The most significant breakthrough in this field was by


25

Orito et al.50 Heterogeneous platinum catalysts modified with Cinchona alkaloids proved to be excellent systems for the reduction of α–keto esters giving ee’s up to 82%. This process was applied successfully on ton scale by Ciba–Geigy (now Novartis) for the development of benazepril (scheme 15).51 The first homogeneous catalytic transfer hydrogenation using modified Cinchona alkaloids was reported in 2006.52 With Rh or Ir complexes of epi–9–amino–cinchonidine for the asymmetric reduction of aryl alkyl ketones ee’s up to 97% were obtained.

Scheme 15. Pt–Cinchona catalyzed hydrogenation of an α–keto ester for the synthesis of benazepril.

In addition to the reduction of carbonyl compounds, (modified) Cinchona alkaloids have also been applied successfully as chiral ligands in the asymmetric nucleophilic addition to carbonyl or imine compounds,53 especially with alkylzinc reagents53a–d and in Pd–catalyzed asymmetric allylic substitutions54 and Claisen rearrangements55. The most well–known reaction, however, in which Cinchona alkaloids are used as chiral ligands is the asymmetric oxidation of double bonds and in particular the Os–catalyzed asymmetric dihydroxylation developed by Sharpless.56 In 1980 the first attempts were made to perform this reaction asymmetrically by using acetate protected quinine or quinidine as chiral ligands.57 With this catalytic system ee’s up to 83% were obtained, but the reactivity of this system proved to be substrate dependent. Optimization studies by Sharpless resulted in the development of dimeric Cinchona alkaloid based ligands (figure 4).

Figure 4. Dimeric ligands used for the asymmetric dihydroxylation.

In 1992 Sharpless introduced the AD–mix α and β. These mixture were able to form chiral diols with high levels of enantioselectivity for a wide variety of substrates.58 Both these mixtures contain of K2OsO2(OH)4, K3Fe(CN)6 and K2CO3. In AD–mix α (DHQ)2PHAL is used as the chiral ligand while in AD–mix β (DHQD)2PHAL is used. These mixture can now be purchased from different suppliers.59

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1.3.3 Chiral organocatalysts

The first example of the use of Cinchona alkaloids as organocatalysts dates back to 1912.60 In that year Bredig and Fiske reported the addition of HCN to benzaldehyde giving optically active cyanohydrins. Although poor ee (< 10%) was obtained this represents one of the first examples of asymmetric catalysis. About 50 years later Pracejus reported the first reaction catalyzed by Cinchona alkaloids with significant levels of enantioselectivity (scheme 16).61 O–Acetylquinine was used as a chiral Lewis base for the addition of methanol to phenylmethylketene affording optically active α–phenyl methylpropionate.

Scheme 16. Chiral base catalyzed addition of methanol to ketenes.

This inspired Wynberg to further investigate the use of Cinchona alkaloids as chiral Lewis bases/nucleophilic catalysts. In the 1970’s and 1980’s the group of Wynberg developed several highly enantioselective reactions catalyzed by Cinchona alkaloids.5 For example, the addition of various nucleophiles to methyl vinyl ketone catalyzed by quinine.62 Later, they reported the Cinchona alkaloid catalyzed addition of aromatic thiols to cyclic enones (scheme 17).63

Scheme 17. Addition of an aromatic thiol to cylic enone and proposal of bifunctional activation.

In 1981 a detailed study on the mechanism was reported.63b Cinchonidine catalyzed the addition with ee’s up to 75%. Hiemstra and Wynberg showed that both the C9 hydroxy group and the basic quinuclidine were responsible for the ee. Acetylating, removing or substituting the C9 hydroxy group resulted in a drastic decrease of the ee. Also by inverting the stereochemistry at the C9–position resulted in poor enantioselectivity. This was attributed to an intramolecular hydrogen bond between the C9 alcohol and the quinuclidine nitrogen in the epi–bases. This intramolecular hydrogen bond cannot be formed in the natural alkaloid, because the hydroxyl group cannot come within close proximity of the tertiary amine of the quinuclidine ring. Hiemstra and Wynberg proposed


27

a mechanism in which the catalyst adopts an anti–open conformation with both substrates being activated by the catalyst.

Wynberg et al. also investigated other types of activation by Cinchona alkaloids; quinidine and quinine catalyzed the addition of ketene to chlorinated ketones and aldehydes yielding substituted oxetan–2–ones with high levels of enantioselectivity (ee up to 98%) (scheme 18).64 In this reaction the catalyst acts as a Lewis base activating the ketene. Comparing the results obtained with quinidine and quinine showed that quinidine was the better catalyst. Since quinine and quinidine are pseudoenantiomers, the outcome in terms of enantioselectivity is different. In this reaction the position of the vinyl group of the catalyst is crucial for obtaining ee’s above 90%.

Scheme 18. Ketene addition to 2,2,2–trichloroacetaldehyde.

Organocatalysis with Cinchona alkaloids received extensive interest at the end of the last century. One of the first examples was the asymmetric Morita–Baylis–Hillman reaction reported by Hatakeyama15b mentioned in section 1.1.2. In 2004 the group of Deng reported an example of non–covalent bifunctional catalysis with cupreine and cupreidine (these alkaloids are also found in the Cinchona tree bark but to a much lower extent than the four major alkaloids) in the conjugate addition of malonates to nitroalkenes (scheme 19).65 Deng and coworkers proposed that the phenolic OH could serve as hydrogen bond donor activating the electrophile. This was in fact observed and higher enantioselectivities and rates were obtained than with quinine and quinidine.

Scheme 19. Malonate addition to nitrostyrene catalyzed by cupreine and cupreidine.

In 2005 a great impulse was given to this field by four research groups. They reported independently the use of a modified Cinchona alkaloid containing a thiourea function at the C9–position (figure 5).66

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Figure 5. Types of hydrogen bond donors and the year they were introduced.

The presence of a thiourea at C9 appeared vital in order to obtain high conversion and enantioselectivity in a number of conjugate additions. The success of this catalyst was attributed to the strong hydrogen donor capability of the thiourea moiety at C9. Since then many groups have performed research with Cinchona alkaloids as non–covalent bifunctional organocatalysts.67 In particular the C9–position has been modified with different functional groups, like urea68, sulfonamide69, squaramide70, and guanidine71.

Also the introduction of an amine group at the C9–position proved to be a success in the field of organocatalysis with Cinchona alkaloids. In 2007 different groups applied these types of catalysts for the functionalization of branched carbonyl compounds. Connon and coworkers demonstrated that the C9–epi–amine catalysts could be used successfully for the conjugate addition of aldehydes and (cyclic) ketones to nitroalkenes via enamine catalysis.72 Iminium catalysis was successfully demonstrated by Deng, Chen and Melchiorre.73

1.3.4 Mechanism of non–covalent bifunctional cataly sis

Strong hydrogen bond donors were also introduced at other sites than the C9–position. In 2006, Hiemstra and coworkers reported the use of a Cinchona derived catalyst bearing a thiourea moiety at the C6’–position; this proved to be an effective catalyst in the Henry–reaction (scheme 20).74 A collaboration between the groups of Hiemstra and Himo resulted in more insight in the mechanism of this reaction based on DFT–calculations.74b The calculations indicated that two possible transition states are important. After deprotonation of the nitromethane by the basic quinuclidine, the benzaldehyde can be activated by the thiourea or by the protonated quinuclidine. Both transition states give the same direction of stereocontrol. In this reaction the activation of the benzaldehyde by the thiourea was slightly more favored. This is the opposite of what Papai et al. concluded on the basis of their calculations of the mechanism of the addition of 1,3–dicarbonyl compounds to nitroalkenes (section 1.1.3, scheme 9).18 Despite the good results obtained with C6’ thiourea catalysts only a few other reports have appeared in which C6’–modified catalyst have been successfully applied as organocatalysts.75 Possible reasons are the slightly more lengthy synthesis of these catalysts and the fact that these catalysts are not commercially available.


29

N

N

OBn

NH

Ph

O

H+

NO2 Ph

OH

NO2

catalyst(10 mol%)

THF, –20 °C 92% ee

S

NH

CF3

CF3

N HH

NO

N

N

S

PhH

H

HO

NO

Ph

H O

N HH

NO

N

N

S

PhH

H

HO

Ph H O

ON

Ph

OH

NO2

Slightly favored by1.6 kcal/mol

Scheme 20. Henry reaction and the two proposed transition states.

Although calculations support the outcome of non–covalent bifunctional organocatalysis only a few publications describe experimental results that support the proposed mechanisms. A strategy to gain more mechanistic insight is to prepare analogues of organocatalysts and then compare the results. Such a strategy was reported by the group of Merschaert. 76

Table 2. Intramolecular oxa–Michael addition of phenol to α,β–unsaturated esters.

entry R = conversion (%) ee (%) entry R = conversion (%) ee (%) 1 vinyl 45 64 6

20 80

2 Et 75 72 7

35 80

3 H 35 30 8 CH2OH 42 74 4a

34 78 9 CN <2 nd

5

23 76 10 CHO <2 nd

a) Used as a 1:2 mixture of E:Z–isomers

They investigated the influence of the vinyl group of cinchonine in the intramolecular oxa–Michael addition of phenol to α,β–unsaturated esters leading to 2–substituted chiral chromanes (table 2). They prepared several analogues with an increased or a

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decreased steric demand of the vinyl group. In addition, they replaced the vinyl group for more electron withdrawing groups. First cinchonine was examined which gave after 24 h of reaction gave 45% conversion leading to an ee of 64% (entry 1). If the double bond was reduced the conversion increased to 75% and the ee increased to 74% (entry 2). If the vinyl group was removed this lowered the conversion and also the enantioselectivity (entry 3). By replacing the terminal alkene protons with more bulky groups the ee was increased up to 80% (entries 4–6). There was a slight difference in ee on changing the configuration of the double bond (entries 5 and 6). Reduction of the double bond increased the conversion without influencing the ee (entry 7). The introduction of a polar hydroxyl function was tolerated (entry 8) contrary to strong electron withdrawing groups, which gave significantly poorer results (entries 9 and 10).

The increase of the conversion (entry 2) was attributed to increase of the basicity of the nitrogen of the quinuclidine ring. The group of Merschaert calculated the basicity of cinchonine and dihydrocinchonine. It was found that dihydrocinchonine was more basic than cinchonine (pKAH for dihydrocinchonine 9.99, for cinchonine 9.18). Also if strongly electron withdrawing substituents were present almost no conversion was observed, indicating that the basicity influences the conversion. The difference in pKAH was explained by the inductive effect of the appropriate groups.

Calculations showed that the reaction could involve two types of mechanisms (figure 6): in the first mechanism the phenol is deprotonated by the quinuclidine and the α,β–unsaturated ester is activated by the benzylic OH of the catalyst. In the second pathway quinuclidine and the hydroxyl group of the catalyst both participate in a concerted mechanism. The group of Merschaert suggested that the second pathway is more likely because it does not involve formation of a charged enolate after cyclization which is less favored energetically in apolar solvents.

Figure 6. Intermediates proposed by Merschaert.

The group of Hintermann investigated this reaction further and studied the mechanism in more detail.77 They considered a 5–exo–trig cyclization of 4–(2’–hydroxy–phenyl)–crotonates to benzodihydro–2–furanyl acetates as the model for optimization of the reaction conditions (scheme 21). They found that the best results were obtained with cinchonine as the catalyst and chloroform as the solvent. With the optimized conditions the role of the ester was investigated. First different types of unsaturated reactants were used, revealing that a change in the ester group did not have a drastic effect on the enantioselectivity. A large influence of steric bulk on the ester group on the enantioselectivity might have been expected as a hydrogen bond activation mode


31

requires close proximity of the carbonyl group of the substrate and catalyst. Also the nitrile substrate cyclized with comparable selectivity as the esters, even though a nitrile is a less efficient hydrogen bond acceptor than an ester.

Scheme 21. 5–exo–trig cyclization of various α,β–unsaturated systems.

Finally they examined the cyclization of substrates without a heteroatomic hydrogen bond acceptor (scheme 22). With quinine as the catalyst the cyclization proceeded with notable selectivity. The presence of the hydroxyl group in the catalyst is crucial for the cyclization, as O–acetyl–quinine proved to be an inefficient catalyst. These experiments showed that the catalyst still has bifunctional character, but a heteroatomic hydrogen bond acceptor motif in the substrate is not a necessity. This suggests that a concerted mechanism is more likely than a stepwise process. This was further supported by deuterium labeling studies. It must be noted that a concerted mechanism is not a general mechanism for Cinchona alkaloid catalyzed reaction. In a personal communication Hintermann highlighted that the thiol addition to cyclic enones reported by Hiemstra and Wynberg is likely to proceed to the proposed stepwise process (scheme 17).63

Scheme 22. Cyclization of fluorenylene substrate.

1.3.5 Applications of Cinchona alkaloid catalyzed reactions

With (non)–modified Cinchona alkaloids many reactions are catalyzed giving the products in high enantiopurity.65 Many authors claim that their organocatalytic reactions are useful for applications in the drug or the food industry, irrespective of the fact that only a limited number of applications are known.78 Most of these applications concern the synthesis of natural products and only a few examples are reported of enantioselective reactions catalyzed by (modified) Cinchona alkaloids leading to products important to the pharmaceutical industry. An example is the Cinchona based phase–transfer catalyst used by Merck for the synthesis of (+)–indacrinone (scheme 23).85

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Scheme 23. Synthesis of (+)–indacrinone.

Cinchona based phase–transfer catalysts have also been used successfully for the asymmetric synthesis of unnatural amino acids.80 A large scale application with a thiourea containing Cinchona alkaloid was reported by Roche Palo Alto and concerned the synthesis of a series of P2X7 antagonists (scheme 24).81 The key step involved the desymmetrizaion of the cyclic anhydride with methanol. The thiourea catalyst was used in a pilot–plant synthesis involving the desymmetrization of 15 kg of cyclic anhydride with 850 g of catalyst. The product was obtained after recrystallization in 97% ee.

Scheme 24. Large scale application with thiourea containing Cinchona alkaloid.

1.4 Outline of this thesis

Since the end of the last century many organic reactions have been catalyzed by Cinchona alkaloids and derivatives, especially through non–covalent activation modes. However, only a limited number of applications are known in which the enantiomerically enriched products are used in further applications. Also, in almost all reactions catalyzed by Cinchona alkaloids and derivatives no hard experimental proof exist that the proposed transition states are responsible for the observed selectivity.

The research described in this thesis focuses on the use of Cinchona alkaloids as non–covalent bifunctional organocatalysts. Two subject will be addressed: the development of new asymmetric conjugate additions yielding products that can be used in peptide chemistry and the second part is focused on the synthesis of novel analogues of Cinchona alkaloids. The second part is directed towards obtaining more insight in the mechanism of Cinchona alkaloids catalyzed reactions.


33

In chapter 2 the development of a new method for the functionalization of amino acids with thiols on the β–carbon atom is described. Suitable substrates were synthesized and successfully used as Michael acceptors. C6’–Functionalized Cinchona alkaloids proved to be good catalysts in the addition of several thiols to dehydroaminoacid derivatives.

In chapter 3 optimizations studies were performed with the purpose of improving the addition of thiols to α,β–unsaturated N–acetylated oxazolidinone systems. Cinchona alkaloids bearing sulfonamides at the C6’–positions were found to be excellent catalysts for the conjugate additions. Also the application of β–thiol functionalized amino acids in native chemical ligation is described.

Chapter 4 describes synthetic studies performed in order to gain more insight in to the role of the quinuclidine ring system of Cinchona alkaloids in asymmetric organocatalytic reactions. Several analogues were prepared with modifications in the quinuclidine ring system. These analogues were applied as catalysts in several conjugate additions with the purpose of examining the influence of the modifications in the quinuclidine ring on the enantioselectivity.

In chapter 5 a new approach towards 2–methylenequinuclidines is described based on a silver catalyzed intramolecular hydroamination reaction. This study was performed in order to develop new routes for the synthesis of Cinchona alkaloids analogues and for further mechanistic studies of Cinchona alkaloid catalyzed reactions.

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57) Hentges, S. G.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 4263–4265. 58) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K.–S.; Kwong,

H.–L.; Morikawa, K.; Wang, Z. M.; Xu, D.; Zhang, X.–L. J. Org. Chem. 1992, 57, 2768–2771. 59) Prices from Sigma–Aldrich website (January 2014): AD–mix α, 50g – € 77.30 and AD–mix β, 50

g – € 75.90 60) Bredig, G.; Fiske, W. S. Biochem. Z. 1912, 7. 61) Pracejus, H. Liebigs Ann. Chem. 1960, 634, 9–22. 62) Wynberg, H.; Helder, R. Tetrahedron Lett. 1975, 16, 4057–4060. 63) a) Helder. R.; Arends, R.; Bolt, W.; Hiemstra, H.; Wynberg, H. Tetrahedron Lett. 1977, 18, 2181–

2182 b) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417–430. 64) a) Wynberg, H.; Starring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166–168 b) Wynberg, H.;

Starring, E. G. J. J. Org. Chem. 1985, 50, 1977–1979. 65) Li, L.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906–9907. 66) a) Li, B–J.; Jiang, L.; Liu, M.; Chen, L.–S.; Wu, Y. Synlett, 2005, 603–606 b) Vakulya, B.; Varga,

S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967–1969 c) McCooey, S. H.; Connon, S. J. Angew. Chem. Int. Ed. 2005, 44, 6367–6370 d) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Comm. 2005, 35, 4481–4483.

67) a) Marcelli, T.; Hiemstra, H. Synthesis 2010, 1229–1279 b) Ingemann, S.; Hiemstra, H. Comprehensive Enantioselectivity Organocatalysis, Vol 1, Dalko, P. I. Ed.; Wiley–VCH: Weinheim, 2013, 119–160.

68) Rana, N. K.; Selvakumar, S.; Singh, V. K. J. Org. Chem. 2010, 75, 2089–2091. 69) Oh, S. H.; Rho, H. S.; Lee, J. W.; Lee, J. E.; Youk, S. H.; Chin, J.; Song, C. E. Angew. Chem. Int.

Ed. 2008, 47, 7872–7875. 70) a) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416–14417 b)

Alemán, J.; Alejandro Parra, A.; Jiang H,; Jørgensen, K. A. Chem. Eur. J. 2011, 17, 6890–6899. 71) Zhang, L.; Lee, M–M.; Lee, S–M.; Lee, J.; Cheng, M.; Jeong, B–S.; Park, H–G.; Jew, S–S. Adv.

Synth. Catal. 2009, 351, 3063–3066. 72) McCooey, S. H.; Connon, S. J. Org. Lett. 2007, 9, 599–602.

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73) a) Xie, J.–W.; Chen, W.; Li, R.; Zeng, M.; Du, W.; Yue, L.; Chen, Y.–C. Wu, Y.; Zhu, J.; Deng, J.–G. Angew. Chem. Int. Ed. 2007, 46, 389–392 b) Chen, W.; Du, W.; Yeu, L.; Li, R.; Wu, Y.; Ding, L.–S..; Chen, Y.–C. Org. Biomol. Chem. 2007, 5, 816–821 c) Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.; Sambri, L.; Melchiorre, P. Org. Lett. 2007, 9, 1403–1405.

74) a) Marcelli, T.; van der Haas, R. N. S.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem. Int. Edit. 2006, 45, 929–931 b) Hammar, P.; Marcelli, T.; Hiemstra, H.; Himo, F. Adv. Synth. Catal. 2007, 349, 2537–2548.

75) a) Liu, Y.; Sun, B. F.; Wang, B. M.; Wakem, M.; Deng, L. J. Am. Chem. Soc. 2009, 131, 418–419 b) Xiao, X.; Liu, M.; Rong, C.; Xue, F.; Li, S.; Xie, Y.; Shi, Y. Org. Lett. 2012, 14, 5270–5273.

76) Merschaert, A.; Delbeke, P.; Dalozeb, D.; Dive, G. Tetrahedron Lett. 2004, 45, 4697–4701. 77) Hintermann, L.; Ackerstaff, J.; Boeck, F. Chem. Eur. J. 2013, 19, 2311–2321. 78) Alemán, J.; Cabrera, S. Chem. Soc. Rev. 2013, 42, 774–793. 79) Dolling, U.H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106, 446–447. 80) Maruoka, K. Org. Process Res. Dev. 2008, 12, 679–697. 81) Huang, X.; Broadbent, S.; Dvorak, C.; Zhao, S.–H. Org. Proc. Res. Dev. 2010, 14, 612–616.

Enantioselective Organocatalytic Thiol Addition to α,β–Unsaturated α–Amino Acid Derivatives

37

CHAPTER 2

Enantioselective Organocatalytic Thiol Addition to α,β–Unsaturated

α–Amino Acid Derivatives *

Abstract: A new class of Michael acceptors based on α,β–unsaturated α–amino acids were prepared and applied in asymmetric organocatalysis. Using thiourea derivatives of Cinchona alkaloids as catalysts, efficient addition of thiols to the Michael acceptors occurred with formation of β–thiol functionalized α–amino acid derivatives in high yields, moderate diastereoselectivities and ee values up to 95%.

*Part of this work has been published in:

Breman, A. C.; Smits, J. M. M.; de Gelder, R.; van Maarseveen, J. H.; Ingemann, S.; Hiemstra, H. Synlett

2012, 23, 2195–2200.

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2.1 Introduction

In the last decade many organic reactions have been catalyzed by chiral organocatalysts yielding products in high enantiopurity.1 The formation of carbon–carbon bonds has been studied intensively. However, the formation of carbon–heteroatom bonds has gained much less attention. Despite the fact that products can be obtained in high enantiopurity, only a limited number of applications are known where these products are applied further, for example for pharmaceutical purposes or total syntheses. To further extend the field of asymmetric organocatalysis new applicable reactions should be developed. The β–thiol functionalization of α–amino acids through a thiol addition to substituted α,β–dehydro–α–amino acids could provide useful building blocks for peptide chemistry (scheme 1).

Scheme 1. Thiol addition to substituted α,β–dehydro–α–amino acids.

2.1.1 Conjugate additions of thiols

Carbon–sulfur bond formation can be achieved in various ways. One of the most powerful methods is the conjugate addition of thiols to electron deficient multiple bonds (scheme 2).2 Especially the asymmetric synthesis of chiral thioesters and thioethers can be of great importance for the synthesis of natural products and biologically active compounds.3

Scheme 2. Principle of asymmetric conjugate additions of thiols.

The first reports on asymmetric conjugate additions with the formation of thioethers date back to the 1970’s. The group of Wynberg used quinine to catalyze the addition of aromatic thiols to cyclic enones with up to 46% ee.4 Also the use of chiral metal complexes or chiral auxiliaries are well known and have been explored for the formation of chiral thioesters and thioethers.2 In most cases relatively acidic sulfur compounds have been used like thioacetic acid or thiophenols because these compounds are more reactive than their benzylic and aliphatic counterparts.

Nowadays, bifunctional organocatalysis is an important area of research for the synthesis of chiral thioethers.5 The group of Deng used Cinchona alkaloid derivatives bearing a thiourea group at the C6’–position as catalyst for the addition of aliphatic and benzylic thiols to various α,β–unsaturated N–acetylated oxazolidin–2–ones (scheme 3).5a


39

Scheme 3. Conjugate addition of thiols catalyzed by C6’–thiourea Cinchona alkaloids.

They showed that steric effects played a crucial role to obtain high levels of enantiomeric excess. For example, catalyst A (R = benzyl)6 led to only 68% ee for the addition of phenylmethanethiol to the α,β–unsaturated N–acetylated oxazolidin–2–one (R1 = Me) at room temperature while the more sterically congested system B (R = 9–methylanthracyl) gave 85% ee. This was further improved to 94% ee by performing the reaction at –20 °C. The group of Chen performed this reaction at room temperature by using Cinchona alkaloid derivatives with a squaramide group at the C9–position giving up to 99% ee.5d They were also able to lower the catalyst loading to 1 mol% for the addition of phenylmethanethiol to α,β–unsaturated N–acetylated oxazolidin–2–one (R1 = Me) providing the product in 99% ee. The group of Singh investigated the enantioselective protonation of α,β–unsaturated N–acetylated oxazolidin–2–ones.5f The best results were obtained with a Cinchona alkaloid derivative with a thiourea group at the C9–position giving the products with up to 96% ee.

2.1.2 α,β–Dehydro– α–amino acids

α,β–Dehydro–α–amino acids are often used in synthetic applications because of their easy synthesis and tunable reactivity. The β–carbon atom has both nucleophilic and electrophilic character (scheme 4).

Scheme 4. Resonance structures of α,β–dehydro–α–amino acids.

α,β–Dehydro–α–amino acids are also found in a wide variety of biologically active natural products, for example in tentoxin and phomopsin A (figure 1).7,8 In biological systems these α,β–unsaturated–α–amino acids also serve as good Michael acceptors especially for the cysteine residue.4 Several naturally occurring peptides, therefore, have a macrocycle containing a thioether. Such peptides are called lanthionines.

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Figure 1. Biologically active peptides with an α,β–dehydro–α–amino acid or a thioether.

In the field of asymmetric organocatalysis conjugate additions have been reported so far only for unsubstituted α,β–dehydro–α–amino acids (scheme 5).9–11 Reasons for this could be that the β–substituent makes the substrates less reactive and hydrogen bonding between substrate and catalyst is quite weak leading to poor control of the diastereoselectivity. The first example was published in 1977 by Pracejus et al. who investigated the addition of phenylmethanethiol to methyl 2–phthalimidoacrylate catalyzed by Cinchona alkaloids (I), providing thioethers with up to 54% ee.9a Despite their promising results it was not until 2008 when it was reported that a guanidine–derived organocatalyst (II) catalyzed this reaction with ee’s above 90%.9b The group of Glorius used dehydroamino acids as substrates for the Stetter reaction and a chiral N–heterocyclic carbene (NHC) (III) as organocatalyst.10 They could catalyze the addition of various aldehydes to unsubstituted α,β–dehydro–α–amino acids with ee’s up to 99%. Also thiourea–derived Cinchona alkaloid catalysts (IV) gave high ee’s (up to 99%) with α,β–dehydro–α–amino acids as Michael acceptors.11

Scheme 5. Examples of asymmetric organocatalysis with dehydroaminoacids.

2.1.3 β–Functionalized cysteines

Although β–thiol functionalized amino acids can be of significant interest in peptidomimetics, limited attention has been given to asymmetric syntheses of these compounds (scheme 6). The reported methods include conjugate addition of thiols to α,β–unsaturated amino acids leading to racemates (A)12 and mesylation of the hydroxyl group of threonine analogues followed by nucleophilic substitution by a thiol (B).13 The


41

latter method leads to the formation of enantiomerically pure unnatural amino acids but it is limited to species with a hydroxyl group at the β–position. Protected aspartic acid could also be functionalized with a thiol at the β–carbon, by making a di–anion of the amino acid prior to the reaction with a sulfenylating reagent giving a 9:1 diastereomeric mixture in favor of the syn–isomer (C).14

Scheme 6. Methods for the synthesis of β–thiol functionalized amino acids.

In order to extend the possibilities for asymmetric synthesis of β–thiol functionalized amino acids, it was decided to prepare a novel series of α,β–unsaturated N–acetylated oxazolidin–2–ones bearing a protected amine group at the α–position (scheme 7). It was anticipated that the thiol addition to these novel molecules catalyzed by Cinchona alkaloid derivatives may provide enantiomerically enriched compounds that could be easily converted into β–thiol amino acids. These amino acids can be used in several applications, for example ligation reactions, CLIPS–technology, lanthionine synthesis or the formation of specific disulfide bridges in peptides.15–17

Scheme 7. Thiol addition to substituted α,β–dehydro–α–amino acids.

2.2 Substrate synthesis

Several methods are known for the synthesis of α,β–dehydro–α–amino acids.18–20 The Erlenmeyer–Plöchl azlactone synthesis is most commonly used for the synthesis of aromatic α,β–dehydro–α–amino acids,18 while the Horner–Wadsworth–Emmons reaction is used mostly for the synthesis of aliphatic α,β–dehydro–α–amino acids.19

Initially, α,β–dehydro–α–amino acid 3 was prepared with an acetyl group at the enamine

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nitrogen atom by the Erlenmeyer–Plöchl azlactone synthesis18 followed by ring opening with oxazolidinone (scheme 8).

Scheme 8. Synthesis and catalysis of acetate protected dehydroaminoacid derivative.

Subsequently, this substrate was reacted with thiophenol in the presence of a C6′ thiourea Cinchona alkaloid derivative A described previously.6 However, β–thiol functionalized amino acid 4 was not observed, indicating a low reactivity of the β–carbon atom in the substrate, possibly as a result of the pronounced enamine character at this position. In order to increase the susceptibility of the β–carbon atom for nucleophilic attack, it was decided to introduce a trifluoroacetyl group as the protective group at the enamine nitrogen atom.

The Erlenmeyer–Plöchl azlactone synthesis with TFAA is known, but leads to unstable products.21 All attempts to prepare the trifluoromethyl–substituted azlactones by this strategy therefore failed to give isolable products as required for the reaction with oxazolidinone under basic conditions (scheme 9).

Scheme 9. Attempt to synthesize trifluoroazlactone in one step.

It was decided, therefore, to prepare the desired α,β–unsaturated N–trifluoracetylated oxazolidin–2–ones by treatment of amino acids 5a–e with TFAA thus leading to the stable pseudoazlactones 6a–e in moderate to good yields (scheme 10).22

Scheme 10. Preparation of the dehydroamino acid derivatives 8a–e.


43

Bromination in 1,2–dichloroethane (DCE) resulted in the formation of 7a–e in good to excellent yields.23 In agreement with the literature, small amounts of dibrominated compounds were formed in the reaction of pseudoazlactones derived from norvaline (5c) and norleucine (5d).24 Treatment of brominated pseudoazlactones 7a–e with two equiv of aniline was previously reported to result in elimination of HBr with in situ formation of azlactones prior to ring opening to afford dehydroamino acid anilides.23 Thus, 7a–e were treated with 2.2 equiv of the sodium salt of oxazolidinone in THF. This resulted in the formation of dehydroamino acids 8a and c–e in poor to reasonable yields and in most cases with a preference for the Z–isomer. The E–and Z–isomers were subsequently separated by recrystallization from a mixture of PE and EtOAc or by column chromatography.

In case of 7b only a trace of the desired product could be detected. Possible elimination of HBr leads to a vinyl substituted pseudoazlactone, which may undergo decomposition even though the pathway remains unclear (scheme 11). Substrates 7a and 7e which do not have an alternative elimination mechanism or are sterically shielded give good yields, while substrates 7c and 7d that contain two hydrogens next to the bromine atom give poor yields.

Scheme 11. Possible decomposition pathway of 7b.

Next the addition of thiophenol to substrate 8a with Cinchona–derived catalyst A6 was tested. After stirring overnight complete consumption of the starting material was observed (scheme 12).

Scheme 12. Addition of thiophenol to dehydroaminoacid derivative 8a.

The higher reactivity of 8a as compared to the related N–acetyl protected species 3 is the result of a decrease in electron density at the β–position upon introduction of a trifluoroacetyl group at the enamine nitrogen atom. This is also apparent from the 13C NMR chemical shift of this carbon atom being 132.19 ppm for 8a and only 112.47 ppm for 3.

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2.3 Catalyst screening

In order to establish the optimal conditions for the asymmetric thiol addition, the pure Z–isomer of substrate 8a was reacted with thiophenol in a series of solvents and in the presence of one of the three thiourea derivatives A–C of quinidine or the thiourea derived organocatalyst D developed by Takemoto as shown in table 1.5a,6,25,26

Table 1. Optimization screening of the addition of thiophenol to dehydroaminoacid derivative 8a.

entrya catalyst solvent equiv. PhSH conversion (%)b syn/anti ee (%)c

1 A CH2Cl2 1.2 100 75:25 79/57 2 A CHCl3 1.2 100 80:20 47/36 3d A THF 1.2 70 75:25 60/45 4d A toluene 1.2 50 75:25 85/63 5 A toluene 2.0 100 75:25 2/46 6 B CH2Cl2 1.2 100 75:25 90/75 7 B CHCl3 1.2 100 75:25 80/60 8d B toluene 1.2 60 67:33 90/74 9 B toluene 2.0 100 75:25 42/57

10d C CH2Cl2 1.2 75 83:17 28/45 11d C CHCl3 1.2 75 85:15 28/–18 12d C toluene 1.2 57 91:9 57/30 13 D CH2Cl2 1.2 100 95:5 –70/36

a) Standard reaction conditions: 0.2M substrate, room temperature, reaction time 12 h b) Conversion determined by 1H NMR spectroscopic analysis c) The ee was determined by chiral HPLC (AD column) analysis d) No improvement of the conversion was

observed with a reaction time of 24 h

The reaction proceeded efficiently to give full conversion after 12 h in CH2Cl2 in the presence of 10 mol% of the C6′ thiourea derivative A (table 1, entry 1).6 The product 9 of the 1,4–addition of thiophenol was formed with moderate diastereoselectivity and with good enantioselectivity for the major diastereoisomer (79%). With CHCl3 as the solvent, full conversion was also observed after 12 h. The diastereoselectivity was similar as in CH2Cl2 but the enantioselectivity was lower for both diastereoisomers (entry 2). A reasonable enantioselectivity was observed in THF, although the conversion was only 70% (entry 3). A further increase in enantioselectivity was seen in toluene, but again the conversion was only 50% after 12 h (entry 4). Addition of 2.0 equiv of thiophenol instead of 1.2 equiv gave full conversion after 12 h. However, a significant decrease in the enantioselectivity was observed. Replacing the benzyl group in catalyst A with a 9–


45

methylanthracyl moiety led to the formation of the sterically more congested catalyst B.5a With this catalyst and CH2Cl2 as the solvent the major diastereomer was obtained with an ee of 90% and the minor diastereomer in 75% ee (entry 6). The enantioselectivity was moderate for both diastereoisomers in CHCl3 (entry 7) and higher in toluene, even though the conversion was only 60% after 12 h with 1.2 equiv of thiophenol (entry 8). As observed with catalyst A, addition of 2.0 equiv of thiophenol resulted in full conversion after 12 h with formation of the diastereoisomers in moderate enantioselectivity (entry 9). The diastereoisomeric ratio was changed when catalyst C was used (entries 10–12).25 However, full conversion was not observed and the enantioselectivity was low for both diastereomers.

To determine the relative and absolute configuration of the addition product, several attempts were made to obtain a pure sample of the major isomer by recrystallization using the conditions given in table 1, entry 6. However, despite several attempts a mixture of diastereoisomers was obtained. In order to obtain enantiomerically pure crystals, the thiophenol addition was performed with the bifunctional organocatalyst D (entry 13).26 In this case, the same diastereoisomer was obtained as the major one with excellent diastereoselectivity and moderate enantioselectivity. However, the opposite configuration of the major diastereoisomer was formed as in the reaction catalyzed by B as revealed by HPLC. The major isomer was recrystallized from PE/EtOAc and an X–ray crystal structure analysis was performed in order to determine the relative and absolute configuration (figure 2).

Figure 2. X–Ray crystal structure of the major enantiomer of 9 obtained with catalyst D.

The analysis showed that the major diastereoisomer formed in the reaction catalyzed by D has the syn–configuration and both stereogenic carbons atoms have the R–configuration. So, catalyst B provides the S–configuration for both stereogenic carbon atoms of the major isomer of the addition product.

2.4 Substrate scope

The catalytic reactions between the substrates 8a, c–e and a series of thiols were examined in CH2Cl2 with catalyst B (table 2). In the experiments with ethanethiol, 2–propene–1–thiol, phenylmethanethiol and substituted analogues 3.0 equiv of the thiol were added. This resulted in a decrease in the reaction time without a change in the enantioselectivity. The reaction of the Z–isomer of the phenyl–substituted substrate 8a with ethanethiol was slow and gave the diastereoisomers in almost equal amounts (entry 1). High enantioselectivity was observed for the major diastereoisomer while only a

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moderate ee was obtained for the minor isomer. A lower enantioselectivity was seen with 2–propene–1–thiol as the nucleophile (entry 2); that is, the ee of the major diastereoisomer was 86% but only 25% for the minor isomer. Phenylmethanethiol reacted with 8a within 4 h with a slight preference for one diastereoisomer (entry 3). The major diastereomer was formed with high enantioselectivity (94% ee), while the ee for the minor isomer (47%) was significantly lower also compared with the results for thiophenol as the nucleophile (table 1, entry 6). The diastereoselectivity was 67:33 with 4–methoxy–phenylmethanethiol and an excellent enantioselectivity was obtained for the major isomer (entry 4). Also catalyst D was examined further with 4–methoxy–phenylmethanethiol (entry 5). Both the diastereoselectivity and the enantioselectivity decreased significantly as compared to the addition of thiophenol catalyzed by D (table 1, entry 13).

Table 2. Scope of the thiol addition to dehydroamino acid derivatives.

entrya substrateb R1 = R2 = equiv. of thiol time (h) product yield (%)c syn/anti ee (%)d

1 8a Ph Et 3 16 10 96 47:53 52/94 2 8a Ph allyl 3 8 11 97 48:52 25/86 3 8a Ph Bn 3 4 12 93 47:53 47/94 4 8a Ph 4–MeOBn 3 6 13 96 33:67 46/95 5e 8a Ph 4–MeOBn 3 8 13 92 37:63 24/25 6 8c Et allyl 3 16 14 94 58:42 57/80 7 8c Et Ph 1.2 8 15 92 80:20 87/51 8 8c Et Bn 3 16 16 95 52:48 71/90 9 8c Et 4–MeOBn 3 16 17 91 53:47 58/80

10a (Z)–8d n–Pr Ph 1.2 16 18 91 80:20 80/65 10b (E)–8d n–Pr Ph 1.2 16 18 92 70:30 57/24 10c (E,Z)–8d f n–Pr Ph 1.2 16 18 93 67:33 63/28 11 8d n–Pr Bn 3 16 19 95 55:45 44/72 12g 8e i–Pr 4–MeOBn 3 16 20 90 75:25 37/56

a) Standard conditions: 0.2 M substrate, rt b) Experiments were performed with the Z–isomer of the substrates unless otherwise stated c) The combined yield of both diastereoisomers d) The ee values were determined by chiral HPLC analysis. e) Catalyst D

was used f) The composition of the mixture was 30% E– and 70% Z–isomer g) Catalyst A was used in order to obtain full conversion

By comparing the 1H NMR spectra of the conjugate addition products of substrate 8a there was a remarkable difference in the chemical shifts for the major diastereoisomer formed in the reaction with thiophenol (pKa = 6.52 in water) (table 1) and the major diastereoisomer formed with the less acidic thiols (pKa’s between 9.43 and 10.65 in water) (table 2, entries 1–5).27 The position of the α–proton of the major diastereoisomer in compound 9 was at 6.12 ppm and the minor was at 6.33 ppm. When the less acidic thiols were used as nucleophiles (compounds 10–13) the α–protons of the major diastereoisomers lay between 6.33 and 6.35 ppm and the minor diastereoisomer between 6.02 and 6.12 ppm. In order to see whether the diastereoselectivity with the less acidic thiols is opposite to that obtained with thiophenol, crystals were obtained of


47

the major isomer of compound 13 obtained with catalyst B (entry 4) and an X–ray crystal structure analysis was performed (figure 3).

Figure 3. X–Ray crystal structure of the major enantiomer of 13.

The X–ray revealed that the anti–diastereoisomer was formed as the major diastereoisomer having the S–configuration at α–carbon and the R–configuration at the β–carbon of the amino acid derivative. By changing the nucleophile from thiophenol to 4–methoxy–phenylmethanethiol there was inversion of the stereochemistry at the β–carbon atom, so apparently the precise nature of the transition state is different for the addition of thiophenol and the less acidic thiols.

The reaction of the Z–isomer of the ethyl–substituted substrate 8c with thiophenol gave the products in good diastereoselectivity, and the enantioselectivity was also relatively high for the major isomer (table 2, entry 7). With the less reactive thiols, 2–propene–1–thiol, phenylmethanethiol, and 4–methoxy–phenylmethanethiol, an inversion with respect to the diastereoselectivity was observed (entries 6, 8 and 9). In these reactions, the highest ee values were observed for the minor diastereoisomer with only a slight change in enantioselectivity as compared with the phenyl–substituted substrate 8a. In the reactions of the Z–isomer of the n–propyl–substituted substrate 8d (entries 10 and 11) the ee values did not exceed 80%, indicating that 1,4–addition is sterically influenced by the size of the alkyl group at the β–position. The pure E–form of 8d gave low ee values for both diastereoisomers (57% for the major diastereomer and 24% for the minor species), and the ee of the major isomer was only slightly higher (63%; entries 10b and 10c) with the E/Z–mixture. Using substrate 8e no full conversion could be obtained using catalyst B. Only by using the sterically less hindered catalyst A full conversion was obtained, but the enantioselectivity was poor for the major diastereoisomer and moderate for the minor one (entry 12).

2.5 Mechanism of the conjugate addition

The addition of thiophenol and the less acidic thiols give different preference for stereochemistry at the β–carbon; the thiols prefer to attack the double bond from the opposite face. Possible intermediates for the formation of the major isomers are depicted in scheme 11.

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Scheme 13. Proposed intermediates (Ox = oxazolidinone).

For the formation of 9, it is proposed that after deprotonation of the thiophenol the thiophenolate coordinates to the thiourea moiety and that the α,β–dehydro–α–amino acid derivative is activated by the protonated quinuclidine.28 The thiophenolate attacks from the front side and the formed enolate is protonated anti to the thiophenol. For the formation of the anti–diastereoisomer 13, it is proposed that the α,β–dehydro–α–amino acid derivative is activated by the thiourea via double hydrogen bonding and that the phenylmethanethiol is activated by the quinuclidine. The thiol addition occurs from the backside and the enolate is protonated syn to the phenylmethanethiol. Although it is hard to predict the exact orientation of the α,β–dehydro–α–amino acid derivative, the proposed transition states fit the outcome in terms of enantioselectivity. The reactions with the less acidic thiols gave poor diastereoselectivities. A reason for this could be that the reaction to a large extent proceeds through the transition state in which the thiourea stabilizes the thiol–anion.

2.6 Follow–up chemistry

To examine the applicability of the products of the thiol addition for solid–phase Fmoc–chemistry, a one–pot procedure was developed to remove the trifluoroacetyl and the oxazolidinone groups from the pure anti–diastereoisomer 13, followed by protection of the primary amine function with an Fmoc–group (scheme 14). This resulted in 68% yield of the corresponding Fmoc–protected amino acid 21. Furthermore, the 4–methoxybenzyl group could be easily removed with TFA and i–Pr3SiH in CH2Cl2. This resulted in formation of the Fmoc–protected phenyl–substituted cysteine 22 in 95% yield.


49

Scheme 14. Formation of enantiopure β–phenyl substituted cysteine protected with a Fmoc group at the amine moiety.

2.7 Conclusion

In conclusion, a new class of substrates based on α,β–dehydro–α–amino acids for asymmetric organocatalyzed thiol additions have been prepared. These compounds contain phenyl, ethyl, n–propyl and isopropyl groups. The synthesis of the substrate with a methyl substituent was not successful. With the new substrates Cinchona alkaloid–catalyzed conjugate thiol additions were performed in good yields, modest to excellent enantioselectivities and low to moderate diastereoselectivities. Inversion of the stereochemistry on the β–carbon atom was observed if 4–methoxy–phenylmethanethiol was used as the nucleophile instead of thiophenol. The final products can be converted into β–thiol amino acids as was shown for one example.

2.8 Acknowledgments

Jan M. M. Smits and dr. René de Gelder of the Radboud University Nijmegen are gratefully acknowledged for the X–ray crystal structure analyses.

2.9 Experimental section

(Z)–N–(3–Oxo–3–(2–oxooxazolidin–3–yl)–1–phenylprop–1–en– 2–yl)acetamide 3: N–Acetylglycine (1, 3.0 g, 25.6 mmol) was dissolved in 15 mL acetic anhydride, sodium acetate (2.1 g, 25.6 mmol) was added and the mixture was stirred for 30 min. Next, benzaldehyde (2.6 mL, 25.6 mmol) was added and the resulting mixture was stirred for 1 h at rt and 5 h at 50 °C. The reaction mixture was cooled to rt and 50 mL of water was added. The insoluble material was filtered, washed 3

times with water and the azlactone was dried overnight. Oxazolidinone (11.1 g, 128 mmol) was dissolved in 300 mL THF, NaH (60% in mineral oil, 3.1 g, 128 mmol,) was added and the resultant mixture was stirred for 30 min. Next a solution of THF (50 mL) containing azlactone 2 was added and the mixture was stirred for 2 h. The mixture was quenched with saturated NH4Cl and extracted 3 times with EtOAc. The organic layers were combined, dried with MgSO4 and the crude was concentrated. The product was purified with column chromatography (PE/EtOAc 2:1) yielding dehydroaminoacid 3 (3.5 g, 12.8 mmol, 50%) as a white solid. mp 134–137 °C; IR (neat, cm–1) ν 3250, 1772,

CHAPTER 2

50

1741, 1716, 1662, 1498, 1443, 1230; 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.48–7.40 (m, 5H), 6.79 (s, 1H), 4.35 (t, 2H, J = 5.4 Hz), 3.93 (t, 2H, J = 5.4 Hz), 2.03 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 170.8, 163.9, 155.8, 132.7, 129.2, 129.1, 129.0, 125.7, 112.5, 61.0, 37.8, 20.7; Elemental analysis for C14H14N2O4: calculated: C 61.31%, H 5.14%, N 10.21% found: C 60.82%, H 4.98%, N 10.06%. General procedure for the synthesis of the 4–substi tuted oxazolin–5–ones. A mixture of an amino acid and TFAA (2.3 equiv) was refluxed for 1 h. After removing the excess reagent the product was distilled under reduced pressure.

4–Propyl–2–(trifluoromethyl)oxazol–5(2 H)–one 6c: According to the general procedure for the formation of 4–substituted oxazolin–5–ones, norvaline 5c (11.7 g, 100 mmol) reacted with TFAA (32 mL, 230 mmol) to afford 6c (19.0 g, 97.4 mmol, 97%) as a colorless oil after distillation under reduced pressure (0.8 mbar, 81 °C). IR (neat, cm–1) ν 2972, 1802,1648, 1153, 1008, 699; 1H NMR (400 MHz, CDCl3) δ 6.13 (m, 1H), 2.70 (t, 2H, J = 5.2 Hz), 1.83 (m, 2H), 1.04 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz,

CDCl3) δ 169.2, 163.8, 120.2 (q, J = 279.8 Hz) 93.1 (q, J = 34.9 Hz), 30.0, 18.6, 13.2; HRMS (FAB) for C7H9F3NO2: calculated (MH+): 196.0585, found (MH+): 196.0591. 4–Butyl–2–(trifluoromethyl)oxazol–5(2 H)–one 6d: According to the general

procedure for the formation of 4–substituted oxazolin–5–ones, norleucine 5d (13.1 g, 100 mmol) reacted with TFAA (32 mL, 230 mmol) to afford 6d (18.3 g, 88 mmol, 88%) as a colorless oil after distillation under reduced pressure (0.9 mbar, 82 °C). IR (neat, cm–1) ν 2965, 1802, 1648, 1153,1016, 699; 1H NMR (400 MHz, CDCl3) δ 6.12 (m, 1H), 2.73 (dt, 2H, J = 7.2, 2 Hz), 1.77 (m, 2H), 1.44 (m, 2H), 1.00 (t, 3H, J = 8.0

Hz); 13C NMR (100 MHz, CDCl3) δ 169.3, 163.8, 120.1 (q, J = 279.7 Hz), 93.0 (q, J = 34.9 Hz), 27.9, 27.1, 22.0, 13.4; HRMS (FAB) for C8H11F3NO2: calculated (MH+): 210.0742, found (MH+): 210.0744. General procedure for bromination of 4–substituted oxazolin–5–ones. The 4–substituted oxazolin–5–one was dissolved in 1,2–dichloroethane and cooled to 0 °C. To the solution a small portion of a solution of bromine (1 equiv) in 1,2–dichloroethane was added. A small sample was withdrawn and gently heated until it became colorless and then returned to the flask. This procedure was repeated until the mixture in the flask became colorless. Next the rest of the bromine solution was added. The mixture was allowed to come to rt and stirred until all the starting material had disappeared according to TLC. The product was concentrated under reduced pressure and purified by distillation under reduced pressure. 4–(1–Bromopropyl)–2–(trifluoromethyl)oxazol–5(2 H)–one 7c: According to the

general procedure for the bromination of the 4–substituted oxazolin–5–ones, 6c (5.85 g, 30 mmol) was dissolved in 60 mL 1,2–dichloroethane and was brominated by Br2 (1.54 mL, 30 mmol) in 20 mL 1,2–dichloroethane to afford 7c (7.25 g, 26.7 mmol, 89%) as a colorless oil after distillation under reduced pressure (0.4 mbar, 110 °C). IR (neat, cm–1) ν 2978, 1806, 1643, 1366, 1305, 1154, 1016, 704; 1H NMR (400

MHz, CDCl3) δ 6.21 (m, 1H), 4.81 (m, 1H), 2.33 (m, 2H), 1.14 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 166.4, 166.2, 161.3, 161.2, 120.0, (q, J = 280.1 Hz), 92.4 (q,

NO

Et

CF3H

OBr


51

J = 34.9 Hz), 42.2, 42.0, 27.4, 27.3, 11.9, 11.7; HRMS (FAB) for C7H8BrF3NO2: calculated (MH+): 271.9534, found (MH+): 271.9539. 4–(1–Bromobutyl)–2–(trifluoromethyl)oxazol–5(2 H)–one 7d: According to the

general procedure for the bromination of the 4–substituted oxazolin–5–ones, 6d (7.5 g, 35.9 mmol) was dissolved in 70 mL 1,2–dichloroethane and was brominated by Br2 (1.8 mL, 35.9 mmol) in 20 mL 1,2–dichloroethane to afford 7d (8.0 g, 28.0 mmol, 78%) as a colorless oil after distillation under reduced pressure (0.3 mbar, 175 °C). IR (neat, cm–1) ν 2967, 1806, 1642, 1309, 1195, 1155, 1023, 705; 1H NMR (400

MHz, CDCl3) δ 6.21 (m, 1H), 4.88 (t, 1H, J = 7.2 Hz), 2.26 (m, 2H), 1.65 (m, 1H), 1.51 (m 1H), 1.01 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 166.5, 166.3, 161.4, 161.3, 120.0 (q, J = 279.9 Hz), 92.3 (q, J = 34.9 Hz), 40.4, 40.2, 35.7, 35.6, 20.6, 20.5, 13.0; HRMS (FAB) for C8H10BrF3NO2: calculated (MH+): 287.9847, found (MH+): 287.9843. General procedure for the formation of the addition substrate. Oxazolidinone (2.3 equiv) was dissolved in THF. NaH (2.2 equiv) was added in portions and the resulting mixture was stirred for 45 min. Next, a solution of bromo “pseudo” azlactone in THF was added dropwise. The resulting mixture was stirred for 30 min and then quenched with saturated NH4Cl. The layers were separated and the water layer was extracted 2 times with EtOAc. The organic layers were combined, washed with brine and dried with MgSO4. The crude was concentrated and purified by column chromatography and if possible the product was recrystallized to obtain the pure Z–isomer. (Z)–2,2,2–Trifluoro– N–(3–oxo–3–(2–oxooxazolidin–3–yl)–1–phenylprop–1–en– 2–

yl)–acetamide 8a: According to the general procedure for the formation of the addition substrate, to a solution of oxazolidinone (5.0 g, 57.4 mmol) in 250 mL THF was added NaH (60% in mineral oil, 1.3 g, 55 mmol), followed by bromo–compound 7a (8.0 g, 25 mmol) in 50 mL THF afforded a mixture of isomers

(Z/E 10:1) of compound 8a (5.3 g, 15.5 mmol, 62%) as a white solid after column chromatography (PE/EtOAc 2:1). The Z–isomer could be obtained by recrystallization from PE/EtOAc. IR (neat, cm–1) ν 3253, 1617, 1717, 1685, 1529, 1388, 1209, 1184, 1155; Z–isomer: mp 139–141 °C; 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 7.47–7.40 (m, 5H), 6.94 (s, 1H), 4.44 (t, 2H, J = 7.6 Hz), 4.05 (t, 2H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 164.5, 155.5 (q, J = 38.0 Hz), 152.9, 132.2, 131.6, 128.8, 129.4, 129.0, 125.6, 115.4 (q, J = 286.0 Hz) 63.0, 42.9; E–isomer: 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.49–7.42 (m, 5H), 6.65 (s, 1H), 4.43 (t, 2H, J = 8.0 Hz), 4.07 (t, 2H, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 162.3, 155.7 (q, J = 38.0 Hz), 151.9, 132.0, 130.1, 129.7, 129.5, 129.1, 125.9, 115.4 (q, J = 286.0 Hz), 62.5, 42.0; HRMS (FAB) for C14H12F3N2O4: calculated (MH+): 329.0749, found (MH+): 329.0746; Elemental analysis for C14H11F3N2O4: calculated: C 51.23%, H 3.38%, F 17.36%, N 8.53% found: C 51.33%, H 3.38%, F 17.22% N 8.48%.

NH

Ph

O

N O

O

O

F3C

CHAPTER 2

52

(Z)–2,2,2–Trifluoro– N–(1–oxo–1–(2–oxooxazolidin–3–yl)pent–2–en–2–yl)–acetamide 8c: According to the general procedure for the formation of the addition substrate, to a solution of oxazolidinone (1.47 g, 16.9 mmol) in 100 mL THF was added NaH (60% in mineral oil, 387 mg, 16.2 mmol), followed by bromo–compound 7c (2.0 g, 7.3 mmol) in 30 mL THF afforded a mixture of isomers (Z/E

2:1) of compound 8c (603 mg, 2.2 mmol, 29%) as an oil. The isomers were purified and separated by column chromatography (PE/Et2O 1:1). IR (neat, cm–1) ν 3286, 1766, 1718, 1691, 1532, 1388, 1322, 1192, 1157; Z–isomer: 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 6.54 (t, 1H J = 7.6 Hz), 4.51 (t, 2H, J = 8.0 Hz), 4.09 (t, 2H, J = 8.0 Hz), 2.24 (m, 2H), 1.33 (dt, 3H, J = 7.6, 1.2 Hz); 13C NMR (100 MHz, CDCl3) δ 164.3, 155.6 (q, J = 37.8 Hz), 153.8, 142.2, 125.6, 115.5 (q, J = 286.0 Hz), 63.2, 43.2, 21.1, 12.3; E–isomer: 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 5.92 (t, 1H, J = 8.0 Hz), 4.56 (t, 2H, J = 8.0 Hz), 4.13 (t, 2H, J = 8.0 Hz), 2.62 (m, 2H), 1.09 (t, 3H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 162.7, 154.8 (q, J = 38.1 Hz), 152.7, 131.2, 125.9, 115.3 (q, J = 285.6 Hz), 62.8, 42.2, 20.8, 13.2; HRMS (FAB) for C10H12F3N2O4: calculated (MH+): 281.0749, found (MH+): 281.0747. (Z)–2,2,2–Trifluoro– N–(1–oxo–1–(2–oxooxazolidin–3–yl)hex–2–en–2–yl)–

acetamide 8d: According to the general procedure for the formation of the addition substrate, to a solution of oxazolidinone (1.40 g, 16.0 mmol) in 100 mL THF was added NaH (60% in mineral oil, 380 mg, 15.8 mmol), followed by bromo–compound 7d (2.0 g, 7.0 mmol) in 30 mL THF afforded a mixture isomers

(Z/E 3:1) of compound 8d (640 mg, 2.2 mmol, 31%) as an oil. The isomers were purified and separated by column chromatography (PE/EtOAc 2:1). IR (neat, cm–1) ν 3279, 1765, 1718, 1690, 1530, 1387, 1308, 1186, 1153; Z–isomer: 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 6.55 (dt, 1H, J = 7.6, 1.2 Hz), 4.50, (t, 2H, J, = 8.0 Hz), 4.09 (t, 2H, J = 8.0 Hz), 2.21 (q, 2H, J = 7.6 Hz), 1.55 (m, 2H), 0.99 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 164.4, 155.6 (q, J = 38 Hz), 153.7, 140.2, 126.3, 115.5 (q, J = 286.0 Hz), 63.2, 43.1, 29.4, 21.1, 13.6; E–isomer: 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 5.93 (t, 1H, J = 8.0 Hz), 4.50 (t, 2H, J = 8.0 Hz), 4.08 (t, 2H, J = 8.0 Hz), 2.20 (m, 2H), 1.48 (m, 2H), 0.95 (t, 3H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 162.7, 154.7 (q, J = 37.9 Hz), 152.7, 129.4, 126.5. 115.3 (q, J = 285.6 Hz), 62.8, 42.2, 29.0, 22.0, 13.3; HRMS (FAB) for C11H14F3N2O4: calculated (MH+): 295.0906, found (MH+): 295.0906. (Z)–2,2,2–Trifluoro– N–(4–methyl–1–oxo–1–(2–oxooxazolidin–3–yl)pent–2–en– 2–

yl)–acetamide 8e : According to the general procedure for the formation of the addition substrate, to a solution of oxazolidinone (2.4 g, 27.7 mmol) in 120 mL THF was added NaH (60% in mineral oil, 634 mg, 26.4 mmol), followed by bromo–compound 7e (3.45 g, 12.0 mmol) in 40 mL THF afforded a mixture isomers

(Z/E 2.5:1) compound 8e (2.6 g, 9.0 mmol, 75%) as a white solid after column chromatography (PE/EtOAc 2:1). The Z–isomer could be obtained by recrystallization from PE/EtOAc. IR (neat, cm–1) ν 3273, 2969, 1784, 1718, 1696, 1533, 1389, 1219, 1197, 1129; Z–isomer: mp 125–128 °C; 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 6.32 (d, 1H, J = 10.4 Hz), 4.46 (t, 2H, J = 8.1 Hz), 4.08 (t, 2H, J = 8.1 Hz), 2.62 (m, 1H), 1.11 (d, 6H, J = 6.6 Hz); 13C NMR (100 MHz, CDCl3) δ 164.6, 155.8 (q, J = 38.0 Hz), 153.6, 145.4, 124.3, 115.4 (q, J = 285.9 Hz), 63.1, 43.0, 27.0, 21.5; E–isomer: 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 5.70 (d, 1H, J = 10.6 Hz), 4.94 (t, 2H, J = 8.6 Hz), 4.08 (t,

NH

Pr

O

N O

O

O

F3C

NH

iPr

O

N O

O

O

F3C


53

2H, J = 8.6 Hz), 2.62 (m, 1H), 1.07 (d, 6H, J = 6.6 Hz); 13C NMR (100 MHz, CDCl3) δ 162.8, 155.8 (q, J = 38.0 Hz), 152.6, 134.8, 124.8, 115.4 (q, J = 292.0 Hz), 62.7, 42.2, 27.4, 22.4. General procedure for the Cinchona alkaloid catalyzed 1,4–addition. Pure Z–alkene (0.2 mmol/mL) and Cinchona alkaloid derived catalyst B (10 mol%) were dissolved in CH2Cl2. A thiol was added and the resulting mixture was stirred until all the alkene had reacted. The product was concentrated and purified by column chromatography. Preparation of the racemates: All racemic compounds were made according to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition, only Et3N was used as catalyst instead of catalyst B. 2,2,2–Trifluoro– N–(1–oxo–1–(2–oxooxazolidin–3–yl)–3–phenyl–3–(phenyl thio)–

propan–2–yl)acetamide 9: According to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition alkene 8a (26 mg, 0.08mmol), catalyst B (6 mg, 0.008 mmol) and thiophenol (9.8 μL, 0.096 mmol) in 0.4 mL CH2Cl2 gave an inseparable mixture of diastereoisomers (syn/anti 75:25) of compound 9 (35

mg, 0.077 mmol, 96%) as a white powder (ee syn = 90%, anti = 75%). (determined by HPLC Daicel chiralcel AD, i–PrOH/heptane 5:95 (1.0 mL, λ = 220 nm), tr syn–diastereoisomer 36.8 min (major) and 32.4 min (minor), tr anti–diastereoisomer 66.3 min (major) and 45.5 min (minor)). IR (neat, cm–1) ν 3324, 1777, 1729, 1699, 1390, 1214, 1165, 641; 1H NMR (400 MHz, CDCl3) δ 7.45–7.27 (m, 10.75H), 7.07 (d, 0.25H, J = 8.6 Hz), 6.33 (t, 0.25H, J = 8.5 Hz), 6.12 (dd, 0.75H, J = 8.9, 4.6 Hz), 5.08 (d, 0.75H, J = 4.6 Hz), 4.70 (d, 0.25H, J = 8.1 Hz), 4.42 (t, 0.75H, J = 7.6 Hz), 4.32 (m, 0.5H), 4.02 (m, 1H), 3.94 (m, 0.25H), 3.80 (m, 0.75H), 3.14 (m, 0.75 H); 13C NMR (100 MHz, CDCl3) δ 168.4, 167.6, 156.5 (q, J = 37.6 Hz), 152.9, 152.7, 137.0, 136.3, 133.6, 132.9, 132.7, 132.5, 129.0, 128.9, 128.7, 128.5, 128.2, 128.1, 127.8, 127.5, 115.5 (q, J = 286.0 Hz), 115.4 (q, J = 286.2 Hz), 62.6, 56.2, 55.2, 54.9, 54.5, 42.5, 42.0.

2,2,2–Trifluoro– N–((2R,3R)–1–oxo–1–(2–oxooxazolidin–3–yl)–3–phenyl–3–(phenylthio)–propan–2–yl)acetamide: According to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition alkene 8a (130 mg, 0.4mmol), catalyst D (6 mg, 0.04 mmol) and thiophenol (49 μL, 0.48 mmol) in 2 mL CH2Cl2 gave an inseparable mixture of diastereoisomers (syn/anti 95:5) of compound 9 (162

mg, 0.37 mmol, 93%) as a white powder (ee syn = –70 %, anti = 36%). (determined by HPLC Daicel chiralcel AD, i–PrOH/heptane 5:95 (1.0 mL, λ = 220 nm), tr syn–diastereoisomer 32.4 min (major) and 36.8 min (minor), tr anti–diastereoisomer 45.5 min (major) and 66.6 min (minor)). Crystallization from PE/EtOAc provided the syn–isomer as a single enantiomer. mp 170–171 °C; [α]D = –38.8 (c = 0.4, MeOH); IR (neat, cm–1) ν 3319, 1780, 1731, 1702, 1536, 1478, 1392, 1217, 1171;1H NMR (500 MHz, CDCl3) δ 7.44 (m, 4H), 7.38–7.29 (m, 7H), 6.12 (dd, 1H, J = 9.0, 4.5 Hz), 5.10 (d, 1H, J = 4.5 Hz), 4.33 (m, 1H), 4.02 (q, 1H, J = 8.5 Hz), 3.81 (q, 1H, J = 9.0 Hz), 3.15 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 167.7, 156.6 (q, J = 37.5 Hz), 152.7, 137.0, 133.7, 133.9, 129.1, 128.7, 128.3, 127.8, 127.8, 115.5 (q, J = 286.3 Hz), 62.6, 56.3, 55.2, 42.2.

CHAPTER 2

54

N–(1–(Ethylthio)–3–oxo–3–(2–oxooxazolidin–3–yl)–1–ph enylpropan–2–yl)–2,2,2–tri–fluoroacetamide 10 : According to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition alkene 8a (26 mg, 0.08mmol), catalyst B (6 mg, 0.008 mmol) and ethanethiol (18 μL, 0.24 mmol) in 0.4 mL CH2Cl2 gave an inseparable mixture of diastereoisomers (syn/anti 47:53) of compound 10 (30 mg, 0.077

mmol, 96%) as a white powder (ee syn = 52 %, anti = 94%). (determined by HPLC Daicel chiralcel ADH, i–PrOH/heptane 8:92 (1.0 mL, λ = 220 nm), tr syn–diastereoisomer 27.6 min (major) and 37.9 min (minor), tr anti–diastereoisomer 34.5 min (major) and 29.2 min (minor)) IR (neat, cm–1) ν 3322, 1777, 1727, 1695, 1601, 1478, 1209, 1153, 699; 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 1H), 7.93–7.23 (m, 4 H), 7.24 (d, 0.53H, J = 6.8 Hz), 6.92 (d, 0.47H, J = 8.4 Hz), 6.35 (t, 0.53H, J = 7.2 Hz) 6.09 (t, 0.47H, J = 6.8 Hz), 4.58–4.52 (m, 1.53H), 4.48–4.42 (m, 0.47H), 4.38 (d, 0.53H, J = 7.2 Hz), 4.31 (q, 0.47H, J = 12.8 Hz), 4.13–3.95 (m, 1.53H), 3.88–3.81 (m, 0.47H), 2.95–2.52 (m, 1.06H), 2.39 (q, 0.94H, J = 7.6 Hz), 1.20 (t, 1.59H, J = 7.6 Hz), 1.17 (t, 1.41H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 168.8, 168.6, 156.6 (q, J = 38 Hz) 156.5 (q, J = 38 Hz), 153.0, 152.9, 136.7, 136.6, 129.6, 129.4, 129.2, 128.9, 128.7, 128.4, 128.3, 128.2, 128.1, 115.6, (q, J = 287 Hz), 62.7, 62.6, 55.7, 54.1, 51.1, 50.9, 42.6, 42.5, 25.9, 25.6, 14.1; HRMS (FAB) for C16H18F3N2O4S: calculated (MH+): 391.0939, found (MH+): 391.0937. N–(1–(Allylthio)–3–oxo–3–(2–oxooxazolidin–3–yl)–1–ph enylpropan–2–yl)–2,2,2–

tri–fluoroacetamide 11: According to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition alkene 8a (26 mg, 0.08mmol), catalyst B (6 mg, 0.008 mmol) and 2–propene–1–thiol (20 μL, 0.24 mmol) in 0.4 mL CH2Cl2 gave an inseparable mixture of diastereoisomers (syn/anti 48:52) of compound 11 (31 mg,

0.078 mmol, 97%) as a white powder (ee syn = 25%, anti = 86%). (determined by HPLC Daicel chiralcel AD, i–PrOH/heptane 3:97 (0–60 min) then 10:90 (60–90 min) (1.0 mL, λ = 220 nm), tr syn–diastereoisomer 39.1 min (major) and 53.0 min (minor), tr anti–diastereoisomer 80.9 min (major) and 42.3 min (minor)) IR (neat, cm–1) ν 3325 1777, 1728, 1695, 1536, 1478, 1268, 1209, 701; 1H NMR (400 MHz, CDCl3) δ 7.46–7.28 (m, 5H), 7.22 (d, 0.48H, J = 9.6 Hz), 6.97 (d, 0.52H, J = 8.4 Hz), 6.36 (t, 0.52H, J = 7.6 Hz), 6.12 (t, 0.48H, J = 6.4 Hz), 5.78–5.68 (m, 1H), 5.13 (d, 1.04H, J = 10.4 Hz), 5.10 (d, 0.48H, J = 18.4 Hz), 4.96 (d, 0.48H, J = 16.8 Hz), 4.52–4.41 (m, 2H), 4.30–4.26 (m, 1H), 4.12–3.96 (m, 1.52H), 3.84–3.80 (m, 0.48H), 3.21–3.17 (m, 0.52H), 3.09–2.99 (m, 1H), 2.92–2.86 (m, 0.48H); 13C NMR (100 MHz, CDCl3) δ 168.7, 168.5, 156.6 (q, J = 38 Hz) 156.5 (q, J = 38 Hz), 152.9, 152.7, 136.5, 136.4, 133.2, 133.0, 128.9, 128.7, 128.6, 128.4, 128.3, 128.0, 118.5, 118.3, 115.6, (q, J = 287 Hz), 62.7, 62.6, 55.7, 55.4, 54.1, 50.2, 49.8, 42.6, 42.5, 34.4, 34.0; HRMS (FAB) for C17H18F3N2O4S: calculated (MH+): 403.0939, found (MH+): 403.0945. N–(1–(Benzylthio)–3–oxo–3–(2–oxooxazolidin–3–yl)–1–p henylpropan–2–yl)–

2,2,2–tri–fluoroacetamide 12: According to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition alkene 8a (26 mg, 0.08mmol), catalyst B (6 mg, 0.008 mmol) and phenylmethanethiol (28 μL, 0.24 mmol) in 0.4 mL CH2Cl2

gave an inseparable mixture of diastereoisomers (syn/anti 47:53) of compound 12 (33 mg, 0.074 mmol, 93%) as a white powder (ee syn = 47%, anti = 94%). (determined by HPLC Daicel chiralcel AD, i–PrOH/heptane 10:90 (1.0 mL, λ = 220 nm), tr syn–diastereoisomer 27.4 min (major) and 18.7 min (minor), tr anti–

NH

*

*Ph

O

N O

O

SEtO

F3C

NH

*

*Ph

O

N O

O

SallylO

F3C


55

diastereoisomer 92.3 min (major) and 22.1 min (minor),) IR (neat, cm–1) ν 3317, 2962, 2924, 1778, 1727, 1699, 1478, 1210, 1161, 699; 1H NMR (400 MHz, CDCl3) δ 7.51 (dd, 1H, J = 6.8, 0.8 Hz), 7.42–7.24 (m, 9H), 7.01 (d, 0.47H, J = 6.8 Hz), 6.94 (d, 0.53H J = 8.8 Hz), 6.34 (t, 0.53H, J = 8.4 Hz), 6.03 (dd, 0.47H, J = 8.4, 5.6 Hz), 4.47 (t, 1.06H, J = 8.0 Hz), 4.35 (m, 0.47H), 4.29 (d, 0.53H, J = 4.4 Hz), 4.24 (d, 0.53H, J = 3.2 Hz), 4.15 (m, 0.94H), 3.97 (m, 0.94H), 3.78 (d, 0.53H, J = 12.8 Hz), 3.68–3.60 (m, 1.53H), 3.40 (d, 0.47H, J = 13.6 Hz); 13C NMR (100 MHz, CDCl3) δ 167.6, 167.2, (q, J = 38 Hz), 156.5 (q, J = 38 Hz), 151.9, 151.4, 136.4, 135.8, 135.5, 135.2, 128.9, 128.7, 128.6, 128.5, 128.3, 128.0, 127.9, 127.7, 127.5, 127.4, 127.2, 127.0, 119.4, 119.3, 115.6, (q, J = 287 Hz), 61.6, 61.4, 55.2, 53.1, 49.8, 48.7, 41.6, 41.3, 35.0, 34.1; HRMS (FAB) for C21H20F3N2O4S: calculated (MH+): 453.1096, found (MH+): 453.1101. 2,2,2–Trifluoro– N–(1–((4–methoxybenzyl)thio)–3–oxo–3–(2–oxooxazolidi n–3–yl)–

1–phenylpropan–2–yl)acetamide 13: According to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition alkene 8a (885 mg, 2.69 mmol), catalyst B (207 mg, 0.27 mmol) and 4–MeO–phenylmethanethiol (1.12 mL, 8.07 mmol) in 13 mL CH2Cl2 gave an inseparable mixture of diastereoisomers (syn/anti 33:67) compound 13 (1.24 g, 2.58 mmol, 96%) as a white powder (ee syn = 46%, anti = 95%). (determined by HPLC Daicel chiralcel AD, i–

PrOH/heptane 15:85 (0–40 min) then 30:70 (40–120 min) (1.0 mL, λ = 220 nm), tr syn–diastereoisomer 14.9 min (major) and 29.5 min (minor), tr anti–diastereoisomer 110.8 min (major) and 21.5 min (minor)) IR (neat, cm–1) ν 3319, 1779, 1728, 1698, 1537, 1214, 1173, 702; 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, 1H, J = 8.4, 1.6 Hz), 7.41–7.32 (m, 3H), 7.28–7.26 (m, 1H), 7.16 (dd, 1.33H, J = 6.4, 2.0 Hz), 7.10 (dd, 0.67H, J = 6.4, 2.0 Hz), 7.00 (d, 1H, J = 9.6 Hz), 6.87 (dd, 0.67H, J = 6.4, 2.0 Hz), 6.84 (dd, 1.33H, J = 6.4, 2.0 Hz), 6.33 (t, 0.67H, J = 7.6 Hz), 6.02 (dd, 0.33H, J = 8.4, 5.2 Hz), 4.46 (t, 1.33H, J = 8.0 Hz), 4.36 (m, 0.33H), 4.29 (d, 0.33H, J = 5.2 Hz), 4.23 (d, 0.67H, J = 7.6 Hz), 4.15 (m, 0.67H), 4.06 (m, 0.67H), 3.98–3.92 (m, 1.33H), 3.83 (s, 1H), 3.83 (s, 2H), 3.73 (d, 0.67H, J = 12.8 Hz), 3.65–3.60 (m, 0.67H), 3.34 (d, 0.33H, J = 13.6 Hz); 13C NMR (100 MHz, CDCl3) δ 168.6, 168.2, 158.9, 158.8, 156.6 (q, J = 38 Hz), 156.5 (q, J = 38 Hz), 152.9, 152.5, 136.8, 136.3, 130.2, 130.1, 129.3, 129.1, 128.9, 128.7, 128.7, 128.6, 128.5, 128.4, 128.3, 121.6, 115.5 (q, J = 286 Hz), 113.9, 62.6, 62.4, 56.4, 55.3, 54.1, 50.7, 49.4, 42.6, 42.5, 35.4, 34.6; HRMS (FAB) for C22H22F3N2O5S: calculated (MH+): 483.1202, found (MH+): 483.1207. Recrystallization of the crude product (EtOAc/PE) gave the minor syn–isomer as a racemate (120 mg, 0.25 mmol, 9%). The mother liquor was concentrated and further recrystallized (EtOAc/PE) to give the anti–isomer as a pure enantiomer (503 mg, 1.04 mmol, 39%). mp 142–144 °C; [α]D = –203.4 (c = 0.42, MeOH); 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 3H), 7.28 (m, 2H), 7.16 (d, 1H, J = 8.4 Hz), 6.98 (d, 1H, J = 8.8 Hz), 6.83 (d, 1H, J = 8.8 Hz), 6.32 (t, 1H, J = 8.4 Hz), 4.48 (t, 2H, J =8.0 Hz), 4.23 (d, 1H, J = 7.2 Hz), 4.07–4.01 (m, 1H), 3.99–3.94 (m, 1H), 3.81 (s, 3H), 3.74 (d, 1H, J = 8.8 Hz), 3.63 (d, 1H, J = 8.8 Hz); 13C NMR (100 MHz, CDCl3) δ168.6, 158.8, 156.5 (q, J = 38 Hz), 152.8, 136.8, 136.3, 130.2, 129.3, 128.7, 128.6, 128.4, 115.5 (q, J = 286 Hz), 113.9, 62.4, 55.2, 54.1, 50.7, 42.5, 35.4.

NH

*

*Ph

O

N O

O

SO

F3C

OMe

CHAPTER 2

56

N–(3–(Allylthio)–1–oxo–1–(2–oxooxazolidin–3–yl)penta n–2–yl)–2,2,2–trifluoro–acetamide 14: According to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition alkene 8c (22 mg, 0.08 mmol), catalyst B (6 mg, 0.008 mmol) and 2–propene–1–thiol (20 μL, 0.24 mmol) in 0.4 mL CH2Cl2 gave an inseparable mixture of diastereoisomers (syn/anti 58:42) of compound 14 (26

mg, 0.075 mmol, 94%) as a white powder (ee syn = 57%, anti = 80%). (determined by HPLC Daicel chiralcel ODH, i–PrOH/heptane 7:93 (1.0 mL, λ = 220 nm), tr syn–diastereoisomer 33.2 min (major) and 60.9 min (minor), tr anti–diastereoisomer 47.2 min (major) and 70.3 min (minor)) IR (neat, cm–1) ν 3330, 2970, 2922, 1777, 1727, 1697, 1530, 1389, 1207, 1157; 1H NMR (400 MHz, CDCl3) δ 7.30 (d, 0.58H, J = 8.8 Hz), 7.06 (d, 0.42H, J = 8.4 Hz), 6.07 (dd, 0.42H, J = 8.4, 6.0 Hz), 5.85 (dd, 0.58H), J = 9.2, 6.4 Hz), 5.82–5.70 (m, 1H), 5.21 (dd, 0.42H, J = 8.8, 1.2 Hz), 5.11 (dd, 1H, J = 10, 1.6 Hz), 5.03 (dd, 0.58H, J = 17.2, 1.6 Hz), 4.57–4.49 (m, 2H), 4.17 (m, 1H), 3.99 (m, 1H), 3.32 (dd, 0.42H, J = 13.6, 7.2 Hz), 3.21 (dd, 0.42H J = 13.2, 6.4 Hz), 3.14 (m, 1H), 3.05 (m, 1.16H), 1.18 (m, 0.84H), 1.16 (m, 1.16H), 1.10 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 169.3, 169.2, 156.6 (q, J = 38 Hz), 156.5 (q, J = 38 Hz), 152.8, 134.3, 134.0, 117.8, 117.6, 115.5 (q, J = 286 Hz), 62.8, 62.7, 54.8, 54.4, 53.7, 53.5, 48.0, 47.9, 34.8, 34.4, 27.4, 26.1, 22.7, 22.1, 11.7, 11.6; HRMS (FAB) for C13H17F3N2O4S: calculated (MH+): 355.0939, found (MH+): 355.0938. 2,2,2–Trifluoro– N–(1–oxo–1–(2–oxooxazolidin–3–yl)–3–(phenylthio)pent an–2–

yl)–acetamide 15: According to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition alkene 8c (22 mg, 0.08 mmol), catalyst B (6 mg, 0.008 mmol) and thiophenol (9.8 μL, 0.096 mmol) in 0.4 mL CH2Cl2 gave an inseparable mixture of diastereoisomers (syn/anti 80:20) of compound 15 (25 mg, 0.074 mmol, 92%) as a white powder (ee syn = 87%, anti = 51%).

(determined by HPLC Daicel chiralcel ADH, i–PrOH/heptane 2:98 (1.0 mL, λ = 220 nm), tr syn–diastereoisomer 50.6 min (major) and 47.7 min (major), tr anti–diastereoisomer 110.5 min (major) and 100.5 min (minor)) IR (neat, cm–1) ν 3408, 2971, 2878, 1778, 1728, 1701, 1583, 1440, 1161; 1H NMR (400 MHz, CDCl3) δ 7.50–7.44 (m, 2H), 7.35–7.28 (m, 4H), 5.90–5.83 (m, 1H), 4.45–4.35 (m, 0.4H), 4.31–4.25 (m, 0.8H), 3.97–3.90 (m, 1H), 3.80–3.75 (m, 0.8H), 3.73–3.67 (m, 0.8H), 3.59–3.56 (m, 0.2H), 2.90–2.83 (m, 1H), 1.88–1.78 (m, 0.4H), 1.76–1.63 (m, 1.6H), 1.27 (t, 2.4H, J = 7.2Hz), 1.18 (t, 0.6H, J = 7.2Hz); 13C NMR (100 MHz, CDCl3) δ 168.8, 168.1, 156.6 (q, J = 38 Hz), 156.5 (q, J = 38 Hz), 152.8, 152.7, 134.5, 133.4, 132.3, 129.3, 129.1, 129.0, 128.0, 127.7, 115.5 (q, J = 286 Hz), 62.7, 62.6, 55.2, 55.1, 54.6, 52.3, 42.6, 42.0, 26.4, 23.8, 12.0, 11.5. N–(3–(Benzylthio)–1–oxo–1–(2–oxooxazolidin–3–yl)pent an–2–yl)–2,2,2–trifluoro–

acetamide 16: According to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition alkene 8c (22 mg, 0.08 mmol), catalyst B (6 mg, 0.008 mmol) and phenylmethanethiol (28 μL, 0.24 mmol) in 0.4 mL CH2Cl2 gave an inseparable mixture of diastereoisomers (syn/anti 52:48) of compound 16 (31

mg, 0.076 mmol, 95%) as a white powder (ee syn = 71%, anti = 90%). (determined by HPLC Daicel chiralcel ADH, i–PrOH/heptane 3:97 (1.0 mL, λ = 220 nm), tr syn–diastereoisomer 55.5 min (major) and 51.5 min (minor), tr anti–diastereoisomer 112.2 min (major) and 63.4 min (minor)) IR (neat, cm–1) ν 3327, 2932, 2878, 1778, 1725, 1696, 1539, 1391, 1201, 1163; 1H NMR (400 MHz, CDCl3) δ 7.30–7.12 (m, 5.52H), 6.95 (d,


57

0.48H, J = 8.6 Hz), 6.00 (dd, 0.48H, J = 8.6, 5.8 Hz), 5.70 (dd, 0.52H, J = 9.0, 2.2 Hz), 4.43 (t, 0.96H, J = 16.2 Hz), 4.35 (m, 0.52H), 4.12 (m, 0.52H), 4.02 (m, 1H), 3.87 (s 0.96H), 3.63 (m, 2.04H), 3.09 (m, 1H), 1.82 (m, 0.52H), 1.65 (m, 1H), 1.36 (m, 0.48H), 1.08 (t, 1.56H, J = 7.4 Hz), 0.99 (t, 1.44H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 169.2, 169.0, 157 (q, J = 37.0 Hz), 137.9, 137.7, 129.8, 129.1, 128.6, 127.3, 115.7 (q, J = 287.0 Hz), 115.3 (q, J = 287.0 Hz), 62.6, 62.6, 54.9, 54.0, 48.6, 48.1, 42.6, 42.4, 36.0, 35.8, 27.8, 23.0, 11.7, 11.6; HRMS (ESI) for C17H19F3N2O4SNa: calculated (MNa+): 427.0910, found (MNa+): 427.0905. 2,2,2–Trifluoro– N–(3–((4–methoxybenzyl)thio)–1–oxo–1–(2–oxooxazolidi n–3–

yl)pentan–2–yl)acetamide 17: According to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition alkene 8c (22 mg, 0.08 mmol), catalyst B (6 mg, 0.008 mmol) and 4–MeO–phenylmethanethiol (34 μL, 0.24 mmol) in 0.4 mL CH2Cl2 gave an inseparable mixture of diastereoisomers (syn/anti 53:47) of compound 17 (31 mg, 0.073 mmol, 91%) as a white powder (ee syn = 58%, anti = 80%). (determined by HPLC Daicel chiralcel ADH, i–

PrOH/heptane 8:92 (1.0 mL, λ = 220 nm), tr syn–diastereoisomer 28.7 min (major) and 23.4 min (minor), tr anti–diastereoisomer 71.4 min (major) and 32.5 min (minor)) IR (neat, cm–1) ν 3329, 2968, 2928, 1778, 1728, 1699, 1511, 1211, 1173, 1070; 1H NMR (400 MHz, CDCl3) δ 7.26 (d, 1H, J = 8.8 Hz), 7.18 (d, 0.53H, J = 8.0 Hz), 7.16 (d, 1H, J = 8.8 Hz), 7.06 (d, 0.47H, J = 8.0 Hz), 6.87 (d, 1.06H, J = 8.8 Hz), 6.84 (d, 0.94H, J = 8.8 Hz), 6.08 (dd, 0.47H, J = 8.8, 6.0 Hz), 5.77 (dd, 0.53H, J = 9.2, 2.4 Hz), 4.50 (t, 0.94, J = 8.0 Hz), 4.44–4.39 (m, 0.53H), 4.30 (q, 0.53H, J = 7.2 Hz), 4.14–4.09 (m, 0.47H), 4.08–3.93 (m, 1.06H), 3.82 (s, 1.59H), 3.80 (s, 1.41H), 3.68–3.57 (m, 2.47H), 3.09–3.01 (m, 1H), 1.86–1.79 (m, 0.94H), 1.74–1.63 (m, 1.06H), 1.11 (t, 1.59H, J = 7.2 Hz), 0.99 (t, 1.41H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 169.2, 168.9, 158.8, 158.7, 156.6 (q, J = 38 Hz), 156.5 (q, J = 38 Hz), 152.9, 152.5, 130.2, 130.2, 129.8, 129.5, 115.5 (q, J = 286 Hz), 114.2, 62.6, 62.5, 55.3, 55.2, 55.0, 54.0, 48.4, 47.7, 42.6, 42.5, 35.4, 35.2, 27.9, 23.05, 11.8, 11.6; HRMS (FAB) for C18H22F3N2O5S: calculated (MH+): 435.1202, found (MH+): 435,1201. 2,2,2–Trifluoro– N–(1–oxo–1–(2–oxooxazolidin–3–yl)–3–(phenylthio)hexa n–2–yl)–

acetamide 18: According to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition alkene 8d (24 mg, 0.08 mmol), catalyst B (6 mg, 0.008 mmol) and thiophenol (9.8 μL, 0.096 mmol) in 0.4 mL CH2Cl2 gave an inseparable mixture of diastereoisomers (syn/anti 80:20) of compound 18 (30 mg, 0.073

mmol, 91%) as a white powder (ee syn = 80%, anti = 65%). (determined by HPLC Daicel chiralcel ADH, i–PrOH/heptane 2:98 (1.0 mL, λ = 220 nm), tr syn–diastereoisomer 25.9 min (major) and 28.1 min (minor), tr anti–diastereoisomer 56.5 min (major) and 49.2 min (minor)) IR (neat, cm–1) ν 3407, 2962, 2932, 1778, 1729, 1702, 1573, 1440, 1208, 1163; 1H NMR (400 MHz, CDCl3) δ 7.46 (m, 2H), 7.34 (m, 4H), 5.84 (d, 0.8H, J = 9.2 Hz), 5.80 (t, 0.2H, J = 7.6 Hz), 4.42 (m, 0.4H), 4.29 (m, 0.8H), 3.94 (m, 2H), 3.71 (m, 1H), 2.84 (m, 0.8H), 1.81–1.62 (m, 4H), 1.03 (t, 2.4H, J = 6.4 Hz), 0.94 (t, 0.6H, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 168.7, 168.0, 156.6 (q, J = 38 Hz), 156.5 (q, J = 38 Hz), 152.8, 152.6, 134.6, 133.2, 133.1, 129.3, 129.1, 129.0, 127.7, 115.5 (q, J = 286 Hz), 62.7, 62.6, 55.6, 55.3, 52.4, 50.2, 42.6, 42.0, 35.0, 32.5, 20.3, 20.1, 13.7; HRMS (FAB) for C18H20F3N2O4S: calculated (MH+): 405.1096, found (MH+): 405.1101.

NH

*

*Pr

O

N O

O

SPhO

F3C

NH

*

*Et

O

N O

O

SO

F3C

OMe

CHAPTER 2

58

N–(3–(Benzylthio)–1–oxo–1–(2–oxooxazolidin–3–yl)hexa n–2–yl)–2,2,2–trifluoro–

acetamide 19: According to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition alkene 8d (24 mg, 0.08 mmol), catalyst B (6 mg, 0.008 mmol) and phenylmethanethiol (28 μL, 0.24 mmol) in 0.4 mL CH2Cl2 gave an inseparable mixture of diastereoisomers (syn/anti 55:45) of compound 19 (32 mg,

0.076 mmol, 95%) as a white powder (ee syn = 44%, anti = 72%). (determined by HPLC Daicel chiralcel ADH, i–PrOH/heptane 2:98 (1.0 mL, λ = 220 nm), tr syn–diastereoisomer 40.5 min (major/minor) and 37.6 min (minor), tr anti–diastereoisomer 89.6 min (major) and 42.5 min (minor)) IR (neat, cm–1) ν 3326, 2962, 2933, 1778, 1727, 1698, 1390, 1209, 1163, 758; 1H NMR (400 MHz, CDCl3) δ 7.37–7.25 (m, 5.55H), 7.03 (d, 0.45H J = 7.6 Hz), 6.09 (dd, 0.45H, J = 8.4, 5.2 Hz), 5.77 (dd, 0.55H, J = 8.8, 2.0 Hz), 4.15 (m, 0.9H), 4.42 (m, 0.55H), 4.32 (q, 0.55H, J = 6.4 Hz), 4.11 (m, 0.45H), 3.99 (m, 1.1H), 3.62 (m, 2.45H), 3.14 (m, 1H), 1.82–1.42 (m, 4H), 0.91 (t, 1.65H, J = 7.2 Hz), 0.83 (t, 1.35H, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 169.1, 169.0, 156.6 (q, J = 38 Hz), 156.5 (q, J = 38 Hz), 152.9, 152.6, 137.9, 137.7, 129.3, 129.1, 128.9, 128.6, 128.5, 127.3, 127.2, 115.5 (q, J = 286 Hz), 62.8, 62.7, 55.1, 53.5, 46.5, 46.2, 42.6, 42.4, 36.6, 36.0, 35.7, 31.7, 20.1, 13.7; HRMS (FAB) for C18H22F3N2O4S: calculated (MH+): 419.1252, found (MH+): 419.1255. 2,2,2–Trifluoro– N–(3–((4–methoxybenzyl)thio)–4–methyl–1–oxo–1–(2–oxo –

oxazolidin–3–yl)pentan–2–yl)acetamide 20: According to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition alkene 8e (24 mg, 0.08 mmol), catalyst A (5 mg, 0.008 mmol) and 4–MeO–phenylmethanethiol (34 μL, 0.24 mmol) in 0.4 mL CH2Cl2

gave an inseparable mixture of diastereoisomers (syn/anti 75:25) of compound 20 (32 mg, 0.072 mmol, 90%) as a white powder (ee syn = 37%, anti = 56%). (determined by HPLC Daicel chiralcel ODH, i–PrOH/heptane 5:95 (0.5 mL,

λ = 220 nm), tr syn–diastereoisomer 18.0 min (major) and 15.3 min (minor), tr anti–diastereoisomer 13.0 min (major) and 14.1 min (minor)) IR (neat, cm–1) ν 3332, 2965, 2933, 1781, 1727, 1701, 1512, 1390, 1216, 1173; 1H NMR (400 MHz, CDCl3) δ 7.20 (m, 1H), 7.16 (d, 1.5H, J = 8.6 Hz), 7.00 (d, 0.25H, J = 8.6 Hz), 6.89 (m, 2H), 6.20 (t, 0.25H, J = 9.0 Hz), 5.78 (dd, 0.75H, J = 9.2, 1.8 Hz), 4.52–4.42 (m, 1.25H), 4.34 (m, 0.75H), 4.13 (m, 0.25H), 4.08 (m, 1H), 3.83 (s, 2.25H), 3.82 (s, 0.75H), 3.68 (m, 0.75H) 3.63 (s, 0.5H), 3.61 (s, 1.5H), 2.96 (dd, 0.75H, J = 6.7, 1.8 Hz), 2.85 (dd, 0.25H, J = 9.6, 6.7 Hz), 2.02 (m, 0.75H), 1.92 (m, 0.25H) 1.10 (d, 2.25H, J = 6.7 Hz), 1.07 (d, 2.25H, J = 6.7 Hz), 0.96 (d, 0.75H, J = 6.6 Hz), 0.86 (d, 0.75H, J = 6.6 Hz); 13C NMR (100 MHz, CDCl3) δ 170.1, 169.3, 158.9, 158.8, 156.5 (q, J = 38.0 Hz), 152.9, 152.7, 130.3, 130.3, 129.6, 129.4, 115.6 (q, J = 286.0 Hz), 113.9, 113.9, 62.6, 62.2, 55.3, 55.3, 54.5, 53.7, 52.8, 51.9, 43.3, 42.6, 37.4, 36.5, 33.6, 28.8, 21.4, 21.0, 20.8, 19.6.


59

(2S,3R)–2–((((9H–Fluoren–9–yl)methoxy)carbonyl)amino)–3–((4–methoxy –benzyl)–thio)–3–phenylpropanoic–acid 21: Enantiomerically pure compound 13 (220 mg, 0.45 mmol) was dissolved in 10 mL of HCl (0.33M) in MeOH and refluxed overnight. The solvent was removed and the crude was dissolved in a 1:2 mixture of 2 M KOH and MeOH (6 mL total volume) and stirred for 2 h. The resulting mixture was neutralized with 2 M HCl and the methanol was removed by evaporation. Ammonium bicarbonate (355 mg, 4.5 mmol) and a solution of Fmoc–OSu (152 mg, 0.45 mmol) in MeCN (4 mL) were added

and the resulting mixture was stirred for 4 h. The mixture was acidified with 2 M HCl until pH 2. The mixture was extracted 3 times with EtOAc and the organic layers were combined, washed with brine and dried with MgSO4. The solvents were evaporated and the product was purified by column chromatography (PE/EtOAc/AcOH 3:2:0.1) yielding 21 (165 mg, 0.31 mmol, 68%) as a white solid. mp 60–62 °C; [α]D = –72.1 (c = 0.37, MeOH); IR (neat, cm–1) ν 3063, 3032, 2953, 1710, 1511, 1478, 1247, 1214, 1175, 701; 1H NMR (400 MHz, CDCl3): δ 7.80 (d, 2H, J = 4.4 Hz), 7.58 (t, 2H, J = 8.0 Hz), 7.49–7.31 (m, 9H), 7.18 (d, 2H, J = 5.5 Hz), 6.82 (d, 2H, J = 8.4 Hz), 5.27 (d, 1H, J = 9.2 Hz), 4.94 (m, 1H), 4.44 (d, 1H, J = 6.8 Hz), 4.35 (t, 1H, J = 7.2 Hz), 4.26 (m, 2H), 3.79 (s, 3H), 3.68 (d, 1H, J = 13.2 Hz), 3.56 (d, 1H, J = 13.2 Hz); 13C NMR (100 MHz, CDCl3): δ 174.1, 158.6, 143.7, 141.2, 136.4, 132.5, 130.5, 130.1, 129.7, 129.0, 128.7, 128.6, 128.2, 127.7, 127.1, 125.2, 125.1, 124.9, 119.9, 113.9, 67.4, 57.4, 55.2, 50.5, 47.0, 35.2; HRMS (FAB) for C32H30NO5S: calculated (MH+): 540.1839, found (MH+): 540.1877. (2S,3R)–2–((((9H–Fluoren–9–yl)methoxy)carbonyl)amino)–3–mercapto–3– phenyl

–propanoic acid 22: Fmoc–protected amino acid 21 (50 mg, 0.09 mmol) was dissolved in 1 mL of a 9:1 mixture of TFA and dichloromethane and 0.1 mL of i–Pr3SiH was added. The resulting mixture was stirred at 50 °C for 1 h. The solvent was removed and the product was purified with column chromatography (PE/EtOAc/AcOH, 3:2:0.1) yielding free thiol 22 (36 mg, 0.086 mmol,

95%) as a white solid. mp 66–68 °C; [α]D = –46.8 (c = 0.37, CH2Cl2); IR (neat, cm–1) ν 3311, 3064, 1716, 1515, 1477, 1249, 1225, 740; 1H NMR (400 MHz, CDCl3) δ 8.90 (br, 1H), 7.78 (d, 2H, J = 7.4 Hz), 7.56 (m, 2H), 7.44–7.28 (m, 9H), 5.41 (d, 1H, J = 8.9 Hz), 4.95 (t, 1H, J = 7.9 Hz), 4.60 (m, 1H), 4.49 (m, 1H), 4.34 (t, 1H, J = 9.8 Hz), 4.21 (t, 1H, J = 6.6 Hz), 2.27 (d, 1H, J = 6.2 Hz); 13C NMR (100 MHz, CDCl3) δ 173.9, 156.1, 143.5, 141.3, 138.1, 128.7, 128.3, 127.8, 127.0, 125.1, 124.9, 120.0, 67.3, 60.4, 47.0, 45.0.

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Table 3. Crystal structure and structure refinements for 9 and 13.

Compound number 9 13

Crystal color colorless cubes colorless platelet Crystal size 0.22 x 0.20 x 0.18 mm 0.27 x 0.22 x 0.06 mm

Empirical formula C20H17F3N2O4S C22H21F3N2O5S Formula weight 438.42 482.27 Temperature 208 K 208 K

Radiation / wavelength MoKα (graphite mon.) / 0.71073 Å MoKα (graphite mon.) / 0.71073 Å Crystal system, space group Orthorhombic, P212121 Orthorhombic, P212121

Unit cell dimension a 8.6285(14) Å 10.0062 (7) Å

b 12.441(4) Å 11.8687 (4) Å c 18.309(3) Å 18.6029 (12) Å α 90° 90°

β 90° 90° γ 90° 90°

Volume 1965.3(7) Å3 2209.3(2) Å3

Z / calc. denisity 4 / 1.482 Mg/m3 4 / 1.451 Mg/m3

Diffractometer / scan Nonius KappaCCD with area detector π and ω scan

Nonius KappaCCD with area detector π and ω scan

Θ range 2.22 to 27.52° 2.04 to 27.50° Index ranges –11<=h<=11 –12<=h<=12 –16<=k<=16 –15<=k<=15

–23<=l<=23 –24<=l<=24 Reflections collected 105534 66682 Reflections observed 4079 4371

Refinement method Full–matrix least–squares on F2 Full–matrix least–squares on F2

Computing SHELXL–97 (Sheldrick, 1997) SHELXL–97 (Sheldrick, 1997) R indices (all data) R1 = 0.0618, wR2 = 0.1410 R1 = 0.0806, wR2 = 0.1998

Largest diff. peak and hole 0.55 and –0.34 eA–3 1.334 and –0.562 eA–3

2.10 References

1) a) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743 b) Dondoni, A.; Massi, A. Angew. Chem. Int. Ed. 2008, 47, 4638–4660 c) Yu, X. H.; Wang, W. Chem. Asian J. 2008, 3, 516–532 d) Connon, S. J. Chem. Commun. 2008, 2499–2510 e) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178–2189 f) Marcelli, T.; Hiemstra, H. Synthesis 2010, 1229–1279.

2) Enders, D.; Luettgen, K.; Narine, A. A. Synthesis 2007, 959–980. 3) Fraústo da Silva, J. R.; Williams, R. J. P. The biological Chemistry of Elements; Oxford University

Press: New York, 2001. 4) a) Helder R.; Arends, R.; Bolt, W.; Hiemstra, H.; Wynberg, H. Tetrahedron Lett. 1977, 18, 2181–

2182 b) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417–430. 5) a) Liu, Y.; Sun, B. F.; Wang, B. M.; Wakem, M.; Deng, L. J. Am. Chem. Soc. 2009, 131, 418–419

b) Rana, N. K.; Selvakumar, S.; Singh, V. K. J. Org. Chem. 2010, 75, 2089–2091 c) Tian, X.; Cassani, C.; Liu, Y.; Moran, A.; Urakawa, A.; Galzerano, P.; Arceo, E.; Melchiorre, P. J. Am. Chem. Soc. 2011, 133, 17934–17941 d) Dai, L.; Yang, H.; Chen, F. Eur. J. Org. Chem. 2011, 5071–5076 e) Pei, Q.–L.: Sun, H.–W.; Wu, Z.–J.: Du, X.–L.; Zhang, X.–M.; Yuan, W.–C. J. Org. Chem. 2011, 76, 7849–7859 f) Rana, N. K.; Singh, V. K. Org. Lett. 2011, 13, 6520–6523 g) Palacio, C.; Connon, S. J. Chem. Commun. 2012, 48, 2849–2851 h) Geng, Z.–C.; Li, N.; Chen, J. Huang, X.–F.; Wu, B.; Liu, G.–G; Wang, X.–W. Chem. Commun. 2012, 48, 4713–4715.

6) Marcelli, T.; van der Haas, R. N. S.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem. Int. Ed. 2006, 45, 929–931.

7) a) Templeton, G. E. Microb. Toxins 1972, 8, 160–192 b) Rich, D. H.; Bhatnagar, P.; Mathiaparanam, P.; Grant, J. A.; Tam, J. P. J. Org. Chem. 1978, 43, 296–302 c) Botes, D. P.;


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Tuinman, A. A.; Wessels, P. L.; Viljoen, C. C.; Kruger, H.; Williams, D. H.; Santikarn, S.; Smith, R. J.; Hammond, S. J. J. Chem. Soc., Perkin Trans. 1 1984, 2311–2318 d) Valentekovich, R. J.; Schreiber, S. L. J. Am. Chem. Soc. 1995, 117, 9069–9070.

8) Mackay, M. F.; Van Donkelaar, A.; Culvenor, C. C. J. J. Chem. Soc., Chem. Commun. 1986, 1219–1221.

9) a) Pracejus, H.; Wilke, F.–W.; Hanneman, K. J. Prakt. Chem. 1977, 319, 219–229 b) Leow, D.; Lin, S. S.; Chittimalla, S. K.; Fu, X.; Tan, C. H. Angew. Chem. Int. Ed. 2008, 47, 5641–5645.

10) Jousseaume, T.; Wurz, N. E.; Glorius, F. Angew. Chem. Int. Ed. 2011, 50, 1410–1414. 11) Duan, S. W.; An, J.; Chen, J. R.; Xiao, W. J. Org. Lett. 2011, 13, 2290–2293. 12) a) Nagasawa, H. T.; Elberling, J. E.; Roberts, J. C. J. Med. Chem. 1987, 30, 1373–1378 b) Nagai,

U.; Pavone, V. Heterocycles 1989, 28, 589–592 c) Villeneuve, G.; Dimaio, J.; Chan, T. H.; Michel, A. J. Chem. Soc. Perkin Trans. 1 1993, 1897–1904.

13) Crich, D.; Banerjee, A. J. Am. Chem. Soc. 2007, 129, 10064–10065. 14) a) Shibata, N.; Baldwin, J. E.; Jacobs, A.; Wood, M. E. Tetrahedron 1996, 52, 12839–12852

b)Thompson, R. E.; Chan, B.; Radom, L.; Jolliffe, K. A.; Payne, R. J. Angew. Chem. Int. Ed. 2013, 52, 9723–9727.

15) a) Dawson, P. E.; Muir, T. W.; Clark–Lewis, I.; Kent, S. B. H. Science 1994, 266, 776–779 b) Dawson, P. E.; Kent, S. B. H. Annu. Rev. Biochem. 2000, 69, 923–960 c) Hackenberger C. P. R.; Schwarzer, D. Angew. Chem. Int. Ed. 2008, 47, 10030–10074.

16) Timmerman P.; Beld J.; Puijk W. C.; Meloen R. H. ChemBioChem 2005, 6, 821–824. 17) a) Chatterjee, C.; Paul, M.; Xie, L.; van der Donk, W. A. Chem. Rev. 2005, 105, 633–683 b)

Champak Chatterjee, C.; Patton, G. C.; Cooper, L.; Paul, M.; van der Donk, W. A. Chemistry & Biology 2006, 13, 1109–1117 c) Tabor, A. B. Org. Biomol. Chem. 2011, 9, 7606–7628.

18) a) Plöchl, J. Ber. Dtsch. Chem. Ges. 1883, 16, 2815–2825 b) Erlenmeyer, E. Liebigs Ann. Chem. 1893, 275, 1–8 c) Panella, L.; Aleixandre, A. M.; Kruidhof, G. J.; Robertus, J.; Feringa, B. L.; de Vries, J. G.; Minnaard, A. J. Org. Chem. 2006, 71, 2026–2036 d) Humphrey, C. E.; Furegati, M.; Laumen, K.; La Vecchia, L.; Leutert, T.; Müller–Hartwieg, J. C. D.; Vögtle, M. Org. Process Res. Dev. 2007, 11, 1069–1075.

19) a) Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht, A.; Mangold, R.; Meyer, R.; Riedl, B. Synthesis–Stuttgart 1992, 487–490 b) Adamczyk, M.; Akireddy, S. R.; Reddy, R. E. Org. Lett. 2000, 2, 3421–3423 c) Adamczyk, M.; Akireddy, S. R.; Reddy, R. E. Org. Lett. 2001, 3, 3157–3159 d) Zhang, J. Y.; Xiong, C. Y.; Ying, J. F.; Wang, W.; Hruby, V. J. Org. Lett. 2003, 5, 3115–3118.

20) For some examples see: a) Miller, M. J.; J. Org. Chem. 1980, 45, 3131–3132 b) Somekh, L.; Shanzer, A. J. Org. Chem. 1983, 48, 907–908 c) Cherney, R. J.; Wang, L. J. Org. Chem., 1996, 61, 2544–2546 d) Bernardes, G. J. L.; Chalker, J. M.; Errey, J. C.; Davis, B. G. J. Am. Chem. Soc. 2008, 130, 5052–5053.

21) Weygand, F. Chem. Ber. 1954, 87, 248–256. 22) a) Weygand, F.; Steglich, W. Angew. Chem. 1961, 73, 433–434 b) Weygand, F.; Steglich, W.;

Tanner, H. Justus Liebigs Ann. Chem. 1962, 658, 128–150 c) Weygand, F.; Steglich, W.; Mayer, D.; von Philipsborn, W. Chem. Ber. 1964, 97, 2023–2028.

23) Breitholle, E. G.; Stammer, C. H. J. Org. Chem. 1976, 41, 1344–1349. 24) The same observation was reported by the group of Stammer; see ref. 23. 25) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967–1969. 26) Hoashi, Y.; Okino, T.; Takamoto, Y. Angew. Chem. Int. Ed. 2005, 4032–4035. 27) Kreevoy, M. M.; Harper, E. T.; Duvall, R. E.; Wilgus III, H. S.; Ditsch, L. T. J. Am. Chem. Soc.

1960, 82, 4899–4902. 28) These types of transition states have been found based on calculations in different type of

reactions: a) Hamza, A.; Schubert, G.; Soόs, T.; Pápai, I. J. Am. Chem. Soc. 2006, 128, 13151–13160 b) Hammar, P.; Marcelli, T.; Hiemstra, H.; Himo, F. Adv. Synth. Catal. 2007, 349, 2537–2548.

Optimization of the Thiol Addition to α,β–Unsaturated α–Amino Acid Derivatives

63

CHAPTER 3

Optimization of the Thiol Addition to α,β–Unsaturated α–Amino Acid

Derivatives and Applications in Peptide Chemistry *

Abstract: Several types of hydrogen bond donors were introduced on the C6’–position of quinidine. The products were examined as organocatalysts in the thiol addition to α,β–unsaturated N–acetylated oxazolidinones and α,β–unsaturated α–amino acids in order to overcome the limitations that were observed with the previously reported C6’–thiourea catalyst. The results showed that C6’ sulfonamide catalysts were the most effective in both reactions. Excellent yields, high levels of enantioselectivity and good to excellent diastereoselectivities were obtained. The addition products were easily transformed into suitable substrates for native chemical ligation. *The research in this chapter will be published:

Breman, A. C.; van Santen, R.; Telderman, S.; Scott, J.; van Maarseveen, J. H.; Ingemann, S.; Hiemstra,

H. J. Org. Chem. manuscript in preparation

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3.1 Introduction

To increase the applicability of the method for the synthesis of β–thiol functionalized α–amino acids (chapter 2) two major issues should be addressed: i) improvement of the diastereoselectivity with benzylic or allylic thiols and ii) the use of catalysts that can easily be synthesized.1 To improve the diastereoselectivity, it was decided to change the type of hydrogen bond donor and thus modify the hydrogen bonding capability. This results in a change of the activity of the catalyst. Other hydrogen bond donors in addition to the thiourea that can be introduced include urea2, benzimidazole3, squaramide4, amide5 or sulfonamides6 (for further details vide infra). It has already been demonstrated that the C6’–thiourea catalyst with a 9–methylanthracyl ether at the C9–position is able to catalyze the reaction leading to β–functionalized α–amino acids with high ee for one diastereoisomer. The main problem with this C6’–thiourea catalyst relies in the synthesis, in which the 9–methylanthracyl group proved to be quite labile during the demethylation of the methoxyquinoline resulting in a poor yield.7 A good alternative is to protect the benzylic OH of quinidine with the more stable benzyl group.8 This leads to a more facile synthesis of the catalyst. In addition to the reaction of thiols with dehydroaminoacid derivatives, the reaction of thiols with α,β–unsaturated N–acetylated oxazolidinones as reported by Deng and coworkers will also be examined in more detail.7

3.1.1 Types of hydrogen bond donors

The nature of the hydrogen bond donor is a crucial factor in non–covalent (bifunctional) organocatalysis.9 Thioureas have proven to be one of the best hydrogen bond donor motifs and many reactions are catalyzed by catalysts bearing this functional group.10 This is mainly due to the relative high acidity11 of thioureas. They also show less tendency to undergo intermolecular self–association than, for example, the corresponding ureas because of the poor hydrogen bond acceptor capability of the thiocarbonyl.12

Although ureas are less acidic and tend to self–associate faster than thioureas, they are also used in non–covalent bifunctional organocatalysis.2 The group of Singh had used a C9–urea functionalized Cinchona alkaloid for the addition of various aromatic thiols to cyclic enones (scheme 1).2a

Scheme 1. Thiol addition catalyzed by (thio)urea.


65

Only 0.1 mol% of catalyst was needed and ee’s up to 99% were obtained. In this reaction the urea catalyst outperformed the thiourea catalyst not only in terms of low catalyst loading but also in terms of enantioselectivity. The urea species (0.1 mol%) catalyzed the addition of thiophenol to a cyclic hexenone with an ee of 94%. While the thiourea catalyst (0.5 mol%) gave an 88% ee for the same reaction.

2–Aminobenzimidazoles can be considered basic or acidic depending on the substituents on the aromatic ring (the protonated non–substituted 2–aminobenzimidazole has a pKa of 7.18 in water).13 Electron withdrawing substituents lower the basicity of the benzimidazole and increase the acidity of the N–H groups of the ring. Therefore 2–aminobenzimidazoles are used in organocatalysis as hydrogen bond acceptors as well as donors. In 2009 two groups reported the use of different types of 2–aminobenzimidazoles in Michael additions to nitrostyrene.3 The group of Nájera used a non–substituted 2–aminobenzimidazole with a trans–cyclohexanediamine substituent for the addition of 1,3–dicarbonyl compounds to nitroolefins.3a Good enantioselectivities (up to 96% ee) were obtained with a catalytic amount of TFA as additive. In this reaction the 2–aminobenzimidazole acts as a base deprotonating the 1,3–dicarbonyl compound, while the protonated amine activates the nitroolefin via a single hydrogen bond (scheme 2).

Scheme 2. Intermediates proposed by Nájera and Jew.

The group of Jew used a Cinchona alkaloid catalyst substituted with a 2–aminobenzimidazole containing two CF3–groups in a study of malonate additions to nitroolefins.3b It appeared unnecessary to add any acidic component in order to obtain good enantioselectivities (up to 99%). They proposed a mechanism in which the 2–aminobenzimidazole activates the nitroolefin via a double hydrogen bond and the basic amine of the Cinchona alkaloid deprotonates the malonate.

Squaramides represent another well investigated class of double hydrogen bond donors.4 They have unique properties in terms of rigidity, H–bond length, H–bond angle and pKa. For example, the distance between the hydrogen atoms is larger as compared to thioureas and 2–aminobenzimidazole (figure 1). Also the relative orientation of the hydrogen atoms is different. While the hydrogens of (thio)urea and 2–aminobenzimidazole are in a 90° angle (N–N–H angle measured), in the squaramide the angle is canted to 79.5°. Recently the pKa’s of several squaramides have been

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determined experimentally.14 Squaramides are in general more acidic than their related thioureas (figure 2).

Figure 1. Distance between hydrogens determined by X–ray crystallography.

The group of Rawal in 2008 reported the first example of squaramides as hydrogen bond donors in organocatalysis.15 They applied a Cinchona derived catalyst for the addition 1,3–dicarbonyl compounds to nitroolefins. In some examples, only 0.1 mol% of catalyst was needed in order to obtain high ee and all reactions were complete within 24 h. They claimed that the high catalyst turnover is due to the greater spacing between the N–H groups in the bisamide which results in a better fit of the nitroolefin.

Amides are one of the most important class of hydrogen bond donors and acceptors. The 3–dimensional structure of peptides is mainly due to interactions of amide groups with each other and with the side chains of amino acids.16 Amides are slightly more acidic than the related urea compounds (figure 2).17

Figure 2. Reported pKa values for (thio)urea, squaramide, amide and sulfonamide.

Like amides, sulfonamides are single hydrogen bond donor and are significantly more acidic than amides (figure 2).18 In bifunctional organocatalysis several types of sulfonamides have been described.6 The group of Chin and Song used a 3,5–bis–(trifluoromethyl)phenylsulfonamide substituted at the C–9 position of a Cinchona alkaloid for the enantioselective ring opening of cyclic anhydrides with methanol (scheme 3, A).6a They also examined the C–9 thiourea catalyst and obtained comparable results in terms of enantioselectivity. However, the sulfonamide catalyzed the reaction much faster than the thiourea. The group of Shi reported the use of benzenesulfonamides substituted at the C6’–position of Cinchona alkaloids in the transamination of α–keto esters to chiral α‑amino esters (scheme 3, B).6b They showed that sterically congested sulfonamides


67

gave the best results, e.g. the 2,4,6–triethylbenzenesulfonamide catalyst gave the best result with ee’s up to 94%.

Scheme 3. Examples of sulfonamides as hydrogen bond donors in organocatalysis.

3.1.2 Sulfur protecting groups

In order to improve the applicability of the organocatalytic thiol addition to α,β–unsaturated α–amino acids, thiols with easliy removable R–groups should be used. Currently, the most suitable protecting group which is commonly introduced in thiol addition reactions is the 4–methoxybenzyl group. However, deprotection involves elevated temperatures and TFA as the solvent.1,7 Recently, the group of Albericio reported a new SH–protecting group in cysteine (scheme 4).19 They used diphenylmethane as the corresponding protecting group which is removed at rt in 1 h by using a 60:40 mixture of TFA and CH2Cl2 in combination with 2.5% of H2O and 2.5% of i–Pr3SiH as scavengers.

Scheme 4. Deprotection of cysteine in a tripeptide.

To improve the results described in chapter 2, a series of different types of hydrogen bond donors will be introduced on the C6’–position of benzyl protected quinidine. These catalyst were examined in two thiol additions. First the addition of thiols to N–acetylated

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oxazolidinones will be explored followed by the thiol addition to α,β–dehydroaminoacid derivatives. With the optimized conditions the reaction scope of both reaction will be further examined. Diphenylmethanethiol20 will be included as a nucleophile in order to provide a facile entry into β–thiol functionalized amino acids. To demonstrate the applicability of this chemistry, the β–thiol functionalized α–amino acids will be applied in native chemical ligation.


N–Acetylated oxazolidinones were prepared according to the literature procedure (scheme 5).21 The corresponding acid chlorides were reacted with oxazolidinone in the presence of NaH providing 1, 2 and 3 in good yields.

Scheme 5. Synthesis of the α,β–unsaturated N–acetylated oxazolidinones.

The α,β–unsaturated α–amino acid derivatives were synthesized as described in chapter 2 of this thesis (scheme 6). For example, treating commercially available rac–O–methyl protected tyrosine 6 with TFAA provided the pseudoazlactone in good yield, followed by bromination with Br2 to afford 7 in good yield. Bromide 7 was then treated with an excess of oxazolidinone and NaH. Dehydroaminoacid 8 was obtained as a 10:1 mixture of Z:E–isomers in 75% yield. Recrystallization from EtOAc/PE gave the Z–isomer.

Scheme 6. Synthesis of the dehydroaminoacid 8.

3.3 Catalyst synthesis

The synthesis of the Cinchona alkaloids with the various types of hydrogen bond donors on the C6’–position involved formation of amine 11 from quinidine 9 by a five step procedure (scheme 7).8 The urea catalyst 13 was obtained with the same procedure as


69

described for the thiourea catalyst 12, using isocyanate instead of isothiocyanate. The thiourea 12 and urea 13 catalysts were obtained in 95% and 93% yields, respectively.

Scheme 7. Synthesis of amine 11 and its conversion to the (thio)urea catalysts.

In order to introduce the benzimidazole, 2–chlorobenzimidazole (14) was protected with a SEM–group thus yielding the protected chlorobenzimidazole 15 (scheme 8).22

Scheme 8. Synthesis of 2–aminobenzimidazole 16.

Under Buchwald–Hartwig amination conditions23 the corresponding cross coupled product was obtained in 42%. The moderate yield is a result of diarylation leading to a 60:40 ratio of the mono– and di–arylated species. The SEM group was removed by BF3·OEt2 in CH2Cl2 leading to the benzimidazole catalyst 16 in 85% yield.24 The introduction of the squaramide group according to the procedure by Rawal was not successful.15

The amide 18 was obtained in 65% yield by reacting amine 11 with 3,5–bis–(trifluoromethyl)benzoyl chloride 17 in CH2Cl2 in 65% yield (scheme 9).25 Series of

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sulfonamide catalysts 19–26 were prepared, bearing electron withdrawing or electron donating substituents on the phenyl ring.26 The sulfonamides were obtained by reacting 11 with the appropriate benzenesulfonyl chlorides in pyridine at reflux yielding the catalysts in moderate to excellent yields.

Scheme 9. Formation of carboxyamide 18 and sulfonamides 19–26.

Detailed 2D NMR studies were performed in order to assign all the signals to the corresponding hydrogen and carbon atoms in sulfonamide 26. The HSQC data revealed correlations between hydrogen atoms and carbon atoms that were not visible in the 13C APT spectrum. The signal of the benzylic carbon (C10, δ = 80.4 ppm) was not observed in the APT spectrum. Also, two carbons of the quinoline (C17, δ = 119.6 and C23, δ = 113.2) and one carbon of the quinuclidine (C2, δ = 22.6) were not visible. In the 1H uncoupled 13C NMR measurement of sulfonamide 26 broad signals were observed at positions where no signals were observed in the APT spectrum (figure 3). By comparing all the 13C APT measurements of the present catalysts, the same trend was seen. Only by measuring normal 13C NMR all the signals were observed. This also holds for the known thiourea catalysts reported previously by our group and by the group of Deng.7,8


71

carbon δ (ppm) carbon δ (ppm) carbon δ (ppm) carbon δ (ppm) carbon δ (ppm) 1 60.0 7 39.9 13 129.2 19 145.5 25 124.6 2 22.7 8 140.4 14 127.8 20 131.4 26 128.4 3 28.1 9 114.7 15 127.7 21 124.2 27 110.8 4 26.3 10 80.4 16 146.0 22 136.5 28 152.8 5 49.8 11 71.3 17 119.6 23 113.2 29 39.9 6 49.3 12 137.7 18 149.0 24 127.0

Figure 3. 13C NMR spectra of sulfonamide catalyst 26 A) APT and B) 1H uncoupled.

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First the addition of phenylmethanethiol 27 to N–acetylated oxazolidinone 1 was examined with the newly developed catalysts (table 1).

Table 1. Screening of the catalysts for the phenylmethanethiol 27 addition to N–acetylated oxazolidinone 1.

entrya catalyst reaction time (h) conversion (%)b ee (%)c,d

1 12 6 100 68 (R) 2 13 6 100 59 (R) 3 16 4 100 10 (R) 4 18 24 100 20 (R) 5 19 72 90 –50 (S) 6 20 72 81 –65 (S) 7 21 16 100 –84 (S) 8 22 16 100 –81 (S) 9 23 16 100 –81(S)

10 24 6 100 –85 (S) 11 25 16 100 –86 (S) 12 26 16 100 –87 (S)

a) Standard reaction conditions: 0.5M substrate, 3 equiv thiol b) Conversion determined by 1H–NMR c) The ee determined by chiral HPLC (ODH–column) analysis d) enantiomer formed between brackets

The thiourea catalyst 12 gave similar results as previously reported by Deng and coworkers providing 28 in 68% ee in favor of the R–enantiomer (entry 1).7 Next, urea catalyst 13 was examined where a small decrease in the enantioselectivity was observed as compared to 12 (entry 2). The benzimidazole 16 catalyzed the reaction slightly faster than 12 and 13 forming the product with poor enantioselectivity (entry 3). The amide 18 catalyzed the reaction less efficiently than the thiourea 12 and gave also poor enantioselectivity (entry 4). Only 90% conversion was obtained after 72 h with sulfonamide catalyst 19 (entry 5). Significantly, inversion of the stereochemistry was observed giving 50% ee of the S–enantiomer. The mono trifluoromethyl substituted catalyst 20 gave an ee of 65% in favor of the S–enantiomer. Again after 72 h full conversion was not observed (entry 6). The non–substituted benzenesulfonamide 21 gave an ee of –84% and full conversion was obtained after 16 h (entry 7).The introduction of a methyl group on the para–position leads to a slight decrease in the ee (–81%, entry 8). The presence of three methyl groups at the 2,4,6–positions of the phenyl ring did not lead to an improvement of the enantioselectivity (entry 9). Next the catalysts containing electron donating groups were examined (entries 10–12). First the 4–methoxy substituted sulfonamide 24 was observed to give an enantioselectivity of –85% and full conversion in only 6 h (entry 10). The tri–2,4,6–methoxy catalyst 25 gave a slight increase of the ee as compared to the mono–substituted species 24 (entry 11). Finally, catalyst 26 which contains the most electron donating group, according to the Hammett equation27, gave an ee of 87% in favor of the S–enantiomer (entry 12). It is


73

worthwhile to note that in the case of sulfonamide based catalyst, the ee’s tend to be higher and the reaction times shorter, if the aromatic ring bears more electron donating groups.

The results obtained for the addition of phenylmethanethiol 27 to the α,β–dehydroaminoacid derivative 4 are shown in table 2.1

Table 2. Screening of the catalysts for the addition of thiols on to dehydroaminoacids.

entrya catalyst reaction time (h) conversion (%)b anti/syn ee (%)c

1 12 6 100 64:36 93/55 2 13 8 100 29:71 13/–4 3 16 24 100 33:67 31/32 4 18 16 100 42:58 61/–65 5 19 160 100 71:29 92/75 6 20 160 60 80:20 nd 7 21 60 100 81:19 98/12 8 22 60 100 84:16 99/8 9 23 60 100 67:33 98/–24 10 24 60 100 78:22 94/4 11 25 60 100 38:62 88/45 12 26 60 100 81:19 98/12

a) Standard reaction conditions: 0.2M substrate, 3 equiv thiol b) Conversion determined by 1H–NMR c) The ee determined by chiral HPLC (AD–column) analysis

Thiourea catalyst 12 gave similar results as compared to the more sterically congested thiourea catalyst with a 9–methylanthracyl–ether group at the C9–position, although an increase in the diastereoselectivity was observed (dr 53:47 vs 64:36) (entry 1). The urea catalyst 13 gave a remarkable result (entry 2). The anti/syn ratio was inverted as compared to the thiourea catalyst 12 together with an almost complete loss of the enantioselectivity. The benzimidazole 16 catalyzed the reaction significantly less efficiently than the thiourea 12 (entry 3). Amide catalyst 18 gave a slight preference for the syn diastereoisomer, both diastereoisomers being formed in similar ee’s (entry 4). The reaction time with the sulfonamide catalyst 19 was again long (entry 5). Full conversion was obtained only after 160 h and there was a slight increase in the diastereoselectivity as compared to the thiourea catalyst 12. The anti diastereoisomer was obtained with 92% ee. The para–trifluoromethyl catalyst 20 gave after stirring for 160 h only 60% conversion not allowing the enantioselectivity to be determined (entry 6). However, there was an improvement of the diastereoselectivity with respect to the bis–trifluoromethyl catalyst 19. Without the trifluoromethyl group, the reaction went to completion within 16 h and the enantioselectivity of the major diastereoisomer was improved to 98% (entry 7). With the 4–methyl substituted catalyst 22, a further improvement of the diastereoselectivity and enantioselectivity was observed. The anti–isomer was now formed in 84% and in 99% ee (entry 8). By using the more sterically congested trimethyl substituted catalyst 23 a decrease of the diastereoselectivity was

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observed, although the anti–isomer was obtained in excellent enantioselectivity (entry 9). With the electron donating catalysts further improvement of the diastereoselectivity was not achieved (entries 10–12). When the trimethoxy substituted catalyst 25 was used inversion of the diastereoselectivity was observed. However, the anti–isomer was again obtained in high enantioselectivity (entry 11).

3.5 Scope of the addition reaction

Based on the results in table 1, it was decided to explore the scope of the thiol addition to α,β–unsaturated N–acetylated oxazolidinones with catalyst 26 (table 3). To further enhance the enantioselectivity the reactions were performed at –20 °C. First the addition of phenylmethanethiol to substrate 1 was studied (entry 1). By lowering the temperature the ee was improved to 93%. The addition of 4–methoxy–phenylmethanethiol gave also high levels of enantioselectivity (entry 2). The use of diphenylmethanethiol the decreased the ee to 85% (entry 3). In the addition of 2–propene–1–thiol, the corresponding product was obtained in high yield and excellent enantioselectivity (entry 4). With substrate 2 (R1 = propyl) all the reactions gave high yields and high levels of enantioselectivity (entries 5, 6, and 7). Also, the aromatic Michael acceptor 3 was used in combination with diphenylmethanethiol (entry 8). Due to the poor solubility of 3 at –20 °C the reaction was performed at a lower concentration. This resulted in an increase of the reaction time to 140 h. However, the product could be isolated in high yield and excellent enantioselectivity.

Table 3. Scope of the addition of thiols to α,β–unsaturated N–acetylated oxazolidinones.

entrya R1 = R2 = reaction time (h) product yield (%) ee (%)b

1 Me 1 Bn 84 28 97 93 2 Me 1 4–MeOBn 84 30 98 92 3 Me 1 CH(Ph)2 84 31 99 85 4 Me 1 allyl 84 32 97 91 5 Pr 2 Bn 84 33 99 92 6 Pr 2 4–MeOBn 84 34 96 91 7 Pr 2 CH(Ph)2 84 35 97 92 8c Ph 3 CH(Ph)2 140 36 90 94

a) Standard reaction conditions: 0.5M substrate, 3 equiv thiol b) The ee determined by chiral HPLC analysis c) Reaction was performed at 0.2M substrate concentration

With the optimized conditions for the addition of thiols to dehydroaminoacids, the scope was further investigated (table 4). As previously described, the addition of phenylmethanethiol to substrate 4 gave good diastereoselectivity and excellent enantioselectivity for the anti–isomer, thus the product 29 could be isolated in excellent yield (entry 1). A comparable result was obtained with 4–methoxy–phenylmethanethiol (entry 2). The diastereoselectivity was increased to an anti/syn ratio of 93:7 with


75

diphenylmethanethiol as the nucleophile and the enantioselectivity for the anti–isomer was excellent (entry 3).

Table 4. Scope of the addition reaction of thiols to α,β–unsaturated dehydroaminoacids.

entrya R1 = R2 = reaction time (h) product yield (%) anti/syn ee (%)b

1 Ph 4 Bn 16 29 95 84:16 99/8 2 Ph 4 4–MeOBn 16 37 97 83:17 96/52 3 Ph 4 CH(Ph)2 16 38 97 (80)c 93:7 99 (>99.5)c/33

4 Ph 4 allyl 24 39 93 73:27 99/3 5 4–MeOPh 8 Bn 16 40 99 80:20 98/3 6 4–MeOPh 8 4–MeOBn 16 41 96 80:20 97/6 7 4–MeOPh 8 CH(Ph)2 16 42 96 90:10 98/17 8 Et 5 Bn 24 43 96 82:18 97/29 9 Et 5 4–MeOBn 24 44 99 80:20 96/26 10 Et 5 CH(Ph)2 16 45 96 93:7 98/3 a) Standard reaction conditions: 0.2M substrate, 3 equiv thiol b) The ee determined by chiral HPLC analysis c) Yield and

enantioselectivity after crystallization between brackets

After purification, the anti–isomer could be recrystallized as a single enantiomer in 80% yield. With 2–propene–1–thiol as the nucleophile the anti/syn ratio was 73:27 and again excellent enantioselectivity for the anti–isomer was observed (entry 4). Next, the tyrosine analogue 8 was examined (entries 5–7). Phenylmethanethiol as well as 4–methoxy–phenylmethanethiol provided a 80:20 mixture of diastereoisomers with excellent enantioselectivity for the anti–isomers (entries 5 and 6). An increase in the diastereoselectivity was seen with the more bulky diphenylmethanethiol as the nucleophile (entry 7). Finally dehydroaminoacid 5 was tested, obtaining similar results with phenylmethanethiol and 4–methoxy–phenylmethanethiol and again, an increase of the diastereoselectivity was observed with diphenylmethanethiol as the nucleophile (entries 8–10).

3.7 Mechanism of the thiol addition

The results reveal that the stereochemistry of the addition of thiols to α,β–unsaturated N–acetylated oxazolidinones can be inverted by changing the nature of hydrogen bond donor. The thiourea derived catalyst gives the R–enantiomer while sulfonamide derived catalysts provide the S–enantiomer. Possible transition states are shown in scheme 10. In example A, the thiol anion is coordinated to the thiourea moiety and the α,β–unsaturated N–acetylated oxazolidinone is activated by the protonated quinuclidine. This results in attack of the thiol from the front side. With the sulfonamide derived catalyst the α,β–unsaturated N–acetylated oxazolidinone is coordinated to the sulfonamide and the thiol nucleophile is activated by the quinuclidine (scheme 10, B).

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Scheme 10. Proposed transition states.

This results in attack from the back side of the α,β–unsaturated N–acetylated oxazolidinone. It is also proposed that the sulfonamide is less capable of stabilizing the thiol anion than the protonated quinuclidine. This could explain how the sulfonamide catalysts with electron donating substituents give the best results. These catalysts are likely to be less acidic and thus, less capable of stabilizing the thiol anion. For the thiol addition to α,β–unsaturated dehydroaminoacids a similar transition state as described in chapter 2 can be proposed (scheme 10, C). The thiol is deprotonated by the quinuclidine and the dehydroaminoacid is now activated by the sulfonamide via a single hydrogen bond. In this reaction no inversion of the stereochemistry is observed, which indicates that the sulfonamides and the thiourea activate the substrates through a similar transition state.

3.8 Follow up chemistry

The diphenylmethane group could easily be cleaved off with TFA and tri–isopropylsilane in CH2Cl2 at room temperature (scheme 11).19 After stirring for 1 h the corresponding thiol 46 was obtained in 96% yield with no loss of enantiopurity.

Scheme 11. Removal of the diphenylmethane group.

In order to prepare the β–thiol functionalized amino acid derivatives suitable for application in peptide chemistry a three step procedure was developed (scheme 12). The amine in compound 38 was deprotected by HCl in methanol at reflux.28 After removal of the solvent the amine·HCl salt was dissolved in CH2Cl2 followed by Boc–protection of the NH2–group. Finally, the oxazolidinone was removed with K2CO3 in methanol to afford methyl ester 47 in 68% overall and with no loss of enantiopurity. The methyl ester 47 was saponificated with Tesser’s base to yield acid 48 in 88%.29


77

Scheme 12. Functionalization of the β–thiol functionalized amino acid.

The Boc–group and the diphenylmethane group were cleaved off with TFA and tri–isopropylsilane at 50 °C in one pot (scheme 13). A higher temperature was needed in order to remove the diphenylmethane group as the Boc–group was cleaved off first leading to protonation of the free amine and thus hampering the necessary protonation of the thiol. After purification oxidation to the disulfide occurred.

Scheme 13. Cleavage of the Boc and diphenylmethane group at elevated temperature.

In order to apply this methodology in peptide chemistry, it was decided to perform native chemical ligation (NCL), introduced by Kent and co–workers in 1994.30 This technique is used for the synthesis of peptides and moderately sized proteins. An N–terminal cysteine residue reacts with a C–terminal thioester; first trans–thioesterification occurs followed by a rapid intramolecular S– to N–shift, resulting in the formation of an amide bond (scheme 14).

Scheme 14. Principal of native chemical ligation.

Recently, other β–thiol functionalized amino acids have been used successfully in NCL.31 E.g. Crich and Banerjee have used this concept with thiol–functionalized phenylalanine and showed that they could prepare decapeptides.31a Using the present method, several β–thiol functionalized amino acids could be prepared. Applying these

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amino acids in NCL broadens the scope of amino acids, which can be used at the N–terminus.

Recently, our group reported the synthesis of small peptides containing activated esters obtained via the Chan–Lam coupling.32 It was demonstrated that these esters could be prepared without epimerization. With these activated esters native chemical ligation was performed successfully without the formation of any thioester. Also this methodology broadens the scope of NCL. Here, acid 48 was coupled to the tripeptide33 with HATU, HOAt and DIPEA giving the tetrapeptide 50 in 73% yield (scheme 15).

Scheme 15. Coupling of 48 to the tripeptide.

The tetrapeptide 50 was deprotected with TFA and i–Pr3SiH at 50 °C, followed by purification by preparative HPLC yielding 51 as a mixture of free thiol and disulfide (scheme 16).

Scheme 16. Deprotection of the tetrapeptide 50.

First, the standard native chemical ligation conditions were explored.30 The tetrapeptide 51 was reacted with dipeptide 52 containing a thioester (scheme 17).

Scheme 17. Native chemical ligation with tetrapeptide 51.

After overnight stirring the hexapeptide 53 was formed and purified by preparative HPLC. Next native chemical ligation with activated ester 54 was performed.32 Also in this


79

reaction, the hexapeptide 55 could be obtained after overnight stirring. To confirm that the ligation reaction proceded through direct attack of the thiol of the amino acid on the activated ester, no additional thiophenol was added.

3.9 Conclusion

Optimization studies have been performed in order to improve the applicability of the organocatalytic synthesis of unnatural cysteines. Several types of hydrogen bond donors were introduced at the C6’–position of quinidine and examined as organocatalysts in two thiol addition reactions. In the addition of thiols on α,β–unsaturated N–acetylated oxazolidinones, inversion of the stereochemistry was observed if sulfonamides were used instead of the related thiourea. The sulfonamides also proved to be the best catalysts in the thiol addition to α,β–unsaturated dehydroaminoacids. In this reaction the less congested sulfonamides gave the best results with diastereoselectivities up to 93:7 and with ee’s up to 99%. The unnatural cysteines were easily converted into suitable substrates for peptides chemistry such as native chemical ligation.

3.10 Acknowledgments

Suze Telderman is acknowledged for the synthesis of the urea and benzimidazole catalysts. Roy van Santen is acknowledged for the synthesis of the sulfonamide catalysts and their screening. Suzanne Flaton is thanked for the synthesis of the amide catalyst and Rosa Kromhout for the initial screening of some of the catalysts. Finally, Stanimir Popovic is gratefully acknowledged for his help with the peptide chemistry.


4–(4–Methoxybenzyl)–2–(trifluoromethyl)oxazol–5(2 H)–one: A mixture of 4–MeO–phenylalanine 6 (5.0 g, 25.6 mmol) and TFAA (8.3 mL, 58.9 mmol) was refluxed for 1 h. After removing the excess reagent the product was distilled under reduced pressure (0.06 mbar, 200 °C) to afford the desired compound (5.7 g, 21.0 mmol, 82%) as a colorless oil. IR (neat, cm–1) ν 1808, 1606, 1157, 1018, 702;1H NMR (400 MHz, CDCl3) δ 7.26 (d, 2H, J = 8.7 Hz), 6.90

(d, 2H, J = 8.7 Hz), 6.10 (m, 1H), 3.99 (s, 2H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.3, 163.3 159.0, 130.3, 124.1, 120.0 (q, J = 280.0 Hz), 114.3, 92.8 (q, J = 34.9 Hz), 55.1, 33.5. 4–(Bromo(4–methoxyphenyl)methyl)–2–(trifluoromethyl )oxazol–5(2 H)–one 7:

Cyclic tyrosine (5.2 g, 19.0 mmol) was dissolved in 50 mL 1,2–dichloroethane and cooled to 0 °C. A small amount of a Br2 (0.97 mL, 19.0 mmol) in 20 mL 1,2–dichloroethane solution was added. A small sample was withdrawn and gently heated until it became colorless and then returned to the flask. This procedure was repeated until the mixture in the flask became colorless.

Next the rest of the bromine solution was added. The mixture was allowed to come to rt

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and stirred overnight. The solvent was removed to afford the product 7 (5.9 g, 16.7 mmol, 88%) as a 1:1 mixture of diastereoisomers as a greenish oil after column chromatography (PE/EtOAc 30:1). (This product could not be distilled because of the high boiling point. Because of this the product contained a by–product, but this proved not be a problem in the next step of the synthesis). IR (neat, cm–1) ν 1808, 1608, 1513, 1257, 1157; 1H NMR (400 MHz, CDCl3) δ 7.58 (d, 1H, J = 8.8 Hz), 7.53 (d, 1H, J = 8.8 Hz), 6.94 (m, 2H), 6.27 (q, 0.5H, J = 2.9 Hz), 6.18 (q, 0.5H, J = 3.1 Hz), 6.00 (s, 0.5H), 5.98 (s, 0.5H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 165.5, 163.8, 161.0, 160.7, 130.6, 130.4, 125.5, 120.0 (q, J = 280.0 Hz), 119.9 (q, J = 280.0 Hz), 114.6, 114.5, 92.7 (q, J = 35.4 Hz), 92.7 (q, J = 35.5 Hz), 55.3, 41.4, 40.6. (Z)–2,2,2–Trifluoro– N–(1–(4–methoxyphenyl)–3–oxo–3–(2–oxooxazolidin–3–yl )–

prop–1–en–2–yl)acetamide 8: Oxazolidinone (3.1 g, 35.2 mmol) was dissolved in 200 mL THF. Sodium hydride (1.35 g, 33.8 mmol, 60% in mineral oil) was added and the resulting mixture was stirred for 45 min. Next a solution of bromo “pseudo” azlactone 7 (5.4, 15.3 mmol) in 60 mL THF was drop wise added.

The resulting mixture was stirred for 30 min and then quenched with saturated NH4Cl. The layers were separated and the water layer was extracted 2 times with EtOAc. The combined organic layers were washed with brine and dried with MgSO4. The crude was concentrated and purified by column chromatography (PE/EtOAc 2:1) to obtain 8 as a mixture of isomers (Z/E 10:1) as a white solid (4.1 g, 11.5 mmol, 75%). The Z–isomer could be obtained by recrystallization from PE/EtOAc. Z–isomer: mp 176–178 °C; IR (neat, cm–1) ν 3248, 1763, 1717, 1678, 1213, 1176, 1157,1034; 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.45 (d, 2H, J = 9.8 Hz), 7.10 (s, 1H), 6.96 (d, 2H, J = 9.8 Hz), 4.49 (t, 2H, J = 7.9 Hz), 4.12 (t, 2H, J = 7.9 Hz), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.9, 161.2, 155.6 (q, J = 38.0 Hz), 134.1, 131.6, 124.7, 123.0, 115.5 (q, J = 286.0 Hz), 114.1, 63.1, 55.4, 43.2; From the E–isomer no good NMR data was obtained. HRMS (ESI) for C15H13F3N2O5Na: calculated (MNa+): 381.0669, found (MNa+): 381.0656; Elemental analysis for C15H13F3N2O5: calculated: C 50.29%, H 3.66%, F 15.91%, N 7.82% found: C 49.54%, H 3.67%, F 15.61% N 7.61%. 1–(4–((S)–(Benzyloxy)((1 S,2R,4S,5R)–5–vinylquinuclidin–2–yl)methyl)quinolin–6–

yl)–3–(3,5–bis(trifluoromethyl)phenyl)urea 13: To a solution of amine 11 (500 mg, 1.25 mmol) in 15 mL dry THF was added 3,5–bistrifluoromethyl–phenylisocyanate (216 μL, 1.25 mmol) and the mixture was stirred at rt for 1 h under an inert atmosphere. The THF was removed and the product purified with flash chromatography (EtOAc/MeOH 95:5) to give urea 13 (752 mg, 1.15 mmol, 93%) as a white powder. mp 133 °C; [α]D = +65.0 (c = 1.0, CH2Cl2); IR (neat,

cm–1) ν 3235, 3089, 2944, 1714, 1560, 1473, 1364, 1176, 1125, 1057, 1027, 952, 851, 833, 728, 701; 1H NMR (500 MHz, CDCl3) δ 10.0 (s, 1H), 9.47 (s, 1H), 8.70 (d, 1H, J = 4.0 Hz), 8.33 (s, 1H), 7.96 (s, 2H), 7.57 (m, 3H), 7.48 (m, 5H), 7.23 (s, 1H), 6.35 (br, 1H), 5.29 (m, 1H), 5.10 (d, 1H, J = 10.5 Hz), 5.02 (d, 1H, J = 17.5 Hz), 4.92 (d, 1H, J = 10.0 Hz), 4.77 (d, 1H, J = 10.0 Hz), 4.09 (m, 2H), 3.96 (m, 1H), 3.44 (m, 1H), 3.20 (m, 1H), 2.61 (m, 1H), 2.35 (t, 1H, J = 12.0 Hz), 2.00 (s, 1H), 1.93 (m, 1H), 1.84 (m, 1H), 1.20 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 179.3, 153.4, 148.1, 144.4, 141.0, 140.6, 137.0, 136.7, 136.2, 131.4 (q, J = 32.8 Hz), 130.1, 128.8, 128.5, 128.3, 125.1, 124.9, 123.2 (q, J = 271.1 Hz), 122.9, 117.5, 117.3, 114.9, 111.4, 72.4, 60.2, 48.7, 37.4, 27.4, 25.4, 24.4,


81

23.5, 18.4; HRMS (FAB) for C35H33F6N4O2: calculated (MH+): 655.2508, found (MH+) 655.2501. 2–Chloro–4,6–bis(trifluoromethyl)–1–((2–(trimethyls ilyl)ethoxy)methyl)–1 H–

benzo–[d]–imidazole 15 : Benzimidazole 14 (2.0 g, 6.9 mmol) was dissolved in 70 mL dry DMF and cooled to –20 °C. SEMCl (1.24 mL, 6.94 mmol) was added dropwise. After 15 min NaH (560 mg, 14 mmol, 60% dispersion in mineral oil) was added portion wise. The mixture was allowed to warm up to rt and stirred overnight. 30

mL Water was carefully added together with 45 mL EtOAc. The layers were separated, the organic phase was washed with 30 mL of water and dried with Na2SO4. The crude was concentrated and the product was purified with flash chromatography (PE/EtOAc 9:1) yielding protected benzimidazole 15 (2.25 g, 5.4 mmol, 77%) as a colorless liquid which solidified upon standing. mp 44 ºC; IR (neat, cm–1) ν 2956, 2899, 1741, 1636, 1502, 1440, 1280, 1251, 1160, 1089, 885, 835, 789, 695; 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.86 (s, 1H), 5.69 (s, 2H), 3.64–3.60 (m, 2H), 0.97–0.93 (m, 2H), 0.01 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 144.8, 140.5, 135.4, 125.8 (q, J = 33.5 Hz), 123.9 (q, J = 270 Hz), 123.0 (q, J = 270 Hz), 121.7 (q, J = 34 Hz), 117.7, 111.7, 73.7, 67.2, 17.7, –1.81; HRMS (FAB) for C15H18ClF6N2OSi: calculated (MH+): 419.0781, found (MH+) 419.0778. 4–((S)–(Benzyloxy)((1 S,2R,4S,5R)–5–vinylquinuclidin–2–yl)methyl)– N–(5,7–bis–

(trifluoromethyl)–1–((2–(trimethylsilyl)–ethoxy)–me thyl)–1H–benzo[d]imidazol–2–yl)–quinolin–6–amine: Amine 11 (2.31 g, 5.8 mmol) was dissolved in 24 mL of dry THF. To the solution were added protected benzimidazole 15 (2.2 g, 5.3 mmol), PdOAc2 (118 mg, 0.53 mmol), rac–BINAP (327 mg, 0.53 mmol), Cs2CO3 (2.4 g, 7.4 mmol). Prior to heating to reflux temperatures, the mixture was bubbled through with argon gas for 30 minutes. After 4 h consumption of the starting

material was observed, the mixture was allowed to cool to rt and filtrated over Celite. The solvents were removed and the residue was purified with flash chromatography (EtOAc/MeOH 95:5 to 90:10) to give amination compound (1.74, 2.23 mmol, 42%) as a yellow powder. mp 92–95 °C; [α]D = +89.3 (c = 0.7, CH2Cl2); IR (neat, cm–1) ν 3068, 2950, 2873, 1735, 1599, 1456, 1348, 1286, 1273, 1260, 1161, 1122, 992, 859, 778, 728; 1H NMR (400 MHz, CDCl3) δ 8.85 (d, 1H, J = 4.4 Hz), 8.80 (br, 1H), 8.21 (br, 1H), 8.19 (s, 1H), 8.16 (br, 1H), 7.77 (s, 1H), 7.63 (s, 1H), 7.51 (br, 1H), 7.37–7.28 (m, 5H), 5.95 (m, 1H), 5.61 (s, 2H), 5.29 (m, 1H), 4.93 (m, 2H), 4.49 (m, 2H), 3.71–3.69 (t, 2H, J = 8.4 Hz), 3.28 (br, 1H), 3.20 (br, 1H), 2.89 (m, 2H), 2.72 (m, 1H), 2.24 (m, 1H), 2.06 (m, 1H), 1.82 (br, 1H), 1.62–1.57 (m, 3H), 1.06–1.02 (m, 2H), 0.01 (s, 9H); 13C NMR (100 MHz, CDCl3) 153.3, 148.8, 146.2, 145.5, 142.4, 140.4, 138.0, 137.1, 134.5, 131.5, 128.4, 128.0, 127.8, 124.4 (q, J = 270.0 Hz), 123.7 (q, J = 271.0 Hz), 122.6, 122.2, 121.9, 120.4, 118.7 (q, J = 33.0 Hz), 116.8, 116.8, 114.6, 110.4, 107.9, 72.6, 71.8, 67.2, 60.8, 50.5, 49.8, 40.2, 29.8, 28.2, 26.5, 25.0, 17.7, –1.6; HRMS (FAB) for C41H46F6N5O2Si: calculated (MH+): 782.3325, found (MH+) 782.3336.

N

NSEM

Cl

CF3

CF3

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4–((S)–(Benzyloxy)((1 S,2R,4S,5R)–5–vinylquinuclidin–2–yl)methyl)– N–(5,7–bis– (trifluoromethyl)–1 H–benzo[d]imidazole–2–yl)quinolin–

6–amine 16: Protected 2–aminobenzimidazole (1.7 g, 2.2 mmol) was dissolved in 90 mL of dry CH2Cl2, BF3·Et2O (2.66 mL, 21.7 mmol) was added dropwise at 0 °C and the mixture was stirred for 2 h under a nitrogen atmosphere. After removal of the solvent, the product was purified with flash chromatography (EtOAc/MeOH 9:1) to give 16 (1.2 g, 1.84 mmol, 85%) as a yellow powder. mp 95 °C; [α]D = +33.0 (c =

0.2, CH2Cl2); IR (neat, cm–1) ν 3065, 2926, 2870, 1575, 1510, 1455, 1366, 1335, 1273, 1261, 1165, 1120, 908, 848; 1H NMR (500 MHz, CDCl3) δ 8.77 (d, 1H, J = 4.0 Hz), 8.43 (br, 2H), 7.93–7.80 (br, 2H), 7.69 (br, 1H), 4.57 (br, 2H), 7.30 (m, 5H), 5.91 (m, 1H), 5.70 (br, 1H), 5.08 (d, 1H, J = 10.5 Hz), 5.04 (d, 1H, J = 17.0 Hz), 4.55 (d, 1H, J = 16.5 Hz), 4.43 (d, 1H, J = 16.5 Hz), 3.69 (br, 1H), 3.45 (br, 1H), 3.22 (br, 1H), 3.12 (m, 1H), 2.92 (m, 1H), 2.41 (m, 1H), 2.24 (br, 1H), 1.93 (br, 1H), 1.71 (br, 2H), 1.48 (br, 1H); 13C NMR (125 MHz, CDCl3): 153.1, 148.0, 147.8, 144.6, 144.0, 138.0, 137.0, 130.7, 130.6, 128.7, 128.4, 128.2, 127.7, 127.5, 127.0, 124.8 (q, J = 270.1 Hz), 123.7 (q, J = 270.2 Hz), 123.2, 12.1.0, 120.5, 118.9, 116.1, 115.1, 113.4, 108.0, 71.5, 60.7, 49.6, 49.1, 38.7, 27.5, 24.9, 21.4 (C–9 carbon is missing) (broad and double signals due to hindered rotation); HRMS (FAB) for C35H32F6N5O: calculated (MH+): 652.2511, found (MH+) 652.2507. N–(4–((S)–(Benzyloxy)((1 S,2R,4S,5R)–5–vinylquinuclidin–2–yl)methyl)quinolin–

6–yl)–3,5–bis(trifluoromethyl)benzamide 18: Amine 11 (200 mg, 0.5 mmol) was dissolved in 10 mL CH2Cl2. Et3N (74 μL, 0.55 mmol) and 3,5–bis–(trifluromethyl)benzoyl chloride (99 μL, 0.55 mmol) were added and the resulting mixture was stirred overnight. The reaction mixture was washed with NaHCO3, brine and dried with Na2SO4 The crude was concentrated and the product was purified with flash chromatography (EtOAc/MeOH 20:1) giving amide 18 (207 mg, 0.33 mmol, 65%) as a white solid. mp 101–103 °C; [α]D = +33.9 (c = 0.35, CH2Cl2); IR (neat, cm–1) ν 2936, 1626,

1504, 1276, 1127, 794, 753; 1H NMR (500 MHz, CDCl3) δ 10.32 (br, 1H), 8.87 (d, 1H, J = 4.5 Hz), 8.65 (s, 2H), 8.57 (s, 1H), 8.18 (m, 2H), 8.03 (s, 1H), 7.56 (d, 1H, J = 2.8 Hz), 7.41–7.30 (m, 5H), 5.96 (m, 1H), 5.79 (br, 1H), 5.06 (m, 2H), 4.61 (d, 1H, J = 11.0 Hz), 4.51 (d, 1H, J =11.0 Hz), 3.69 (br, 1H), 3.42 (br, 2H), 3.16 (m, 1H), 2.92 (m, 1H), 2.44 (br, 1H), 2.36 (br, 1H), 1.93 (s, 1H), 1.77 (br, 1H), 1.68 (br, 1H), 1.29 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 170.3, 163.5, 149.2, 145.9, 143.6, 139.5, 138.7, 137.8, 137.1, 136.9, 132.1 (q, J = 33.9 Hz), 131.3, 131.0 (q, J = 33.9 Hz), 129.4, 128.5, 128.2, 126.0, 125.3, 124.3, 123.6, 123.0 (q, J = 271.5 Hz), 118.5, 116.4, 112.4, 77.3, 71.9, 60.0, 49.3, 48.8, 38.8, 27.8, 25.0, 20.0 (broad signals due to hindered rotation); HRMS (ESI) for C35H32F6N3O2: calculated (MH+): 640.2393, found (MH+) 640.2365. General procedure for the synthesis of sulfonamide catalysts Amine 11 was dissolved in pyridine (0.2M), followed by the addition of a sulfonyl chloride (1.2 equiv). The resulting mixture was stirred at 110 °C for 16 h. The crude was concentrated under reduced pressure and the product was purified with flash column chromatography. First one column with a mixture of CH2Cl2/MeOH/Et3N, afterwards the product was concentrated and a second column was performed to remove Et3N using

N

OBn

N

NH

O

CF3

CF3


83

EtOAc/MeOH (10:1) (Et3N formed a complex with the sulfonamide catalysts) yielding the sulfonamide catalyst. N–(4–((S)–(Benzyloxy)((1 S,2R,4S,5R)–5–vinylquinuclidin–2–yl)–methyl)quinolin–

6–yl)–3,5–bis(trifluoromethyl)benzenesulfonamide 19 : According to the general procedure for the synthesis of sulfonamide catalysts, amine 11 (160 mg, 0.4 mmol) was reacted with 3,5–bis–(trifluoromethyl)benzenesulfonyl chloride (150 mg, 0.48 mmol) in 2 mL of pyridine at 110 °C. The product was purified with column chromatography CH2Cl2/MeOH/Et3N (100:2:1) followed by EtOAc/MeOH (10:1) yielding sulfonamide 19 (230 mg, 0.34 mmol, 86%) as a yellowish powder. mp 103–106 °C; [α]D = +66.7 (c = 1.00,

MeOH); IR (neat, cm–1) ν 2955, 1624, 1494, 1277, 1239, 1166, 1125, 1038, 902, 843, 731, 698, 681, 621; 1H NMR (500 MHz, CDCl3) δ 8.73 (br, 2H), 8.43 (s, 2H), 8.08 (d, 1H, J = 4.0 Hz), 7.91 (s, 1H), 7.89 (m, 2H), 7.38 (m, 1H), 7.30 (m, 3H), 7.11 (m, 2H), 5.82 (m, 1H), 5.77 (br, 1H), 5.04 (d, 1H, J = 10.0 Hz), 4.98 (d, 1H, J = 17.5 Hz), 3.90 (br, 2H), 3.61 (br, 2H), 3.40 (br, 3H), 2.60 (br, 1H), 2.38 (br, 1H), 1.99 (m, 1H), 1.90 (br, 1H), 1.64 (br, 1H) 1.21 (br, 1H); 13C NMR (125 MHz, CDCl3) δ 148.3, 146.5, 145.7, 143.5, 140.8, 136.6, 131.8 (q, J = 33.9 Hz), 131.7, 129.0, 128.6, 128.5 128.2, 127.7, 127.1, 126.2, 124.1, 122.9 (q, J = 271.6 Hz), 119.7, 118.0, 117.0, 115.8, 76.4, 70.9, 59.5, 49.8, 48.7, 37.6, 27.5, 23.8, 18.9 (broad signals due to hindered rotation); HRMS (FAB) for C34H32F6N3O3S: calculated (MH+): 676.2069, found (MH+) 676.2064. N–(4–((S)–(Benzyloxy)((1 S,2R,4S,5R)–5–vinylquinuclidin–2–yl)–methyl)quinolin–

6–yl)–4–(trifluoromethyl)benzenesulfonamide 20: According to the general procedure for the synthesis of sulfonamide catalysts, amine 11 (400 mg, 1 mmol) was reacted with p–trifluoromethylbenzenesulfonyl chloride (291 mg, 1.2 mmol) in 5 mL of pyridine at 110 °C. The product was purified with column chromatography with CH2Cl2/MeOH/Et3N (100:2:1) followed by EtOAc/MeOH (10:1) yielding sulfonamide 20 (588 mg, 0.97 mmol, 97%) as a yellowish powder. mp 122–126 °C; [α]D = +91.2 (c =

1.00, CH2Cl2 IR (neat, cm–1) ν 2938, 1623, 1484, 1370, 1323, 1240, 1166, 1128, 1062, 1008, 841, 716, 633; 1H NMR (500 MHz, CDCl3) δ 9.10 (br, 1H), 8.83 (d, 1H, J = 4.0 Hz), 8.20 (d, 2H, J = 8.0 Hz), 8.16 (s, 1H), 8.12 (m, 1H), 8.03 (m, 1H), 7.71 (d, 2H, J = 8.0 Hz), 7.53 (d, 1H, J = 4.5 Hz), 7.31 (m, 5H), 6.22 (br, 1H), 5.82 (m, 1H), 5.05 (d, 1H, J = 10.0 Hz), 5.02 (d, 1H, J = 17.0 Hz), 4.48 (d, 1H, J = 10.5 Hz), 4.41 (d, 1H, J = 10.5 Hz), 4.04 (br, 1H), 3.77 (br, 1H), 3.58 (m, 1H), 3.43 (t, 1H, J = 9.5 Hz), 3.31 (m, 1H), 2.61 (m, 1H), 2.42 (t, 1H, J = 10.5 Hz), 2.00 (s, 1H), 1.95 (m, 1H), 1.71 (m, 1H), 1.21 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 148.9, 147.7, 145.8, 143.9, 141.2, 138.4, 136.6, 136.3, 133.8 (q, J = 32.6 Hz), 131.7, 128.5, 128.5, 128.1, 128.1, 128.0, 127.9, 126.7, 126.1, 125.7, 124.2, 123.3 (q, J = 271.5 Hz), 120.1, 118.4, 112.9, 71.9, 59.8, 49.6, 48.6, 37.1, 27.3, 23.3, 18.6 (broad signals due to hindered rotation); HRMS (FAB) for C33H33F3N3O3S: calculated (MH+): 608.2195, found (MH+) 608.2197.

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N–(4–((S)–(Benzyloxy)((1 S,2R,4S,5R)–5–vinylquinuclidin–2–yl)methyl)quinolin–6–yl)–benzenesulfonamide 21: According to the general procedure for the synthesis of sulfonamide catalysts, amine 11 (200 mg, 0.5 mmol) was reacted with benzenesulfonyl chloride (115 mg, 0.6 mmol) in 3 mL of pyridine at 110 °C. The product was purified with column chromatography with CH2Cl2/MeOH/Et3N (100:1:1) followed by EtOAc/MeOH (10:1) yielding sulfonamide 21 (189 mg, 0.35 mmol, 70%) as a yellowish powder. mp 98–101 °C; [α]D = +66.9 (c = 0.35, MeOH);

IR (neat, cm–1) ν 2935, 1518, 1495, 1328, 1164, 1092, 580; 1H NMR (500 MHz, CDCl3) δ 8.79 (d, 1H, J = 4.0 Hz), 8.36 (br, 1H), 8.06 (m, 2H), 7.93 (d, 2H, J = 7.5 Hz), 7.81 (br, 1H), 7.48–7.39 (m, 4H), 7.29 (m, 3H), 7.17 (d, 2H, J = 6.0 Hz), 5.89 (m, 1H), 5.34 (br, 1H), 5.01 (s, 1H), 4.99 (d, 1H, J = 9.5 Hz), 4.24 (d, 1H, J = 11.0 Hz), 4.01 (d, 1H, J = 11.0 Hz), 3.32 (m, 1H), 3.13 (m, 1H), 3.00 (m, 2H), 2.82 (m, 1H), 2.31 (m, 1H), 2.09 (m, 1H), 1.80 (s, 1H), 1.59 (m, 1H), 1.45 (m, 1H), 1.26 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 149.1, 146.0, 144.3, 140.6, 138.2, 137.3, 132.3, 131.6, 129.1, 128.9, 128.5, 127.8, 127.4, 126.8, 125.5, 119.4, 115.4, 114.2, 79.4, 71.3, 59.8, 49.7, 49.1, 39.3, 29.7, 28.0, 25.7, 21.7 (broad signals due to hindered rotation); HRMS (FAB) for C32H34N3O3S: calculated (MH+): 540.2321, found (MH+) 540.2317. N–(4–((S)–(Benzyloxy)((1 S,2R,4S,5R)–5–vinylquinuclidin–2–yl)methyl)quinolin–

6–yl)–4–methylbenzenesulfonamide 22: According to the general procedure for the synthesis of sulfonamide catalysts, amine 11 (400 mg, 0.1 mmol) was reacted with tosyl chloride (268 mg, 1.2 mmol) in 5 mL of pyridine at 110 °C. The product was purified with column chromatography with CH2Cl2/MeOH/Et3N (100:1:1) followed by EtOAc/MeOH (10:1) yielding sulfonamide 22 (484 mg, 0.87 mmol, 87%) as a yellowish powder. mp 136–140 °C; [α]D = +153.6 (c = 1.00,

CH2Cl2); IR (neat) ν cm–1 3375, 3031, 2931, 2804, 2545, 1622, 1483, 1326, 1159, 1091, 909, 728; 1H NMR (500 MHz, CDCl3) δ 8.80 (d, 1H, J = 4.5 Hz), 8.05 (d, 1H, J = 9.0 Hz), 7.93 (br, 1H), 7.83 (d, 3H, J = 8.0 Hz), 7.46 (s, 1H), 7.31 (m, 3H), 7.22 (m, 2H), 7.18 (d, 2H, J = 8.0 Hz), 5.92 (m, 1H), 5.57 (m, 2H), 5.02 (d, 1H, J = 2.5 Hz), 5.00 (d, 1H, J = 10.5 Hz), 4.35 (d, 1H, J = 11.0 Hz), 4.27 (d, 1H, J = 11.0 Hz), 3.45 (br, 1H), 3.09 (m, 3H), 2.87 (br, 1H), 2.32 (s, 4H), 2.13 (m, 1H), 1.81 (s, 1H), 1.62 (m, 1H), 1.49 (m, 1H), 1.28 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 148.9, 145.8, 144.1, 143.2, 139.2, 137.3, 137.1, 131.4, 129.9, 129.5, 129.0, 128.4, 127.9, 127.3, 126.6, 126.1, 124.4, 119.6, 115.4, 113.2, 78.6, 71.4, 59.6, 49.6, 49.0, 39.1, 27.9, 25.4, 21.5, 21.4 (broad signals due to hindered rotation); HRMS (FAB) for C33H36N3O3S: calculated (MH+): 554.2477, found (MH+) 554.2469. N–(4–((S)–(Benzyloxy)((1 S,2R,4S,5R)–5–vinylquinuclidin–2–yl)methyl)quinolin–

6–yl)–2,4,6–trimethylbenzenesulfonamide 23: According to the general procedure for the synthesis of sulfonamide catalysts, amine 11 (200 mg, 0.5 mmol) was reacted with mesitylsulfonyl chloride (130 mg, 0.6 mmol) in 3 mL of pyridine at 110 °C. The product was purified with column chromatography with CH2Cl2/MeOH/Et3N (100:1:1) followed by EtOAc/MeOH (10:1) yielding the sulfonamide 23 (93 mg, 0.16 mmol, 32%) as yellowish solid. mp 104–108 °C; [α]D =

N

OBn

N

NH

S

O

O


85

+105.2 (c = 1.00, CH2Cl2); IR (neat, cm–1) ν 3030, 2937, 2871, 1623, 1454, 1324, 1153, 1056, 958, 832, 736, 654; 1H NMR (500 MHz, CDCl3) δ 8.79 (d, 1H, J = 4.5 Hz), 8.65 (br, 1H), 8.09 (s, 1H), 8.01 (d, 1H, J = 9.0 Hz), 7.65 (d, 1H, J = 9.0 Hz), 7.49 (br, 1H), 7.35 (m, 5H), 6.90 (s, 2H), 5.85 (m, 1H), 5.02 (d, 1H, J = 10.5 Hz), 4.99 (d, 1H, J = 17.5 Hz), 4.47 (d, 1H, J = 10.5 Hz), 4.41 (d, 1H, J = 10.5 Hz), 3.72 (br, 1H), 3.31 (br, 2H), 3.05 (br, 1H), 2.76 (m, 7H), 2.45 (br, 1H), 2.23 (m, 4H), 1.89 (s, 1H), 1.76 (br, 1H), 1.63 (m, 1H), 1.26 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 148.6, 145.3, 142.9, 142.2, 139.4, 138.9, 138.0, 137.2, 137.0, 134.3, 132.0, 131.4, 130.9, 128.5, 128.3, 127.8, 127.3, 126.5, 122.4, 118.7, 116.5, 111.5, 71.6, 59.7, 49.7, 48.7, 38.3, 27.7, 24.6, 23.3, 23.2, 20.9 (broad signals due to hindered rotation); HRMS (FAB) for C35H40N3O3S: calculated (MH+): 582.2790, found (MH+) 582.2798. N–(4–((S)–(Benzyloxy)((1 S,2R,4S,5R)–5–vinylquinuclidin–2–yl)methyl)quinolin–

6–yl)–4–methoxybenzenesulfonamide 24: According to the general procedure for the synthesis of sulfonamide catalysts, amine 11 (100 mg, 0.25 mmol) was reacted with p–methoxybenzenesulfonyl chloride (62 mg, 0.3 mmol) in 1 mL of pyridine at 110 °C. The product was purified with column chromatography with CH2Cl2/MeOH/Et3N (100:1:1) followed by EtOAc/MeOH (10:1) yielding sulfonamide 24 (114 mg, 0.2 mmol, 80%) as a yellowish

powder. mp 96–99 °C; [α]D = +73.8 (c = 1.00, CH2Cl2); IR (neat, cm–1) ν 2936, 1623, 1497, 1455, 1327, 1260, 1157, 1093, 1027, 833, 734; 1H NMR (500 MHz, CDCl3) δ 8.08 (d, 1H, J = 4.5 Hz), 8.05 (d, 1H, J = 9.0 Hz), 8.00 (br, 1H), 7.89 (d, 2H, J = 9.0 Hz), 7.81 (d, 1H, J = 8.0 Hz), 7.71 (br, 1H), 7.44 (br, 1H), 7.29 (m, 3H), 7.20 (m, 2H), 6.85 (d, 2H, J = 9.0 Hz), 5.90 (m, 1H), 5.38 (br, 1H), 5.02 (s, 1H), 4.99 (d, 1H, J = 8.5 Hz), 4.28 (d, 1H, J = 11.5 Hz), 4.11 (d, 1H, J = 11.5 Hz), 3.76 (s, 3H), 3.31 (br, 1H), 3.18 (br, 1H), 3.01 (br, 2H), 2.82 (br, 1H), 2.30 (q, 1H, J = 8.0 Hz), 2.07 (br, 1H), 1.79 (s, 1H), 1.59 (m, 1H), 1.46 (m, 1H), 1.28 (br, 1H); 13C NMR (125 MHz, CDCl3) δ 162.8, 149.0, 146.0, 144.6, 139.7, 137.4, 137.3, 131.7, 131.5, 129.5, 128.4, 127.8, 127.8, 126.8, 124.8, 119.2, 115.2, 114.1, 113.7, 79.5, 71.3, 59.8, 55.5, 49.8, 49.1, 39.5, 28.0, 25.7, 21.8; HRMS (FAB) for C33H36N3O4S: calculated (MH+): 570.2427, found (MH+) 570.2429. N–(4–((S)–(Benzyloxy)((1 S,2R,4S,5R)–5–vinylquinuclidin–2–yl)–methyl)quinolin–

6–yl)–2,4,6–trimethoxybenzenesulfonamide 25: According to the general procedure for the synthesis of sulfonamide catalysts, amine 11 (200 mg, 0.5 mmol) was reacted with 2,4,6–methoxybenzenesulfonyl chloride (160mg, 0.6 mmol) in 2.5 mL of pyridine at 110 °C. The product was purified with column chromatography with CH2Cl2/MeOH/Et3N (100:1:1) followed by EtOAc/MeOH (10:1) yielding sulfonamide 25 (296 mg, 0.47 mmol, 78%) as a yellowish powder. mp 99–102 °C; [α]D= +175.0 (c =

0.32, CH2Cl2); IR (neat, cm–1) ν 2934, 1622, 1515, 1454, 1344, 1322, 1152, 1122, 1086;1H NMR (500 MHz, CDCl3) δ 8.78 (d, 1H, J = 4.0 Hz), 8.02 (d, 1H, J = 9.0 Hz), 7.90 (br, 1H), 7.69 (dd, 1H, J = 9.0, 1.5 Hz), 7.42 (br, 1H), 7.37 (m, 2H), 7.30 (m, 3H), 6.05 (s, 2H), 5.94 (m, 1H), 5.18 (br, 1H), 5.05 (d, 1H, J = 9.0 Hz), 5.03 (s, 1H), 4.35 (d, 1H, J = 11.5 Hz), 4.30 (d, 1H, J = 11.5 Hz), 3.88 (s, 6H), 3.74 (s, 3H), 3.20 (br, 1H), 3.11 (br, 1H), 2.88 (m, 1H), 2.84 (br, 1H), 2.70 (br, 1H), 2.24 (m, 1H), 2.00 (br, 1H), 1.78 (s, 1H), 1.46 (m, 2H), 1.41 (br, 1H) (NH of the sulfonamide is missing); 13C NMR (125 MHz,

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CDCl3) δ 164.5, 160.6, 148.9, 146.0, 145.5, 140.4, 137.7, 136.4, 131.4, 128.4, 127.9, 127.8, 127.0, 123.4, 119.7, 114.7, 111.8, 108.5, 91.5, 80.0, 71.3, 60.1, 56.7, 55.4, 49.7, 49.0, 39.8, 28.0, 26.3, 22.7 (broad signals due to hindered rotation); HRMS (ESI) for C35H40N3O6S: calculated (MH+): 630.2638, found (MH+) 630.2640. N–(4–((S)–(Benzyloxy)((1 S,2R,4S,5R)–5–vinylquinuclidin–2–yl)–methyl)quinolin–

6–yl)–4–(dimethylamino)–benzenesulfonamide 26: According to the general procedure for the synthesis of sulfonamide catalysts, amine 11 (400 mg, 1.0 mmol) was reacted with p–(dimethylamine)benzenesulfonyl chloride (263 mg, 1.2 mmol) in 5 mL of pyridine at 110 °C. The product was purified with column chromatography with CH2Cl2/MeOH/Et3N (100:2:1) followed by EtOAc/MeOH (10:1) yielding sulfonamide 26 (582 mg, 0.8 mmol, 80%) as a yellowish powder. mp 105–107 °C; [α]D = +91.6 (c =

0.57, CH2Cl2); IR (neat, cm–1) ν 2931, 2864, 1594, 1514, 1363, 1314, 1164, 1091, 646; 1H NMR (500 MHz, CDCl3) δ 8.80 (d, 1H, J = 4.5 Hz), 8.04 (d, 1H, J = 9.0 Hz), 7.97 (br, 1H), 7.32 (d, 3H, J = 9.0 Hz), 7.43 (br, 1H), 7.31 (m, 3H), 7.23 (d, 2H, J = 6.5 Hz), 7.10 (br, 1H) 6.53 (d, 2H, J = 9.0 Hz), 5.93 (m, 1H), 5.19 (br, 1H), 5.03 (d, 1H, J = 4.0 Hz), 5.00 (s, 1H), 4.31 (d, 1H, J = 11.5 Hz), 4.16 (d, 1H, J = 11.5 Hz), 3.19 (br, 1H), 3.10 (br, 1H), 2.93 (s, 6H), 2.89 (br, 1H), 2.71 (br, 1H), 2.23 (m, 1H), 2.02 (br, 1H), 1.76 (br, 1H). 1.50 (m, 1H), 1.44 (m, 1H), 1.33 (br, 2H); 13C NMR (125 MHz, CDCl3) δ 152.8, 149.0, 146.0, 145.5, 140.4, 137.7, 136.5, 131.4, 129.2, 128.4, 127.8, 127.7, 127.0, 124.7, 124.2, 119.6, 114.7, 113.2, 110.8, 80.4, 71.3, 60.0, 49.8, 49.3, 39.9, 29.9, 28.1, 26.3, 22.7; HRMS for C34H39N4O3S: calculated (MH+): 583.2743, found (MH+) 583.2745. General procedure for the Cinchona alkaloid catalyzed 1,4–addition to N–acetylated oxazolidinones N–acetylated oxazolidinone (0.5 M) and sulfonamide catalyst 26 (10 mol%) were dissolved in CHCl3 and the resulting mixture was cooled to –20 °C. Subsequently a thiol (3 equiv) was added and the resulting mixture was stirred until consumption of the starting material. The mixture was directed put on silica gel and the product was purified with column chromatography. Preparation of the racemates: All racemic compounds were prepared according to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition to N–acetylated oxazolidinones, where Et3N was used instead of catalyst 26. (S)–3–(3–(Benzhydrylthio)butanoyl)oxazolidin–2–one 31 : According to the general

procedure for the Cinchona alkaloid catalyzed 1,4–addition to N–acetylated oxazolidinone, N–acetylated oxazolidinone 1 (31 mg, 0.2 mmol), sulfonamide catalyst 26 (11 mg, 0.02 mmol) and diphenylmethanethiol (110 µL, 0.6 mmol) were dissolved in 400 µL CHCl3. Stirring at –20 °C for 84 h gave full conversion, the product was purified with column chromatography (PE/EtOAc 2:1), yielding

31 (71 mg, 0.2 mmol, 99%) as a colorless oil. (ee = 85%) (determined by HPLC Daicel chiralcel AD, i–PrOH/heptane 10: (1.0 mL, λ = 220 nm), tr major 20.5 min and tr minor 22.4 min). [α]D = +10.9 (c = 0.28, CH2Cl2); IR (neat, cm–1) ν 2867, 1775, 1698, 1386, 1318, 703;1H NMR (400 MHz, CDCl3) δ 7.45 (d, 4H, J = 7.9 Hz), 7.32 (dd, 4H, J = 7.9, 7.3 Hz), 7.23 (t, 2H, J = 7.3 Hz), 5.33 (s, 1H), 4.39 (t, 2H, J = 8.0 Hz), 3.98 (t, 2H, J =


87

8.0 Hz), 3.31 (dd, 1H, J = 16.5, 6.7), 3.19 (m, 1H), 3.05 (dd, 1H, J = 16.5, 6.6 Hz), 1.32 (d, 3H, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 170.8, 153.2, 141.6, 141.4, 128.4, 128.2, 128.2, 127.0, 127.0, 61.9, 53.6, 42.3, 42.3, 36.2, 21.5; HRMS (ESI) for C20H21NO3SNa: calculated (MNa+): 378.1134, found (MNa+) 378.1111. (S)–3–(3–(Benzylthio)hexanoyl)oxazolidin–2–one 33: According to the general

procedure for the Cinchona alkaloid catalyzed 1,4–addition to N–acetylated oxazolidinone, N–acetylated oxazolidinone 2 (37 mg, 0.2 mmol), sulfonamide catalyst 26 (11 mg, 0.02 mmol) and phenylmethanethiol (71 µL, 0.6 mmol) were dissolved in 400 µL CHCl3. Stirring at –20 °C for 84 h gave full conversion, the product was purified with column chromatography (PE/EtOAc 2:1), yielding

33 (61 mg, 0.2 mmol, 99%) as a colorless oil. (ee = 92%) (determined by HPLC Daicel chiralcel ODH, i–PrOH/heptane 30:70 (0.5 mL, λ = 220 nm), tr major 20.6 min and tr minor 29.6 min). [α]D = +21.6 (c = 0.25, CH2Cl2); IR (neat, cm–1) ν 2027, 2957, 2927, 1773, 1695, 1384, 1221, 1183, 704; 1H NMR (400 MHz, CDCl3) δ 7.36–7.23 (m, 5H), 4.01 (t, 2H, J = 8.4 Hz), 4.00 (m, 2H), 3.80 (m, 2H), 3.30 (m, 1H), 3.13 (m, 2H), 1.58 (m, 2H), 1.51 (m, 1H), 1.41 (m, 1H), 0.87 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 171.3, 153.3, 138.6, 128.9, 128.4, 126.8, 62.0, 45.0, 42.4, 41.1, 40.8, 37.4, 35.3, 19.9, 13.7; HRMS (ESI) for C16H21NO3SNa: calculated (MNa+): 330.1134, found (MNa+) 330.1115. (S)–3–(3–(Benzhydrylthio)hexanoyl)oxazolidin–2–one 35 : According to the general

procedure for the Cinchona alkaloid catalyzed 1,4–addition to N–acetylated oxazolidinone, N–acetylated oxazolidinone 2 (37 mg, 0.2 mmol), sulfonamide catalyst 26 (11 mg, 0.02 mmol) and diphenylmethanethiol (110 µL, 0.6 mmol) were dissolved in 400 µL CHCl3. Stirring at –20 °C for 84 h gave full conversion, the product

was purified with column chromatography (PE/EtOAc 2:1), yielding 35 (75 mg, 0.19 mmol, 97%) as a colorless oil. (ee = 92%) (determined by HPLC Daicel chiralcel AD, i–PrOH/heptane 10:90 (1.0 mL, λ = 220 nm), tr major 14.1 min and tr minor 15.7 min). [α]D

= +22.6 (c = 0.81, CH2Cl2); IR (neat, cm–1) ν 2958, 2927, 1778, 1698, 1386, 1222;1H NMR (400 MHz, CDCl3) δ 7.48 (m, 4H), 7.30 (m, 4H), 7.22 (m, 2H), 5.30 (s, 1H), 4.37 (t, 2H, J = 8.1 Hz), 3.97 (t, 2H, J = 8.1 Hz), 3.29 (m, 1H), 3.11 (m, 2H), 1.57 (m, 2H), 1.40 (m, 2H), 0.82 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 171.1, 153.2, 141.8, 141.7, 128.4, 128.3, 128.2, 127.0, 126.9, 61.9, 53.8, 42.4, 41.3, 41.0, 37.4, 19.7, 13.7; HRMS (ESI) for C22H25NO3SNa: calculated (MNa+): 406.1447, found (MNa+) 406.1429. (R)–3–(3–(Benzhydrylthio)–3–phenylpropanoyl)oxazolidi n–2–one 36: According to

the general procedure for the Cinchona alkaloid catalyzed 1,4–addition to N–acetylated oxazolidinone, N–acetylated oxazolidinone 3 (17 mg, 0.2 mmol), sulfonamide catalyst 26 (5 mg, 0.02 mmol) and diphenylmethanethiol (110 µL, 0.6 mmol) were dissolved in 1 mL CHCl3. Stirring at –20 °C for 140 h gave full conversion, the product was purified with column chromatography

(PE/EtOAc 2:1), yielding 36 (75 mg, 0.18 mmol, 90%) as a colorless oil. (ee = 94%) (determined by HPLC Daicel chiralcel AD, i–PrOH/heptane 10:90 (1.0 mL, λ = 220 nm), tr major 12.4 min and tr minor 15.0 min). [α]D= –85.5 (c = 0.33, CH2Cl2); IR (neat, cm–1) ν 2957, 2853, 1778, 1701, 1387, 675;1H NMR (400 MHz, CDCl3) δ 7.43–7.38 (m, 3H), 7.37–7.26 (m, 7H), 7.25–7.17 (m, 5H), 4.80 (s, 1H), 4.38–4.31 (m, 2H), 4.16 (t, 1H, J =

Pr

O

N O

OS

Ph

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88

7.4 Hz), 3.96–3.88 (m, 2H), 3.53 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 170.0, 153.2, 141.1, 140.9, 140.6, 128.6, 128.5, 128.4, 128.3, 128.1, 128.0, 127.4, 127.2, 127.0, 61.9, 53.6, 44.9, 42.3, 41.4; HRMS (ESI) for C25H23NO3SNa: calculated (MNa+): 440.1291, found (MNa+) 440.1272. General procedure for the Cinchona alkaloid catalyzed 1,4–addition to dehydroaminoacids Alkene (0.2 M) and Cinchona alkaloid derived catalyst 22 (10 mol%) were dissolved in CH2Cl2. A thiol (3 equiv) was added and the resulting mixture was stirred until all the starting material had reacted. The mixture was directed put on silica gel and the product was purified with column chromatography. Preparation of the racemates: All racemic compounds were prepared according to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition to dehydroaminoacids, where Et3N was used instead of catalyst 22. N–((1R,2S)–1–(Benzhydrylthio)–3–oxo–3–(2–oxooxazolidin–3–yl) –1–phenyl–

propan–2–yl)–2,2,2–trifluoroacetamide 38: According to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition to dehydroaminoacids, alkene 4 (1.05 g, 3.2 mmol), catalyst 22 (177 mg, 0.32 mmol) and diphenylmethanethiol (1.76 mL, 9.6 mmol) were dissolved in 16 mL CH2Cl2 and the resulting mixture was stirred for 16 h. The product was purified with column chromatography (PE/EtOAc 2:1), yielding 38 (1.63 g, 3.1 mmol,

97%) as a white powder and as an inseparable mixture of diastereoisomers (anti/syn 93:7) (ee anti = 99% and syn 33%) (determined by HPLC Daicel chiralcel AD, i–PrOH/heptane 10:90 (1.0 mL, λ = 220 nm), tr anti diastereoisomer 53.9 min (major) and 19.0 (minor), tr syn diastereoisomer 16.5 min (major) and 23.7 (minor)). IR (neat, cm–1) ν 3412, 3329, 3028, 1782, 1731, 1699, 1391, 1216, 1168, 700; 1H NMR (400 MHz, CDCl3) δ 7.48–7.20 (m, 15H), 7.10 (d, 0.07H, J = 8.2 Hz), 6.92 (d, 0.93H, J = 8.6 Hz), 6.34 (t, 0.93H, J = 8.3 Hz), 6.03 (dd, 0.07H, J = 8.2, 5.3 Hz), 4.93 (s, 0.93H), 4.81 (s, 0.07H), 4.45–4.34 (m, 2H), 4.19 (m, 0.07H), 4.06 (m, 0.93H), 3.97 (m, 1.93H), 3.73 (m, 0.07H); 13C NMR (100 MHz, CDCl3) δ 168.4, 168.1, 156.1 (q, J = 37.6 Hz), 140.5, 140.0, 139.8, 139.6, 136.7, 136.3, 128.8, 128.7, 128.6, 128.5, 128.5, 128.4, 128.4, 128.3, 127.9, 127.8, 127.6, 127.5, 127.3, 127.0, 115.4 (q, J = 286.3 Hz), 62.4, 56.0, 54.1, 53.9, 53.3, 51.5, 51.1, 42.4. HRMS (ESI) for C27H23F3N2O4SNa: calculated (MNa+): 551.1223, found (MNa+) 551.1205. Recrystallization of the product (PE/EtOAc) gave the anti–isomer as a single enantiomer (1.35 g, 2.56 mmol, 80%). mp 198 °C; [α]D = –196.0 (c = 0.48, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.48–7.20 (m, 15H), 6.92 (d, 1H, J = 8.6 Hz), 6.34 (t, 1H, J = 8.3 Hz), 4.93 (s, 1H), 4.47–4.37 (m, 2H), 4.06 (m, 1H), 3.97 (d, 1H, J = 11.3 Hz), 3.94 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 168.3, 156.1 (q, J = 37.6 Hz), 152.6, 140.0, 139.7, 136.3, 128.7, 128.6, 128.6, 128.4, 128.4, 128.3, 128.3, 127.6, 127.3, 115.4 (q, J = 286.3 Hz), 62.4, 54.1, 53.9, 51.5, 42.4.


89

N–((1R,2S)–1–(Benzylthio)–1–(4–methoxyphenyl)–3–oxo–3–(2–oxo oxazolidin–3–yl)–propan–2–yl)–2,2,2–trifluoroacetamide 40: According to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition to dehydroaminoacids, alkene 8 (29 mg, 0.08 mmol), catalyst 22 (4 mg, 0.008 mmol) and phenylmethanethiol (28 μL, 0.24 mmol) were dissolved in 400 µL CH2Cl2 and the resulting mixture was stirred for 16 h. The product was purified with column chromatography (PE/EtOAc 2:1), yielding 40 (36 mg,

0.079 mmol, 99%) as a white powder and as an inseparable mixture of diastereoisomers (anti/syn 80:20) (ee anti = 98% and syn 3%) (determined by HPLC Daicel chiralcel AD, i–PrOH/heptane 30:70 (1.0 mL, λ = 220 nm), tr anti diastereoisomer 23.3 min (major) and 9.8 min (minor), tr syn diastereoisomer 8.2 min (major) and 12.8 min (minor)). IR (neat, cm–1) ν 3323, 2929, 1779, 1728, 1699, 1495, 1251, 1175;1H NMR (400 MHz, CDCl3) δ 7.28–7.17 (m, 5H), 7.15 (m, 2H), 6.95 (d, 0.2H, J = 10.0 Hz), 6.87 (d, 0.8H, J = 8.3 Hz), 6.81 (m, 2H), 6.21 (t, 0.8H, J = 7.7 Hz), 5.91 (dd, 0.2H, J = 8.3, 5.6 Hz), 4.38 (t, 1.6H, J = 8.1 Hz), 4.28 (m, 0.2H), 4.14 (d, 0.2H, J = 5.6 Hz), 4.12 (d, 0.8H, J = 7.3 Hz), 4.03 (m, 0.4H), 3.96 (m, 0.8H), 3.86 (m, 0.8H), 3.74 (s, 0.6H), 3.73 (s, 2.4H), 3.67 (d, 0.8H, J = 12.9 Hz), 3.57–3.50 (m, 1.2H), 3.28 (d, 0.2H, J = 13.6 Hz). 13C NMR (100 MHz, CDCl3) δ 168.7, 168.4, 159.7, 159.6, 156.5 (q, J = 38.0 Hz), 152.9, 152.5, 137.5, 136.9, 129.7, 129.4, 129.1, 129.0, 128.8, 128.6, 128.5, 128.3, 127.9, 127.4, 127.3, 115.5 (q, J = 286.0 Hz), 114.3, 114.1, 62.6, 62.4, 56.3, 55.3, 50.2, 49.2, 42.7, 42.6, 35.9, 35.1; HRMS (ESI) for C22H21F3N2O5SNa: calculated (MNa+): 505.1015, found (MNa+) 505.0998. 2,2,2–Trifluoro– N–((1R,2S)–1–((4–methoxybenzyl)thio)–1–(4–methoxyphenyl)–3–

oxo–3–(2–oxooxazolidin–3–yl)–propan–2–yl)–acetamide 41: According to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition to dehydroaminoacids, alkene 8 (29 mg, 0.08 mmol), catalyst 22 (4 mg, 0.008 mmol) and 4–MeO–phenylmethanethiol (34 μL, 0.24 mmol) were dissolved in 400 µL CH2Cl2 and the resulting mixture was stirred for 16 h. The product was purified with column chromatography (PE/EtOAc 2:1), yielding 41 (37 mg, 0.077 mmol, 96%) as

a white powder and as an inseparable mixture of diastereoisomers (anti/syn 80:20) (ee anti = 96% and syn 52%) (determined by HPLC Daicel chiralcel AD, i–PrOH/heptane 30:70 (1.0 mL, λ = 220 nm), tr anti diastereoisomer 78.5 min (major) and 13.9 min (minor), tr syn diastereoisomer 16.7 min (major) and 9.3 min (minor)). IR (neat, cm–1) ν 3321, 2925, 1779, 1728, 1699, 1583, 1510, 1391, 1249, 1215, 1174, 1033; 1H NMR (400 MHz, CDCl3) δ 7.43 (d, 0.4H, J = 8.7 Hz), 7.20–7.14 (m, 3.2H), 7.09 (d, 0.4H, J = 8.6 Hz), 7.01 (d, 0.2H, J = 8.3 Hz), 6.97 (d, 0.8H, J = 7.5 Hz), 6.89–6.81 (m, 4H), 6.29 (t, 0.8H, J = 7.8 Hz), 5.98 (dd, 0.2H, J = 8.3, 5.3 Hz), 4.47 (t, 1.6H, J = 8.1 Hz), 4.37 (m, 0.2H), 4.23 (m, 1H), 4.06 (m, 0.8H), 3.98 (m, 1H), 3.84 (s, 0.6H), 3.84 (s, 0.6H), 3.82 (s, 2.4H), 3.81 (s, 2.4H), 3.71 (d, 0.8H, J = 12.8 Hz), 3.66–3.58 (m, 1.2H), 3.33 (d, 0.2H, J = 13.6 Hz); 13C NMR (100 MHz, CDCl3) δ 168.6, 168.2, 159.6, 159.5, 158.8, 158.8, 156, 156.4 (q, J = 37.5 Hz), 130.2, 130.1, 129.7, 129.4, 128.7, 128.5, 127.9, 115.5 (q, J = 286.0 Hz), 114.2, 114.1, 114.0, 113.9, 62.6, 62.4, 56.5, 55.3, 55.2, 54.2, 50.0, 48.8, 42.5, 42.5, 35.3, 34.5; HRMS for C23H23F3N2O6SNa: calculated (MNa+): 535.1121, found (MNa+) 535.1101.

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N–((1R,2S)–1–(Benzhydrylthio)–1–(4–methoxyphenyl)–3–oxo–3–(2 –oxo–oxazolidin–3–yl)–propan–2–yl)–2,2,2–trifluoroacetam ide

42: According to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition to dehydroaminoacids, alkene 8 (29 mg, 0.08 mmol), catalyst 22 (4 mg, 0.008 mmol) and diphenylmethanethiol (44 μL, 0.24 mmol) were dissolved in 400 µL CH2Cl2 and the resulting mixture was stirred for 16 h. The product was purified with column chromatography (PE/EtOAc

2:1), yielding 42 (43 mg, 0.077 mmol, 96%) as a white powder and as an inseparable mixture of diastereoisomers (anti/syn 90:10) (ee anti = 98% and syn 17%) (determined by HPLC Daicel chiralcel AD, i–PrOH/heptane 10:90 (1.0 mL, λ = 220 nm), tr anti diastereoisomer 91.2 min (major) and 27.1 min (minor), tr syn diastereoisomer 30.7 min (major) and 36.3 min (minor)). IR (neat, cm–1) ν 3323, 1779, 1729, 1698, 1510, 1390, 1211, 1165, 730, 701; 1H NMR (400 MHz, CDCl3) δ 7.38–7.22 (m, 10H), 7.14 (m, 2.1H), 6.91–6.86 (m, 2.9H), 6.30 (t, 0.9H, J = 8.2 Hz), 6.00 (dd, 0.1H, J = 8.4, 5.4 Hz), 4.91 (s, 0.9H), 4.79 (s, 0.1H), 4.43 (m, 1.8H, 4.20 (m, 0.1H), 4.09 (m, 0.1H), 4.06 (m, 1H), 3.92 (m, 1.9H), 3.84 (s, 3H), 3.73 (m, 0.1H); 13C NMR (100 MHz, CDCl3) δ 168.7, 168.4, 159.7, 159.6, 156.3 (q, J = 38.0 Hz), 140.7, 140.2, 139.9, 139.7, 129.7, 129.6, 128.7, 128.6, 128.6, 128.5, 128.4, 128.1, 128.0, 127.8, 127.7, 127.6, 127.4, 115.5 (q, J = 287.0 Hz), 114.2, 114.1, 62.5, 60.4, 56.2, 55.3, 54.3, 53.9, 53.3, 51.0, 50.5, 42.5; HRMS (ESI) for C28H25F3N2O5SNa: calculated (MNa+): 581.1328, found (MNa+) 581.1307. N–((2S,3R)–3–(Benzhydrylthio)–1–oxo–1–(2–oxooxazolidin–3–yl) pentan–2–yl)–

2,2,2–trifluoroacetamide 45: According to the general procedure for the Cinchona alkaloid catalyzed 1,4–addition on to dehydroaminoacids, alkene 5 (22 mg, 0.08 mmol), catalyst 22 (4 mg, 0.008 mmol) and diphenylmethanethiol (44 μL, 0.24 mmol) were dissolved in 400 µL CH2Cl2 and the resulting mixture was stirred for 16 h. The product was purified with column chromatography (PE/EtOAc 2:1), yielding 45 (37 mg, 0.077

mmol, 96%) as a white powder and as an inseparable mixture of diastereoisomers (anti/syn 93:7) (ee anti = 98% and syn 3%) (determined by HPLC Daicel chiralcel AD, i–PrOH/heptane 10:90 (1.0 mL, λ = 220 nm), tr anti diastereoisomer 20.2 min (major) and 17.9 min (minor), tr syn diastereoisomer 11.7 min (major) and 10.1 min (minor)). IR (neat, cm–1) ν 3328, 1781, 1727, 1697, 1538, 1390, 1207, 1171, 702; 1H NMR (400 MHz, CDCl3) δ 7.54 (d, 1.86H, J = 7.6 Hz), 7.42–7.24 (m, 8.21H), 6.97 (d, 0.93H, J = 8.3 Hz), 6.16 (dd, 0.93H, J = 8.3, 5.8 Hz), 5.74 (d, 0.07H, J = 9.2 Hz). 5.35 (s, 0.93H), 5.14 (s, 0.07H), 4.48–4.36 (m, 1.86H), 4.23 (m, 0.14H), 4.08 (m, 0.93H), 3.95 (m, 1H), 3.70 (m, 0.07H), 3.05 (m, 0.07H), 2.95 (m, 0.93H), 1.85 (m, 0.07H), 1.62 (m, 1H), 1.38 (m, 0.93H), 1.12 (t, 0.21H, J = 7.4 Hz), 0.99 (t, 2.79H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 169.3, 156.9 (q, J = 37.0 Hz), 152.7, 141.0, 140.9, 128.8, 128.8, 128.6, 128.4, 128.4, 128.2, 128.1, 127.8, 127.6, 127.4, 127.3, 115.6 (q, J = 286.0 Hz), 62.5, 62.4, 54.8, 54.1, 53.9, 53.7, 48.9, 42.5, 28.1, 23.3, 11.7, 11.3; HRMS (ESI) for C23H23F3N2O4SNa: calculated (MNa+): 503.1223, found (MNa+) 503.1208.


91

(S)–3–(3–Mercaptohexanoyl)oxazolidin–2–one 46: 35 (70 mg, 0.18 mmol) was dissolved in 1.5 mL TFA and CH2Cl2 (60:40) followed by 0.15 mL iPr3SiH. The resulting mixture was stirred for 1 h and the crude was concentrated and purified with column chromatography (PE/EtOAc 3:1) yielding the free thiol 46 (38, mg, 0.17 mmol, 96%) as a colorless

oil. (ee = 92%) (determined by HPLC Daicel chiralcel ODH, i–PrOH/heptane 15:85 (0.5 mL, λ = 220 nm), tr major 34.3 min and tr minor 32.5 min). All analytical data were the same as reported in literature.7

(2S,3R)–Methyl–3–(benzhydrylthio)–2–(( tert–butoxycarbonyl)amino)–3–phenyl–

propanoate 47: 38 (2.1 g, 3.9 mmol) was dissolved in 120 mL of a mixture of HCl (0.33 M) in methanol the mixture was stirred overnight at reflux temperature. The solvent was evaporated and the crude mixtures was dissolved in 70 mL of CH2Cl2, next Boc2O (1.03 g, 4.7 mmol) was added followed by DIPEA (1.03 mL, 5.9 mmol). The resulting mixture was stirred for 6 h and then quenched with saturated NaHCO3, the layers were separated, dried with MgSO4 and

the crude was concentrated. Next the crude product was dissolved in 75 mL methanol and cooled to 0 °C. K2CO3 (2.2 g, 15.9 mmol) was slowly added and stirring was continued for 5 min. The mixture was quenched with saturated NH4Cl and the resulting mixture was extracted 3 times with EtOAc. The organic layers were combined and dried with MgSO4. The product was purified with flash column chromatography (PE/EtOAc 8:1) yielding 47 (1.28 g, 2.7 mmol, 68%) as a colorless oil and single isomer. (determined by HPLC Daicel chiralcel AD, i–PrOH/heptane 5:95 (1.0 mL, λ = 220 nm), tr anti diastereoisomer 6.6 (major) and 12.4 min (minor), tr syn diastereoisomer 8.2 min (major) and 9.2 min (minor)). [α]D = –134.4 (c = 1.0, CH2Cl2); IR (neat, cm–1) ν 3435, 1746, 1714, 1492, 1162, 700;1H NMR (400 MHz, CDCl3) δ 7.39–7.22 (m, 15H), 5.01 (m, 2H), 4.83 (t, 1H, J = 5.9 Hz), 3.96 (d, 1H, J = 5.6 Hz), 3.64 (s, 3H), 1.41 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 170.7, 155.1, 140.4, 140.3, 137.0, 128.6, 128.5, 128.5, 128.3, 128.1, 127.3, 127.2, 80.0, 57.0, 53.5, 52.1, 51.9, 28.2; HRMS (ESI) for C28H31NO4SNa: calculated (MNa+): 500.1866, found (MNa+) 500.1849. (2S,3R)–3–(Benzhydrylthio)–2–(( tert–butoxycarbonyl)amino)–3–phenylpropanoic

acid 48: 47 (900 mg, 1.9 mmol) was dissolved in a mixture of dioxane (9.4 mL) and methanol (2.5 mL). Next 0.63 mL of 3M NaOH was added and the mixture was stirred overnight. The solution was acidified with 1M KHSO4 to pH = 1 and 3 times extracted with EtOAc. The organic layers were combined and dried with MgSO4. The product was purified with column chromatography (PE/EtOAc/AcOH 8:1:0.2) yielding acid 48 (770 mg, 1.66 mmol, 88%) as a white solid. mp 61–63 °C; [α]D = –

83.6 (c = 0.67, MeOH); IR (neat, cm–1) ν 1706, 1491, 1155, 747; 1H NMR (400 MHz, DMSO, 363 K) (3:1 mixture of rotamers in 1H NMR) δ 7.62 (d, 1H, J = 7.1 Hz), 7.41–7.13 (m, 14H), 6.38 (br, 0.25H), 6.20 (br, 0.75H), 5.00 (s, 0.75H), 4.92 (s, 0.25H), 4.49 (t, 0.75H, J = 8.2 Hz), 4.44 (t, 0.25H, J = 9.1 Hz), 4.08 (d, 0.25H, J = 7.2 Hz), 4.00 (d, 0.75, J = 8.0 Hz), 1.38 (s, 4H), 1.29 (s, 5H); 13C NMR (100 MHz, DMSO, 363 K) (mixture of rotamers): δ 170.7, 140.6, 140.3, 137.8, 133.7, 130.3, 129.2, 128.3, 128.1, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 126.8, 126.6, 126.6, 126.5, 78.5 and 78.2 (rotamers), 53.2, 51.6, 50.4, 27.7 and 27.6 (rotamers); HRMS (ESI) for C27H29NO4SNa: calculated (MNa+): 486.1710, found (MNa+) 486.1695.

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(2S,3R)–Methyl 2–amino–3–mercapto–3–phenylpropanoate 49: 47 (53 mg, 22 mmol) was dissolved in 1 mL TFA followed by the addition of 0.1 mL iPr3SiH. The resulting mixture was stirred for 1 h at 50 °C and then the crude product was dissolved in EtOAc. Saturated K2CO3 was added and the layers were separated. The water layer was extracted 2 more times with EtOAc. The organic layers were combined, dried with Na2SO4 and then concentrated. The product was purified with column

chromatography (EtOAc) yielding 49 as the disulfide (22, mg, 0.052 mmol, 95%) as an oil. [α]D = –102.6 (c = 0.35, MeOH) IR (neat, cm–1) ν 3382, 2951, 1740, 1267, 757; 1H NMR (400 MHz, MeOD) δ 7.26 (m, 3H), 7.10 (m, 2H), 3.95 (d, 1H, J = 6.4 Hz), 3.87 (d, 1H, J = 6.4 Hz), 3.57 (s, 3H). 13C NMR (100 MHz, MeOD) δ 173.9, 137.8, 130.0, 129.9, 129.7, 129.6, 59.2, 58.1, 52.7. HRMS (ESI) for C20H25N2O4S2: calculated (MH+): 421.1250, found (MH+) 421.1237. Tetrapeptide 50: Acid 48 (172 mg, 0.37) was dissolved in 7 mL THF followed by HOAt

(50 mg, 0.37 mmol), HATU (140 mg, 0.37 mmol) and DIPEA (129 μL, 0.74 mmol). Next H2N–Ala–Val–Phe–CO2Me (130 mg, 0.37 mmol) in 1 mL THF was added and the mixture was stirred for 6 h. The crude was acidified with 1 M KHSO4 to pH = 1 and extracted 3 times with EtOAc. The organic layers

were combined, dried with MgSO4 and concentrated. The product was purified with column chromatography (PE/EtOAc 1:1), yielding tetrapeptide 50 (214 mg, 0.27 mmol, 73%) as a white solid. mp 188–190 °C; IR (neat, cm–1) ν 3645, 3272, 2968, 1737, 1714, 1632, 1159, 838; 1H NMR (400 MHz, DMSO, 363 K) δ 8.00 (br, 1H), 7.94 (br, 1H), 7.44 (br, 1H), 7.30–7.21 (m, 18H), 7.11 (d, 2H, J = 7.3 Hz), 6.19 (br, 1H), 4.89 (s, 1H), 4.56 (m, 2H), 4.45 (m, 1H), 4.17 (t, 1H, J = 8.2 Hz), 3.90 (d, 1H, J = 8.2 Hz), 3.60 (s, 3H), 3.00 (m, 1H), 2.97 (m, 1H), 1.97 (m, 1H), 1.37 (d, 3H, J = 4.8 Hz), 1.22 (s, 9H), 0.83 (m, 6H); 13C NMR (100 MHz, DMSO): 171.8, 171.7, 171.1, 169.7, 154.5, 141.4, 140.7, 139.4, 137.1, 129.0, 128.9, 128.6, 128.5, 128.4, 128.3, 128.1, 128.1, 127.9, 127.1, 127.0, 126.6, 77.9, 58.3, 57.4, 53.5, 53.5, 51.8, 50.5, 48.5, 36.5, 30.7, 28.0, 19.1, 18.1, 18.0; HRMS (ESI) for C45H54N4O7SNa: calculated (MNa+): 817.3605, found (MNa+) 817.3566. Tetrapeptide 51: Protected tetrapeptide 50 (50 mg, 0.063 mmol) was dissolved in 5 mL

of TFA and 0.25 mL of iPr3SiH. The resulting mixture was heated for 2 h at 50 °C. The solvent was removed and the peptide was purified by preparative HPLC (BESTA preparative system, Inerstsill ODS C18 column 10x250 mm, gradient H2O/ACN 0.1% TFA 60:40 to 30:70, 30 min) yielding 51 as a TFA salt and

as a mixture of free thiol and disulfide. Low resolution LCMS for free thiol C27H37N4O5S: calculated (MH+): 529.2, found (MH+) 529.2 and for disulfide C54H71N8O10S: calculated (MH+): 1055.5, found (MH+) 1055.4.


93

Dipeptide 52: Boc–β–Ala–Phe–OH (336 mg, 1 mmol) was dissolved in 2 mL THF, thiophenol (113 μL, 1.1 mmol), HATU (380 mg, 1 mmol), DIPEA (348 μL, 2mmol) were added and the reaction mixture was stirred overnight. The mixture was concentrated and then dissolved in EtOAc. The organic layer was washed with 1M KHSO4, brine and dried with Na2SO4 The thioester was purified with column chromatography (PE/EtOAc 3:2) providing thioester 52 (189 mg, 0.43 mmol, 43%) as a white

solid. mp 144–146 °C; IR (neat, cm–1) ν 3354, 3306, 1698, 1680, 1650, 1517, 1076, 781; 1H NMR (500 MHz, DMSO) δ 8.79 (d, 1H, J = 7.5 Hz), 7.48 (m, 3H), 7.38 (m, 2H), 7.26 (m, 5H), 6.69 (br, 1H), 4.68 (m, 1H), 3.15 (m, 3H), 2.92 (dd, 1H, J = 13.5, 10.5 Hz), 2.36 (m, 1H), 2.27 (m, 1H), 1.36 (s, 9H); 13C NMR (125 MHz, DMSO): 198.6, 171.0, 155.4, 137.1, 134.5, 129.4, 129.3, 129.1, 128.3, 127.3, 126.6, 77.6, 60.5, 365, 36.4, 35.5, 28.2. Hexapeptide 53: Tetrapeptide 51 (5 mg, 0.008 mmol) was dissolved in 1 mL of 0.1M

phosphate buffer containing 0.05M TCEP and 2 v/v% thiophenol. The pH was adjusted to pH = 8 with 0.1M NaOH. Next 3 mL of a degassed solution of ACN containing thioester

52 (4 mg, 0.009 mmol) was added and the resulting mixture was stirred overnight. The hexapeptide 53 was purified by preparative HPLC (BESTA preparative system, Inerstsill ODS C18 column 10x250 mm, gradient H2O/ACN 0.1% TFA 60:40 to 20:80, 30 min). Low resolution LCMS for C44H57N6O9S: calculated (MH+): 847.4, found (MH+) 847.1. Hexapeptide 55: Tetrapeptide 51 (5 mg, 0.008 mmol) was dissolved in 1 mL of 0.1M

phosphate buffer containing 0.05M TCEP. The pH was adjusted to pH = 8 with 0.1M NaOH. Next 3 mL of a degassed solution of ACN containing activated ester 54 (5.3 mg, 0.009

mmol) was added and the resulting mixture was stirred overnight. The hexapeptide 55 was purified by preparative HPLC (BESTA preparative system, Inerstsill ODS C18 column 10x250 mm, gradient H2O/ACN 0.1% TFA 60:40 to 20:80, 30 min). Low resolution LCMS for C50H63N6O9S: calculated (MH+): 923.4, found (MH+) 923.1.

3.12 References

1) Breman, A. C.; Smits, J. M. M.; de Gelder, R.; van Maarseveen, J. H.; Ingemann, S.; Hiemstra, H. Synlett 2012, 23, 2195–2200.

2) a) Rana, N. K.; Selvakumar, S.; Singh, V. K. J. Org. Chem. 2010, 75, 2089–2091 b) Connon, S. J. Chem. Eur. J. 2006, 12, 5418–5427 c) McCooey, S. H.; Connon S. J. Angew. Chem. Int. Ed. 2005, 44, 6367–6370.

3) a) Almasi, D.; Alonso, D. A.; Gómez–Bengoa, E.; Nájera, C. J. Org. Chem. 2009, 74, 6163–6168 b) Zhang, L.; Lee, M–M.; Lee, S–M.; Lee, J.; Cheng, M.; Jeong, B–S.; Park, H–G.; Jew, S–S. Adv. Synth. Catal. 2009, 351, 3063–3066.

4) Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Chem. Eur. J. 2011, 17, 6890–6899. 5) Chen, X.–H.; Luo, S.–W.; Tang, Z.; Cun, L.–F.; Mi, A.–Q.; Jiang, Y.–Z.; Gong, L.–Z. Chem. Eur.

J. 2007, 13, 689–701.

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6) a) Oh, S. H.; Rho, H. S.; Lee, J. W.; Lee, J. E.; Youk, S. H.; Chin, J.; Song, C. E. Angew. Chem. Int. Ed. 2008, 47, 7872–7875 b) Xiao, X.; Liu, M.; Rong, C.; Xue, F.; Li, S.; Xie, Y.; Shi, Y. Org. Lett. 2012, 14, 5270–5273.

7) Liu, Y.; Sun, B. F.; Wang, B. M.; Wakem, M.; Deng, L. J. Am. Chem. Soc. 2009, 131, 418–419. 8) Marcelli, T.; van der Haas, R. N. S.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem. Int. Ed.

2006, 45, 929–931. 9) a) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701–1716 b) Yu, X; Wang, W. Chem. Asian J.

2008, 3, 516–532 c) Marcelli, T.; Hiemstra, H. Synthesis 2010, 1229–1279. 10) Zhang Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187–1198. 11) Jakab, G.; Tancon, C.; Zhang, Z.; Lippert, K. M.; Schreiner, P. R. Org. Lett. 2012, 14, 1724–1727. 12) Ishikawa, T. Superbases for Organic Synthesis: Guanidines, Amidines, Phosphazenes and

Related Organocatalysts, John Wiley & Sons, 2009. 13) Brown, T. N.; Mora–Diez, N. J. Phys. Chem. B 2006, 110, 20546–20554. 14) Ni, X.; Li, X.; Wang, Z.; Cheng, J.–P. Org. Lett. 2014, 16, 1786–1789. 15) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416–14417. 16) Arthur, G. The Amide Linkage: Selected Structural Aspects in Chemistry, Biochemistry, and

Materials Science, Ed.; Wiley–VCH: Weinheim, 2000. 17) Huang, X.–Y.; Wang, H.–J.; Shi, J. J. Phys. Chem. A 2010, 114, 1068–1081. 18) Shainyan, B. A.; Tolstikova, L. L. Chem. Rev. 2013, 113, 699−733. 19) Gόngora–Benítez, M.; Mendive–Tapia, L.; Ramos–Tomillero, I.; Breman, A. C.; Tulla–Puche, J.;

Albericio, F. Org. Lett. 2012, 14, 5472–5475. 20) Ohno, M.; Miyamoto, M.; Hoshi, K.; Takeda, T.; Yamada, N.; Ohtake, A. J. Med. Chem. 2005,

48, 5279–5294. 21) Narasaka, K.; Iwasawa, N.; Inoue, M.; Yamada, T.; Nakashima, M.; Sugimori, J. J. Am. Chem.

Soc. 1989, 111, 5340–5345. 22) Whitten, J. P.; Matthews, D. P.; McCarthy, J. R. J. Org. Chem. 1986, 51, 1891–1894. 23) Corey, E. J.; Zhang, J. Org. Lett. 2001, 3, 3211–3214. 24) Palmer, A. M.; Chiesa, V.; Schmid, A.; Munch, G.; Grobbel, B.; Zimmermann, P. J.; Brehm, C.;

Buhr, W.; Simon, W.; Kromer, W.; Postius, S.; Volz, J.; Hess, D. J. Med. Chem. 2010, 53, 3645–3674.

25) Cui, Y.–M.; Yasutomi, E.; Otani, Y.; Yoshinaga, T.; Ido, K.; Sawada, K. Ohwada, T. Bioorg. Med. Chem. Lett. 2008, 18, 5201–5205.

26) Kilpatrick, B.; Heller, M.; Arns, S. Chem. Commun. 2013, 49, 514–516. 27) Hammett, L. P. J. Am. Chem. Soc. 1937, 59, 95–103. 28) King, S. B.; Ganem, B. J. Am. Chem. Soc. 1994, 116, 562–570. 29) Tesser, G. I.; Balvert–Geers, I. C. Int. J. Peptide Protein Res. 1975, 7, 295–305. 30) a) Dawson, P. E.; Muir, T. W.; Clark–Lewis, I.; Kent, S. B. H. Science 1994, 266, 776–779 b)

Dawson, P. E.; Kent, S. B. H. Annu. Rev. Biochem. 2000, 69, 923–960 c) Hackenberger C. P. R.; Schwarzer, D. Angew. Chem. Int. Ed. 2008, 47, 10030–10074.

31) a) Crich, D.; Banerjee, A. J. Am. Chem. Soc. 2007, 129, 10064–10065 b) Thompson, R. E.; Chan, B.; Radom, L.; Jolliffe, K. A.; Payne, R. J. Angew. Chem. Int. Ed. 2013, 52, 9723–9727.

32) Popovic, S.; Bieräugel, H.; Detz, R. J.; Kluwer, A. M.; Koole, J. A. A.; Streefkerk, D. E.; Hiemstra, H.; van Maarseveen, J. H. Chem. Eur. J. 2013, 19, 16934–16937.

33) Zhong, Z.; Liu, J. L.–C.; Dinterman, L. M.; Finkelman, M. A. J.; Mueller, W. T.; Rollence, M. L.; Whitlow, M.; Wong, C.–H. J. Am. Chem. Soc. 1991, 113, 684–686.

Studies on the Role of the Quinuclidine Ring System in Asymmetric Organocatalysis

95

CHAPTER 4

Studies on the Role of the Quinuclidine Ring System in Asymmetric

Organocatalysis *

Abstract: Synthetic analogues of quinidine were prepared with modifications in the quinuclidine ring system. These novel analogues were used as organocatalysts in several asymmetric conjugate addition reactions and compared with three known catalysts. This study was performed in order to understand the role of the quinuclidine ring in asymmetric organocatalysis. The results show that modification of the quinuclidine ring can have a substantial influence not only on the enantioselectivity, but also on the catalyst activity. In addition, the pKAH’s of the novel derivatives were determined successfully with fluorescence spectroscopy.

*Part of this work will be published in:

Breman, A. C.; van der Heijden, G.; van Maarseveen, J. H.; Ingemann, S.; Hiemstra, H. J. Org. Chem.

manuscript in preparation

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4.1 Introduction

Irrespective of the fact that many reactions catalyzed by (modified) Cinchona alkaloids give high levels of enantioselectivity, the nature of the actual transitions states still remains unclear.1 These reactions rely on activation through non–covalent interactions complicating experimental studies of the mechanism of these reactions. Many research groups have proposed transition states that fit the outcome of the reactions in terms of stereochemistry. There is no experimental evidence that the proposed transition states are responsible for the observed enantioselectivity. So far only a limited number of calculations have supported the proposed transition states.2

As described in chapter 1, the studies by Merschaert3 and Hintermann4 showed that the intramolecular oxa–Michael addition of phenol to α,β–unsaturated esters is likely to proceed through a concerted mechanism. Merschaert proposed this type of mechanism based on modifications of the catalyst and calculations.3 This was supported by Hintermann, who modified the substrates and performed deuterium labeling studies.4 A different strategy to gain more insight in the mechanism of Cinchona alkaloid catalyzed reactions is to synthetize analogues of Cinchona alkaloids. The group of Lygo prepared several analogues in which the quinoline ring system was replaced for other functional groups.5 These analogues were further modified to suitable phase transfer catalysts and were examined in the alkylation of glycine imine with benzyl bromide (scheme 1).

Scheme 1. Studies by Lygo et al on the phase transfer alkylation of glycine derivatives.5

From their limited study it appeared that a planar (aryl) substituent at the R–position gave the best results. Also the nature of the aryl group appeared to be important. A more drastic effect was observed when the N–substituent of the quinuclidine ring was changed. The enantioselectivity was improved from 48% to 75% by replacing the benzyl group by a 9–methylanthracyl group (R = Ph in scheme 1). The group of Lygo suggested that the extent and orientation of the π–plane of the aromatic ring of the quaternary ammonium salt is important for the enantioselectivity.

A part of the Cinchona alkaloid that has not yet been structurally modified is the quinuclidine ring. This bicyclic system contains a tertiary nitrogen atom with a pKAH of 11.0 in water if the ring is non–substituted.6 The pKAH of the quinuclidine ring in Cinchona alkaloids have been experimentally determined to lie between 8 and 9.7 The lower pKAH of the quinuclidine ring in Cinchona alkaloids has been ascribed to the electron withdrawing groups on the C–3 and C–8 positions. Further, the nitrogen atom is in a bicyclic system which prevents inversion of the lone pair. As a result, the nitrogen atom is a chiral center and the lone pair is in a fixed direction. Modifying the quinuclidine ring


97

system by removing or adding methylene–groups at several positions represents a new strategy for studying the role of this part of Cinchona alkaloids in organocatalytic reactions (figure 1).

Figure 1 . Modifications of the quinuclidine ring.

These modifications should have a significant influence on both the pKAH and the direction of the lone pair. By removing methylene groups the system will become more rigid, while the addition of CH2–groups will induce more flexibility in the bicyclic system. It was decided, therefore, to synthesize the analogues in figure 1. The vinyl group was not introduced in the novel derivatives, because this would complicate the syntheses.

The analogues will be examined in known asymmetric reactions and the results compared with those obtained with the natural alkaloid. Also the pKAH’s and the activity of the catalysts will be determined, in order to study the possible relationship between the enantioselectivity, pKAH and efficiency of the catalysts.

4.2 Analogue synthesis

The synthesis of the novel analogues involved the same strategy as developed by Jacobsen8a and Kobayashi8b–d for the total synthesis of quinine and quinidine (scheme 2).

Scheme 2. Synthetic approach for the formation of modified bicyclic systems.

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98

In their approach, the quinuclidine ring system was prepared via nucleophilic attack of a secondary amine on a chiral epoxide (see also chapter 1, scheme 13). This chiral epoxide was introduced via asymmetric dihydroxylation of an alkene followed by epoxide formation.9,10 Following this strategy the correct stereochemistry was introduced at the C8– and C9–carbon atoms. Because of the absence of the vinyl group in the novel derivatives in figure 1, the main stereocenters that should be controlled are these two stereocenters.

4.2.1 Synthesis of the [1.2.2]–series

The synthesis towards the [2.1.2]–analogue starts from known (R)–pyrrolidin–3–yl methanol 1 (scheme 3).11 Compound 1 was protected with a Teoc–group using 2–TMS–ethanol, triphosgene and K2CO3 in 73% yield.8b–d The alcohol was oxidized by a Swern oxidation yielding aldehyde 2 in 95%.12 The aldehyde was treated with (methoxymethyl)–triphenylphosphonium chloride and NaHMDS to yield an enol ether as 4:1 mixture of E– and Z–isomers.14 The enol ether was hydrolyzed with CeCl3·7H2O and NaI in 89%. The extended aldehyde was reacted with the lithium salt of commercially available 4–methyl–6–methoxyquinoline which was formed by deprotonation with LDA, giving alcohol 3 as a 1:1 mixture of diastereoisomers.8b–d

Scheme 3. Synthesis of the [2.1.2]–analogue.

The double bond was introduced by mesylation of the alcohol followed by elimination with KOt–Bu yielding the alkene in 96% yield. Diol 4 was obtained as an inseparable


99

mixture of diastereoisomers (4:1) in 78% yield with the use of AD–mix α.9 In a one pot procedure the chiral epoxide was obtained in 88% yield.10 Finally, the epoxide was treated with CsF in DMF and t–BuOH at 110 °C.8b–d Under these conditions the Teoc–group was cleaved and the secondary amine opened the epoxide, leading to a bicyclic amine.

In the cyclization there was a competition between a 5–exo–tet and a 6–endo–tet process (scheme 4). The exo–cyclized product was formed preferentially. According to the Baldwin rules13 the 5–exo–tet cyclization is favored over the 6–endo–tet cyclization. This resulted in the observed selectivity of 3:1 between the isomers. Separation of the regio– and diastereoisomers by column chromatography gave the [2.1.2]–analogue as a single isomer in 53%.

Scheme 4. 5–exo–tet and 6–endo–tet cyclization.

For the synthesis of the [2.2.1]–analogue the same synthetic strategy was used as for the [2.1.2]–analogue, starting from (S)–pyrrolidin–3–yl methanol 6 (scheme 5).11


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100

Teoc protection and Swern oxidation provided aldehyde 7 in good yield. The extension of the aldehyde and addition of the 4–methyl–6–methoxyquinoline provided alcohol 8. The alkene was obtained in 96% over two steps. The asymmetric dihydroxylation provided the other diastereoisomer as compared to the synthesis of the [2.1.2]–analogue with the same diastereoselectivity (4:1) as expected. The epoxide was obtained in 94% yield and treated with CsF at 110 °C. Again competition between 5–exo–tet and 6–endo–tet cyclization was observed. The [2.2.1]–analogue was obtained in moderate yield and as a single isomer.

The synthesis of the [1.2.2]–analogue started from commercially available piperidinone salt 11 that was Teoc protected in good yield (scheme 6). The protected piperidinone 12 was reacted with (methoxymethyl)–triphenylphosphonium chloride and NaHMDS providing the enol ether prior to hydrolysis with CeCl3·7H2O and NaI with the formation of the aldehyde in 77% over two steps. The addition of 4–methyl–6–methoxyquinoline gave alcohol 13 in 75% yield, which was subsequently eliminated to give the prochiral alkene in quantitative yield. The diol was introduced via asymmetric dihydroxylation yielding 14 in 97% ee based on chiral HPLC, followed by epoxide formation in 85% yield. The deprotection and cyclization procedure provided the [1.2.2]–analogue in 75% yield and no trace of the endo cyclization product was observed. Apparently the conformation of the deprotected piperidine allows the 5–exo–tet cyclization to occur much faster than the 6–endo–tet cyclization.

2–TMS–EtOH,triphosgene, K2CO3

THF/H2O, 90%

1) NaHMDS, THF2) CeCl3 . 7H2O, NaIMeCN, 40 °C77% over 2 steps

3) 4–methyl–6–methoxy–quinoline, LDA,THF, –78 °C, 75%

Ph3P OCl

1) MsCl, Et3N, CH2Cl20 °C

2) KOt–Bu, CH2Cl2, 0 °C99% over 2 steps

3) AD–mix , MeSO2NH2

t–BuOH, H2O, 0 °C69%, 97% ee

1) MeC(OMe)3, PPTSCH2Cl2

2) TMSCl, CH2Cl23) K2CO3, MeOH85% over 3 steps

4) CsF, DMF, t–BuOH110 °C, 75%

NH2Cl

HO OH

NTeoc

O

11 12

NTeoc13

HO

N

OMe

NTeoc14

HO

N

OMe

OHN

OH

N

OMe

[1.2.2]



101

4.2.2 Synthesis of the [3.2.2]–series

To obtain the [2.3.2]– and [2.2.3]–analogues a diastereoselective synthesis was performed (scheme 7).

1) AD–mix , MeSO2NH2

t–BuOH, H2O, 0 °C84%, dr 1:1, 98% ee

1) MeC(OMe)3, PPTSCH2Cl2

2) TMSCl, CH2Cl23) K2CO3, MeOH86% over 3 steps

NBoc

O

15

1) BF3 . Et2O, Et2O–20 °C, 99%

2) 4M HCl, reflux100%

3) 2–TMS–EtOH,triphosgene, K2CO3

THF/H2O, 74%

N2

EtO2C

NTeoc

O

16

O

OEt(EtO)2P

O

1) NaH, THF, 87%mixture of 4 isomers

2) Pd/C (5 mol%), H2

MeOH, 100%

NTeoc17

CO2Et

1) 4–methyl–6–methoxy–quinoline, LDA,THF, –78 °C, 74%

2) NaBH4, MeOH, 94%

3) MsCl, Et3N, CH2Cl2, 0 °C4) KOt–Bu, CH2Cl2, 0 °C76% over 2 steps N

Teoc

N

OMe

18

NTeoc

N

OMe

19

O

CsF

NMP, t–BuOH110 °C

N

OH

N

OMe

N

N

OMe

OH

[2.3.2] 23% [2.2.3] 28%

Scheme 7. Synthesis of the [2.3.2]– and [2.2.3]–analogues.

The synthesis started from commercially available N–Boc–protected piperidone 15, which was treated with ethyldiazoacetate and BF3·Et2O in diethyl ether providing the ring expansion product in quantitative yield.15 The ester was decarboxylated and the Boc–group was cleaved with strong acid at elevated temperature to give the hydrochloric acid salt. Protection of the secondary amine with a Teoc–group provided 4–azepinone 16 in 74% yield. The Horner–Wadsworth–Emmons reaction converted the ketone into the alkene as a mixture of four isomers, besides the E– and Z–isomers the double bond had shifted to the endocyclic position.16 In the next step the double bonds were hydrogenated by Pd/C providing ester 17 in quantitative yield. The procedure for the addition of 4–methyl–6–methoxyquinoline was modified, adding this time 2.5 equiv of the quinoline.17 After the attack of the lithiated quinoline to the ester, the benzylic hydrogens are relative acidic and are easily deprotonated by the excess of lithiated quinoline, preventing a second addition. The ketone was reduced with NaBH4 and the alcohol was eliminated to give alkene 18. The asymmetric dihydroxylation provided an inseparable mixture (1:1)

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102

of diastereoisomers in 98% ee for both diastereoisomers based on chiral HPLC. The diols were converted to the epoxides in 86% yield. Cyclization of the azapanes provided the [2.3.2]– and [2.2.3]–analogues in 23% and 28% yield, respectively, after separation by column chromatography. NMR studies elucidated the structures and NOE–experiments allowed the elucidation of their configurations.

In order to take advantage of this epoxide cyclization strategy towards the synthesis of the [3.2.2]–analogue, Teoc–protected piperidinone 12 was reacted with the phosphorus ylide formed by deprotonation of 20 by NaHMDS (scheme 8). The alkene was formed in 92% yield and hydrogenated with Pd/C giving the reduced product in quantitative yield. Cleavage of the acetal was accomplished with sulphuric acid in acetone/H2O providing the aldehyde 21 in 99%.18 Addition of 4–methyl–6–methoxyquinoline gave the alcohol in 68% yield, which was eliminated to provide alkene 22 in 85% yield. Dihydroxylation and epoxide formation gave 23 in high yield (ee was not determined). Next the deprotection/cyclization procedure was tested by using CsF in DMF/t–BuOH at 110 °C. After stirring overnight no formation of the bicyclic ring was observed, but only formylation of the secondary amine by DMF was observed. Consequently, the solvent was changed to NMP, which did not provide the desired product either. Even stirring at 150 °C did not give any of the desired product. Next the epoxide was first deprotected and then treated with Zn(OTf)219 or Y(NO3)3·6H2O20 in acetonitrile at 80 °C. Unfortunately, both Lewis acids did not gave satisfactory results. Although the Baldwin rules13 allow a 7–exo–tet cyclization, this system seemed not to be appropriate for the reaction to proceed.

Scheme 8. Epoxide cyclization approach leading to the [3.2.2]–analogue.


103

A new approach was derived starting from commercially available quinuclidinone hydrochloride 24 which was reacted with quinolinealdehyde 25 under basic condition giving aldol condensation product 26 in good yield (scheme 9).21

NH

O

Cl

N

MeO

NaH

EtOH, 91%

O H

N

O

NMeO

24

27

TMSCHN2, n–BuLi

MeOH, silicagelEt2O, THF

–78 °C to rt, 43%

N

O

N

MeO

26

25

Scheme 9. New approach to the [3.2.2]–analogue.

Next, a ring expansion reaction was performed according to a method recently developed by Lee.22 The ring expansion occurred selectively on the side of the double bond, which isomerized to the α,β–unsaturated system giving 27 in 43% yield. The group of Lee attributed the observed selectivity mainly to conformational and stereoelectronic effects leading to minimization of the syn–pentane–like interaction between the diazonium and the TMS–group (scheme 10).

Scheme 10. Explanation of the observed selectivity during the ring expansion.

The carbonyl was reduced with NaBH4 in methanol (scheme 11). After the reduction of the carbonyl, isomerization of the double bond to the benzylic position was required, because all attempts to directly hydrogenate the double bond with Pd/C catalyst failed. This was achieved by treating the allylic alcohol with KOtBu in a 10:1 mixture of THF/t–BuOH. The isomerized product 28 was obtained as a 10:1 mixture of Z/E–isomers in 73% over two steps. The mixture of isomers was reduced with Pd/C and H2 in the presence of HCl in methanol. HCl was added to decrease the reaction time and to avoid

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104

overreduction. Next the alcohol was reacted with thiocarbonyldiimidazole in THF providing 29 as a 2:1 mixture of diastereoisomers in 64% over two steps.23 Treatment of 29 with n–Bu3SnH and a catalytic amount of AIBN in toluene at reflux temperature cleaved the thioester. Oxidation with O2 and NaH in DMSO at 70 °C provided a 2.5:1 mixture of the racemic [3.2.2]–analogue and its epi–isomer.24 The racemic [3.2.2]–analogue was isolated as a pure compound in 35% over two steps.

Scheme 11. Conversion of 27 to the racemic [3.2.2]–analogue.

The enantiomers were separated by reacting the racemic [3.2.2]–analogue with (S)–(+)–α–methoxyphenylacetic acid using EDC and HOBt in CH2Cl2 (scheme 12).

N

OH

N

OMe

N

O

N

OMe

O

PhMeO

N

O

N

MeO

O

Ph OMe

N

OH

N

OMe

rac [3.2.2]

[3.2.2]

96% ee

30 29% 31 54%4:1 mixtureof 31/30

K2CO3, MeOH89%

Ph CO2H

O

EDC, HOBt

CH2Cl2, 0 °C

Scheme 12. Separation procedure of the racemic [3.2.2]–analogue.


105

The diastereoisomers were separated by column chromatography. The desired diastereoisomer 30 was obtained as a single isomer according to 1H NMR in 29%. The other diastereoisomer was obtained as a 4:1 mixture of 31/30 in 54%. Ester 30 was treated with K2CO3 in methanol to give the [3.2.2]–analogue in 89% and with 96% ee.25

4.3 Catalysis

In order to gain insight into the role of the quinuclidine ring system of Cinchona alkaloids in asymmetric organocatalysis, the analogues were examined in three different types of conjugate additions (scheme 13).26–28 These reactions were chosen for two main reasons: i) each reaction introduces chirality at a different carbon atom and ii) the reactions catalyzed by the natural Cinchona alkaloids gave only moderate enantioselectivities, allowing room for improvement. In the first reaction developed by Pracejus, chirality is introduced at the α–carbon atom through protonation (A).26 In the second reaction studied by the group of Wynberg, the chirality is introduced on the β–carbon atom during the addition of the thiol nucleophile (B).27 The last reaction that will be explored is the Michael addition of indanone to 3–buten–2–one, which was also examined by the group of Wynberg (C).28 In this addition reaction the chirality is introduced on the nucleophilic carbon atom.

Scheme 13. Three test reactions.

4.3.1 Reference catalysts

In order to compare the results obtained with the quinuclidine modified analogues, three reference catalysts were chosen: quinidine (41), dihydroquinidine (42) and des–vinylquinidine (44) (figure 2).

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Figure 2. Catalysts.

The novel quinuclidine modified analogues lack the vinyl substituent and, therefore, des–vinylquinidine (44) would be considered as the best reference for comparison with the results provided by the quinuclidine modified analogues. Des–vinylquinidine (44) was obtained through a new developed procedure (scheme 14).

Scheme 14. Synthesis of des–vinylquinidine (44).

Quinidine (41) was acetylated and the vinyl side chain was dihydroxylated by using AD–mix α. The diol was oxidized with NaIO4 in acetone giving aldehyde 43 as 9:1 mixture isomers in 88% over three steps. Next, aldehyde 43 was decarbonylated by using a rhodium(I) complex which was formed in situ by mixing ((COD)RhCl)2 with dppp in diglyme and refluxing the mixture for 16 h.29 Finally, the acetate group was cleaved with K2CO3 in methanol giving des–vinylquinidine (44) in 81% over two steps.

4.3.2 Screening of the catalysts

The addition of phenylmethanethiol 33 to methyl acrylate 32 was first explored (table 1).26 Quinidine provided an ee of 46%, in accordance with the work of Pracejus (entry 1). Dihydroquinidine (42) gave a slight decrease in enantioselectivity to 41% (entry 2). With des–vinylquinidine (44) the ee dropped to 22% (entry 3). Next, the [1.2.2]–series were examined (entries 4–6) and comparable results were obtained with des–vinylquinidine (44). A slight increase of the enantioselectivity was obtained with the [2.2.1]–analogue (entry 5), while there was a slight decrease in ee with the other two analogues (entries 4 and 6). From the [3.2.2]–series, only the [2.3.2]–species gave comparable results as compared to des–vinylquinidine (44) (entry 7). Surprisingly, with the [2.2.3]– and [3.2.2]–analogues inversion of the stereochemistry was observed although the ee’s obtained were very low (entries 8 and 9).


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Table 1. Addition of phenylmethanethiol 33 to methyl acrylate 32.

entrya catalyst conversion (%)b ee (%)c

1 quinidine (41) >99 45 2 dihydroquinidine (42) >99 41 3 des–vinylquinidine (44) / [2.2.2] >99 22 4 [2.1.2] >99 19 5 [2.2.1] >99 28 6 [1.2.2] >99 13 7 [2.3.2] >99 29 8 [2.2.3] >99 –6 9 [3.2.2] >99 –13 a) Standard reaction conditions: 0.125M substrate, 1.2 equiv thiol b) Conversion

determined by 1H–NMR c) The ee determined by chiral HPLC analysis (AD–column)

Next, the addition of 4–tert–butylthiophenol 36 to cyclohexenone 35 was examined (table 2).27 Comparable results were obtained with quinidine (41) as reported by Wynberg (entry 1). A decrease in the ee was seen when dihydroquinidine (42) and des–vinylquinidine (44) were used (entries 2 and 3). The [2.1.2]–derivative increased the ee as compared to des–vinylquinidine (44) and quinidine (41) (entry 4). When the [2.2.1]– and [1.2.2]–analogues were used the ee decreased towards 22% and 35%, respectively (entries 5 and 6). Comparable results were obtained with the [2.3.2]– and [2.2.3]–analogues as compared to des–vinylquinidine (44) (entries 7 and 8). The [3.2.2]–analogue provided a slight increase in the ee up to 50% (entry 9).

Table 2. Addition of 4–tert–butylthiophenol 36 to cyclohexenone 35.

entrya catalyst conversion (%)b ee (%)c 1 quinidine (41) >99 55 2 dihydroquinidine (42) >99 45 3 des–vinylquinidine (44) / [2.2.2] >99 41 4 [2.1.2] >99 57 5 [2.2.1] >99 22 6 [1.2.2] >99 35 7 [2.3.2] >99 38 8 [2.2.3] >99 40 9 [3.2.2] >99 50 a) Standard reaction conditions: 0.52M substrate, 1.15 equiv thiol b) Conversion

determined by 1H–NMR c) The ee determined by chiral HPLC analysis (AD–column)

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To conclude, the addition of indanone 39 to 3–buten–2–one 38 was explored (table 3).28 First the reference catalysts were tested and all gave comparable results (entries 1–3). In this case, a slight increase in the ee was observed when des–vinylquinidine (44) was used (entry 3). Additionally, the quinuclidine modified analogues provided a wider range of ee values (entries 4–9). Only the [1.2.2]–analogue gave comparable results as compared to the reference catalysts (entry 6),whereas the [2.2.1]–analogue provided an almost racemic product (entry 5). Among the [3.2.2]–series, the [2.3.2]–species gave the best results (entry 7), while the [2.2.3]–derivative provided only 15% ee (entry 8).

Table 3. Addition of indanone 39 to 3–buten–2–one 38.

entrya catalyst conversion (%)b ee (%)c 1 quinidine (41) >99 49 2 dihydroquinidine (42) >99 50 3 des–vinylquinidine (44) / [2.2.2] >99 53 4 [2.1.2] >99 21 5 [2.2.1] >99 3 6 [1.2.2] >99 51 7 [2.3.2] >99 41 8 [2.2.3] >99 15 9 [3.2.2] >99 31

a) Standard reaction conditions: 0.5M substrate, 0.5 equiv nucleophile b) Conversion determined by 1H–NMR c) The ee determined by chiral HPLC analysis (AD–column)

The three reactions examined gave some interesting results. In the first two reactions the presence of the vinyl group in the natural alkaloid is important in order to obtain reasonable ee’s (tables 1 and 2), while in the third reaction this group is unimportant (table 3). A plausible reason for this could be that the vinyl group hinders the rotation around the C8–C9 or C9–C4’ bonds thus causing the catalyst to be slightly more rigid, which is apparently important for the first two reactions. It was proposed by Wynberg that the Cinchona alkaloids adopt anti–open conformations in the thiol addition to cyclohexenone (figure 3).27b So the rotation to syn–open and anti–closed conformations may be partially blocked by the vinyl group.

Figure 3. Proposed activation by Hiemstra and Wynberg.


109

In addition, the results provided by the novel catalysts revealed some interesting features. In each reaction a different analogue gave the best result and only once, a synthetic analogue improved the result of the natural alkaloid, although this improvement was very small (table 2). Surprisingly, in the first reaction the difference in the ee values between the [2.3.2]– and [2.2.3]–analogues is relatively large (table 1). Meanwhile in the second reaction there is almost no difference in ee (table 2). As these analogues are diastereoisomers it is interesting to note that in one reaction that there is a relative large difference while in the other reaction there is almost no difference.

To further explore the novel catalysts behavior another reaction was investigated. In 2012 the group of Lattanzi reported the addition of malonitrile to chalcones catalyzed by Cinchona alkaloids.30 It was found that quinine gave the best results at room temperature (ee 82%). Also quinidine was examined and this gave only an ee of 60%. It seemed that the vinyl group of the Cinchona alkaloid had a negative effect on the ee of the reaction. This reaction, therefore, might be a good candidate to try to improve the results obtained with quinidine. The screening started with quinidine, giving similar results as reported by Lattanzi (table 4, entry 1).

Table 4. Addition of malonitrile 46 to chalcone 45.

entrya catalyst conversion (%)b ee (%)c 1 quinidine (41) >99 60 2 dihydroquinidine (42) >99 66 3 des–vinylquinidine (44) / [2.2.2] >99 80 4 [2.1.2] >99 27 5 [2.2.1] >99 83 6 [1.2.2] >99 52 7 [2.3.2] >99 82 8 [2.2.3] >99 62 9 [3.2.2] >99 16

a) Standard reaction conditions: 0.1M substrate, 1.2 equiv nucleophile b) Conversion determined by 1H–NMR c) The ee determined by chiral HPLC analysis (AD–column)

Dihydroquinidine (42) gave a slight increase of the enantioselectivity (entry 2). Des–vinylquinidine (44) increased the ee to 80% (entry 3). The synthetic analogues showed a larger differences in the ee (entries 4–9). The best results were obtained with [2.2.1]– and [2.3.2]–analogues giving 83% and 82% ee respectively (entries 5 and 7). With the [3.2.2]–species only an ee of 16% was obtained (entry 9). By comparing the [2.1.2]– and [2.2.1]–diastereoisomers, a large difference in the enantioselectivity was observed (entries 4 and 5).

4.3.3 Catalyst activity

Hiemstra and Wynberg monitored the conversion of the addition of thiophenol to cyclohexenone with optical rotation.27b The optical rotation was plotted as a function of

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reaction time and full conversion was assumed when the measured optical rotation did not increase further. The same method was chosen to determine the conversion rates of the modified catalytic systems. The addition of 4–tert–butylthiophenol 36 to cyclohexenone 35 (table 2) was chosen to study the activity of the catalysts. The experiments were performed in duplo and the optical rotations were converted to conversion in percentage. The experiments were averaged and plotted as a function of reaction time (figure 4).

Figure 4. Reaction rates for the catalyzed addition of 4–tert–butylthiophenol 36 to cyclohexenone 35.

The t½ for quinidine (41) was 7.3 min and the 50% conversion point for dihydroquinidine (42) and des–vinylquinidine (44) was decreased to 3.7 and 3.3 min, respectively. The reaction rates for the analogues showed that the modifications in the quinuclidine ring influenced the activity. The [2.1.2]– and [2.3.2]–analogues had almost the same t½–value. This trend was also observed for the [1.2.2]– and [3.2.2]–analogues and to some extent for the [2.2.1]– and [2.2.3]–compounds. The [2.2.1]–analogue gave the fastest conversion of the [1.2.2]–series. The [2.2.3]–catalyst gave the fastest conversion among the [3.2.2]–series. Surprisingly, the reaction time for the [1.2.2]– and [3.2.2]–analogues was drastically increased. Compared to the most active catalyst, des–vinylquinidine (44), the t½–value was increased a 10 fold for both catalysts.

4.4 pKAH determination

The modifications in the quinuclidine ring system should also have an effect on the basicity of the nitrogen atom. This was to some extent investigated by Hine and Chen.31

100

80

60

40

20

0

Con

vers

ion

(%)

140120100806040200Time (min)

quinidine t½ = 7.3 min des-vinylquinidine t½ = 3.3 min di-hydroquinidine t½ = 3.7 min [2.1.2] t½ = 12.2 min [2.2.1] t½ = 9.8 min [1.2.2] t½ = 33.8 min [2.3.2] t½ = 12.5 min [2.2.3] t½ = 5.5 min [3.2.2] t½ = 37.7 min


111

They determined the pKAH’s of quinuclidine and the so–called nor–quinuclidine. Their results showed that quinuclidine was more basic than the nor–compound (pKAH= 10.9 vs 10.5). This can be atrributed to the fact that the quinuclidine has one more CH2–group. This makes the amine more electron rich resulting in better stabilization of the postive charge on the amine. If this trend continues for the [3.2.2]–series the pKAH should be highest for these analogues. The calculations of Merschaert showed that the vinyl group has a negative influence on the basicity (ACD calculations: pKAH for dihydrocinchonine 9.99, for cinchonine 9.18).3

Steady–state fluorescence spectroscopy was used to determine the pKAH’s of the analogues.32 This was achieved by measuring the fluorescence spectra of the built–in quinoline fluorophore as a function of pH.33 The neutral form of the bicyclic amine (pH >> pKAH) can act as an electron donor resulting in an excited–state electron–transfer (ET) process to the quinoline moiety. This process results in quenching of the quinoline emission in polar solvents.34 When the amine is protonated it cannot act as an electron donor anymore and the emission of the quinoline moiety is recovered.

The titration was started with alkaline solution (NaOH aq.) at pH ≈ 13 where the bicyclic amine is completely in the neutral form. The pH was gradually decreased by stepwise additions of dilute aqueous HCl and the absorption and emission spectra (at 325–550 nm) were recorded after each addition. The titration was continued until the emission intensity reached its maximum value (at pH ≈ 7). Further decrease in pH resulted in protonation of the quinoline moiety leading to a decrease in the emission intensity. The excitation wavelength was 310 nm corresponding to the main absorption band of the quinoline moiety. The emission spectra were corrected for the dilution due to the added HCl solution. The corrected emission spectra were integrated and plotted as a function of pH. The pKAH’s were determined by curve fitting of the data to the following equation:35

�tot = � ∗ �protonated + � ∗ �neutral

where Itot is the measured light intensity, Iprotonated the intensity at pH << pKAH and Ineutral the intensity at pH >> pKAH. All samples were measured twice. The average pKAH values and standard deviations are summarized in table 5.

Table 5. The pKAH values of the catalysts.

entry catalyst pKAH in water 1 quinidine (41) 8.75 ± 0.06 2 dihydroquinidine (42) 9.21 ± 0.04 3 des–vinylquinidine (44) / [2.2.2] 9.30 ± 0.03 4 [2.1.2] 8.87 ± 0.03 5 [2.2.1] 9.00 ± 0.06 6 [1.2.2] 8.48 ± 0.09 7 [2.3.2] 9.22 ± 0.09 8 [2.2.3] 9.17 ± 0.05 9 [3.2.2] 9.40 ± 0.09

First, the pKAH of quinidine (41) was determined (entry 1). The pKAH–values of quinidine reported in the literature are between 8 and 9.7 The measured pKAH = 8.75 is in

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agreement with the reported values. Next, the pKAH of dihydroquinidine (42) was determined (entry 2), showing an increase to 9.21. This is in agreement with calculations performed by Merschaert (pKAH for dihydrocinchonine = 9.99 and pKAH for cinchonine = 9.18).3 Although, the values are not the same, a similar trend is observed: the vinyl group has a negative effect on the basicity of the amine. This was further supported by des–vinylquinidine (44) (entry 3). The [1.2.2]–analogues were less basic than des–vinylquinidine (44) (entries 4–6), where the [1.2.2]–analogue was the least basic catalyst (entry 6). The [3.2.2]–analogues exhibited pKAH values which were comparable with the pKAH of des–vinylquinidine (44) (entries 7–9). The most basic catalyst was the [3.2.2]–analogue, but the differences in pKAH values of the analogues were small (entry 9).

The results show the same trend as was reported by Hine31, one CH2–group less reduces the basicity of the amine, but the influence of an extra CH2–group is small. The position of the modification in the bicyclic system also influences the pKAH; the least basic catalyst is the [1.2.2]–analogue and the most basic is the [3.2.2]–analogue. These results indicate that the activity of the catalysts (figure 4) cannot be correlated directly to the pKAH of the catalysts. In the addition of 4–tert–butylthiophenol 36 to cyclohexenone 35, the [1.2.2]– and [3.2.2]–analogues were the most inactive catalysts.

The fluorescence intensities at high pH were different for the [1.2.2]–series than for the reference catalysts and the [3.2.2]–series (figure 5). At pH = 13 there was already significant emission of the quinoline measured with the [1.2.2]–series, while the intensity for the other compounds at high pH was low. This means, that the efficiency of the ET process in the neutral form of the so–called nor–analogues is much lower compared to the other studied compounds. It is possible that the [1.2.2]–series do not have the optimal orientation for the ET process to take place. Also at high pH there was a second equivalence point seen with the [1.2.2]–series. This could be the deprotonation of the C9–OH–group. Although the pKa of the hydroxyl group is not known, the pKa for benzylalcohol is around 15.36

Figure 5. Titration plots of des–vinylquinidine (44), the [2.2.1]– and [2.2.3]–analogues.

4.5 Conclusion

The syntheses and properties of several analogues of Cinchona alkaloids with modifications in the quinuclidine ring system are described. The preferred synthetic route to construct the bicyclic ring system was the cyclization reaction of a secondary amine

800x106

600

400

200

I_co

rrec

ted

121110987pH

des-vinylquinidine (circles) pKAH = 9.2991 ± 0.0256[2.2.3] (squares) pKAH =9.1329 ± 0.0272

400x106

300

200

100

0

I_co

rrec

ted

121110987pH

[2.2.1] pKAH =9.0008 ± 0.0464


113

with a chiral epoxide. Only the synthesis of the [3.2.2]–analogue failed using this procedure. Therefore, a racemic synthesis was performed followed by separation of the enantiomers in order to obtain the enantiomerically pure [3.2.2]–analogue. The analogues were examined as organocatalysts in four conjugate additions and compared to three known reference catalysts. It appeared difficult to observe a trend in the four reactions explored. In some reactions the different catalysts gave almost the same enantioselectivity, but in other reactions the modifications in the quinuclidine system had a relative large impact on the enantioselectivity. Also the vinyl group had an influence on the outcome of the reactions in terms of enantioselectivity. The determination of the activity of the catalysts showed that the conversion rate is influenced by the position where the modifications are made and not on the pKAH. The pKAH were successfully determined with fluorescence spectroscopy. The removal of a CH2–group lowers the basicity while an extra methylene group has less effect on the basicity. The vinyl group is also responsible for the decrease in basicity.

Some characteristic data of the catalysts are summarized in table 6.

Table 6. Experimental data of the catalysts.

catalyst [α]Dc mp (°C) pKAH (water)

H9 in 1H NMR (ppm)e

C9 in 13C NMR (ppm)f

quinidine (41)a +236.0d 170–172 8.75 5.72 (br) 72.0 dihydroquinidine (42)b +226.0d 167–168 9.21 5.57 (br) 71.4 des–vinylquinidine (44) +126.6 81–82 9.30 5.65 (d, J = 3.8 Hz) 71.2

[2.1.2] +64.6 162–165 8.87 5.89 (br) 70.2 [2.2.1] +77.9 108–109 9.00 5.74 (br) 69.2 [1.2.2] +23.3 75–77 8.48 5.95 (br) 65.7 [2.3.2] +108.2 146–148 9.22 5.75 (br) 70.7 [2.2.3] +51.7 129–131 9.17 6.41 (br) 68.1 [3.2.2] +109.8 68–71 9.40 5.39 (d, J = 4.5 Hz) 70.7

a) Data from ref 8a b) data from ref 36 c) Optical rotation measured in CHCl3 d) Optical rotation measured in EtOH e) H9 refers to hydrogen at the 9–position in the natural alkaloid f) C9 refers to carbon at the 9–position in the natural alkaloid.

4.6 Acknowledgments

Gydo van der Heijden is gratefully acknowledged for starting this project, for the synthetic studies towards the [3.2.2]–analogues and the catalysis. Jan Geenevasen, Els Engelen–Goris and Jan Meine Ernsting are all acknowledged for their help with NMR studies. Finally, Tatu Kumpulainen is thanked for the help in the determination of the pKAH’s.


(R)–2–(Trimethylsilyl)ethyl–3–(hydroxymethyl)pyrrolid ine–1–carboxylate: Triphosgene (5.3 g, 17.8 mmol), 2–TMS–ethanol (7.6 mL, 53.4 mmol) and K2CO3 (14.7 g, 106.8 mmol) were dissolved in 130 mL THF and stirred for 2 h. The solution was cooled to 0 °C and (R)–pyrrolidin–3–yl methanol 1 (1.8 g, 17.8 mmol) in 20 mL water was added. The mixture was allowed to come to rt and stirred overnight. The reaction was quenched with saturated NH4Cl and

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the layers were separated. The water layer was 3 times extracted with EtOAc. The organic layers were combined, washed with brine, dried with MgSO4 and the crude was concentrated. The product was purified by column chromatography (PE/EtOAc 2:1) yielding the alcohol (3.3 g, 13.0 mmol, 73%) a colorless oil. [α]D = +10.6 (c = 0.58, MeOH); IR (neat, cm–1) ν 3429, 2951, 2880, 1672, 1432, 835; 1H NMR (400 MHz, CDCl3) δ 4.19 (t, 2H, J = 16.8 Hz), 3.67 (m, 2H), 3.58–3.45 (m, 2H), 3.45–3.39 (m, 1H), 3.20 (m,1H), 2.43 (m, 1H), 2.02 (m, 1H), 1.74 (m, 1H), 1.01 (t, 2H, J = 16.8 Hz), 0.07 (s, 9H) (OH is missing); 13C NMR (100 MHz, CDCl3) δ 155.4, 64.0, 63.1, 48.5, 45.2, 40.9, 27.7, 17.8, –1.5; HRMS (FAB) for C11H24NO3Si: calculated (MH+): 246.1525, found (MH+) 246.1529. (R)–2–(Trimethylsilyl)ethyl–3–formylpyrrolidine–1–car boxylate 2: Oxallylchloride

(2.1 mL, 24.4 mmol) was dissolved in 190 mL CH2Cl2 and cooled to –78 °C. DMSO (3.8 mL, 53.0 mmol) was added dropwise and the mixture was stirred for 30 min. A solution of alcohol (2.7 g, 24.4 mmol) in 10 mL CH2Cl2 was added and stirring was continued for 1 h. Et3N (7.6 mL, 55.1 mmol) was added and the resulting mixture was allowed to reach rt. Water was added and the layers were separated. The organic layer was washed with

saturated NaHCO3 and brine, dried with MgSO4 and the crude was concentrated. The product purified by column chromatography (PE/EtOAc 2:1) yielding aldehyde 2 (2.5 g, 10.1 mmol, 95%) as a colorless oil. [α]D = +8.9 (c = 0.53, MeOH); IR (neat, cm–1) ν 2953, 2893, 1725, 1693, 1455, 1358, 1109, 859; 1H NMR (400 MHz, CDCl3) δ 9.71 (d, 1H, J = 1.6 Hz), 4.20 (t, 2H, J = 8.4 Hz), 3.79 (m, 1H), 3.65–3.43 (m, 3H), 3.06 (m, 1H), 2.19 (m, 1H), 2.06 (m, 1H), 1.02 (t, 2H, J = 8.4 Hz), 0.08 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 200.0, 154.7, 63.1, 50.2, 49.2, 44.1, 44.8, 44.5, 25.6, 24.9, 17.5, –1.7 (double signals due to hindered rotation); HRMS (FAB) for C11H22NO3Si: calculated (MH+): 244.1369, found (MH+) 244.1373.

(S)–2–(Trimethylsilyl)ethyl3–(2–methoxyvinyl)pyrrolid ine–1–carboxylate: (methoxymethyl)–Triphenylphosphonium chloride (10.3 g, 30 mmol) was dissolved in 100 mL THF and cooled to –78 °C. NaHMDS (2 M in toluene, 13.5 mL, 27 mmol) was added dropwise. The resulting mixture was warmed up to 0 °C and stirred for 30 min. Aldehyde 2 (2.4 g, 10.0 mmol) in 50 mL THF was added and stirring was continued for 24 h. The reaction was quenched with saturated NH4Cl and extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried with MgSO4 and the solvent was evaporated. The product purified by column chromatography

(PE/EtOAc 8:1) yielding the enolether (2.52 g, 9.3 mmol, 93%) as a colorless oil in a 4:1 mixture of E/Z isomers. IR (neat, cm–1) ν 2951, 2895, 1698, 1655, 1454, 1112, 837; 1H NMR (400 MHz, CDCl3) δ 6.40 (d, 0.8H, J = 12.8 Hz), 5.92 (d, 0.2H, J = 6.0 Hz), 4.65 (dd, 0.8H, J = 12.8, 8.8 Hz), 4.30 (dd, 0.2H, J = 8.4, 6.3 Hz), 4.18 (t, 2H, J = 8.0 Hz), 3.62–3.46 (m, 5H), 3.30 (m, 1H), 3.19 (m, 0.2H), 2.96 (m, 1H), 2.68 (m, 0.8H), 2.00 (m, 1H), 1.66 (m, 1H), 1.00 (t, 2H, J = 8.0 Hz), 0.06 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.0, 147.1, 147.2, 106.4, 102.6, 62.7, 62.6, 59.4, 55.7, 52.0, 51.8, 51.5, 51.2, 45.5, 45.2, 38.0, 37.1, 34.2, 33.4, 33.2, 31.7, 17.6, –1.6 (double signals due to hindered rotation); HRMS (FAB) for C13H26NO3Si: calculated (MH+): 272.1682, found (MH+) 272.1678.


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(S)–2–(Trimethylsilyl)ethyl–3–(2–oxoethyl)pyrrolidine –1–carboxylate: Enolether (2.5 g, 9.3 mmol) was dissolved in 65 mL MeCN and CeCl3·7 H2O (866 mg, 2.3 mmol) and NaI (174 mg, 1.16 mmol) were added. The resulting mixture was stirred overnight at 40 °C, followed by evaporation of the solvent. The product was purified by column chromatography (PE/EtOAc 4:1) yielding the aldehyde (2.1 g, 8.3 mmol, 89%) as a colorless oil. [α]D = +20.9 (c = 0.97, MeOH) IR (neat, cm–1) ν 2952, 2893, 1723, 1694, 1421, 1333, 838; 1H NMR (400 MHz, CDCl3) δ 9.80 (d, 1H, J = 1.2 Hz), 4.18 (t, 2H, J = 8.0 Hz), 3.68

(m, 1H), 3.49 (m, 1H), 3.33 (m, 1H), 2.97 (m, 1H), 2.67–2.58 (m, 3H), 2.13 (m, 1H), 1.56 (m, 1H), 1.00 (t, 2H, J = 8.0 Hz), 0.07 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 200.3, 155.1, 63.0, 51.0, 50.7, 47.0, 46.9, 45.2, 44.9, 32.7, 31.9, 31.3, 30.6, 17.7, –1.6 (double signals due to hindered rotation); HRMS (FAB) for C12H24NO3Si: calculated (MH+): 258.1525, found (MH+) 258.1521. (3S)–2–(Trimethylsilyl)ethyl3–(2–hydroxy–3–(6–methoxyq uinolin–4–yl)propyl)–

pyrrolidine–1–carboxylate 3: Di–isopropylamine (1.21 mL, 8.7 mmol) was dissolved in 30 mL THF and cooled to –78 °C. n–BuLi (1.6 M in hexane, 4.8 mL, 7.7 mmol) was added and the mixture was warmed to 0 °C. Stirring was continued for 15 min, followed by cooling the mixture again to –78 °C. 4–Methyl 6–methoxyquinoline (1.5 g, 8.7 mmol) dissolved in 7 mL THF was added and the mixture was stirred for 1 h. A solution of aldehyde (1.7 g, 6.7 mmol) in 10 mL THF was added dropwise and stirring was continued for 3 h at –78 °C. The reaction was quenched with

saturated NH4Cl and allowed to reach rt . The resulting mixture was extracted 3 times with EtOAc. The organic layers were combined, washed with brine, dried with MgSO4 and the solvent was evaporated. The product was purified by column chromatography (EtOAc) yielding alcohol 3 (2.35 g, 5.47 mmol, 82%) as a yellowish sticky oil in a 1:1 mixture of diastereoisomers. IR (neat, cm–1) ν 3419, 2951, 2896, 1678, 1432, 1246, 1230, 839; 1H NMR (400 MHz, CDCl3) δ 8.58 (d, 1H, J = 4.0 Hz), 8.02 (d, 1H, J = 8.8 Hz), 7.39 (dd, 1H, J = 9.2 Hz), 7.27 (m, 2H), 4.18 (dt, 2H, J = 8.4, 1.6 Hz), 4.13 (m, 1H), 3.98 (s, 3H), 3.71 (m, 1H), 3.53 (m, 1H), 3.34–3.27 (m, 2H), 3.11 (m, 1H), 3.00 (m, 1H), 2.84 (m, 1H), 2.10 (m, 1H), 1.83–1.52 (br m, 3H), 1.01 (dt, 2H, J = 8.4, 1.6 Hz), 0.07 (s, 9H) (OH is missing);13C NMR (100 MHz, CDCl3) δ 157.5, 155.2, 146.6, 143.9, 143.2, 130.6, 128.6, 128.6, 121.3, 101.9, 69.9, 69.8, 63.0, 55.4, 51.8, 51.7, 51.2, 51.1, 45.7, 45.5, 45.4, 45.2, 44.9, 41.3, 41.1, 48.9, 39.0, 36.2, 35.9, 35.2, 35.0, 32.4, 31.7, 30.8, 17.8, –1.5 (double signals due to hindered rotation); HRMS (FAB) for C23H35N2O4Si: calculated (MH+):431.2366, found (MH+) 431.2357. (R,E)–2–(Trimethylsilyl)ethyl–3–(3–(6–methoxyquinolin–4 –yl)allyl)pyrrolidine–1–

carboxylate: Alcohol 3 (2 g, 4.64 mmol) was dissolved in 20 mL anhydrous CH2Cl2 and cooled to 0 °C. Et3N (0.56 mL, 5.58 mmol) and methanesulfonyl chloride (0.43 mL, 5.58 mmol) were added and the resulting mixture was stirred for 1 h. The reaction was quenched with water and the mixture was warmed to rt. The layers were separated and the water layer was extracted 2 more times with CH2Cl2. The organic layers were combined, washed with brine, dried with MgSO4 and the crude was concentrated. The crude mixture was dissolved in 20 mL anhydrous THF and cooled to 0 °C. KOt–Bu (626 mg, 5.58

mmol) was added and the mixture was stirred for 2 h. The reaction mixture was

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quenched with saturated NH4Cl and the layers were separated. The water layer was extracted 3 times with EtOAc and the organic layers were combined. The organic layer was washed with saturated NaHCO3 and brine and dried with MgSO4. The solvent was evaporated and the product was purified by column chromatography (EtOAc) yielding the alkene (1.84 g, 4.5 mmol, 96%) as a brown oil. [α]D = +0.6 (c = 0.7, MeOH); IR (neat, cm–1) ν 2951, 2893, 1696, 1619, 1429, 1249, 1228, 838 cm–1; 1H NMR (400 MHz, CDCl3) δ 8.71 (d, 1H, J = 4.0 Hz), 8.04 (d, 1H, J = 9.2 Hz), 7.40 (d, 2H, J = 6.0 Hz), 7.30 (d, 1H, J = 2.8 Hz), 7.06 (d, 1H, J = 15.6 Hz), 6.41 (dt, 1H, J = 15.6, 7.6 Hz), 4.20 (t, 2H, J = 8.0 Hz), 3.98 (s, 3H), 3.71–3.53 (m, 2H), 3.38 (m, 1H), 3.19–3.11 (m, 1H), 2.51–2.40 (m, 3H), 2.11 (m, 1H), 1.71 (m, 1H), 1.02 (t, 2H, J = 8.0 Hz), 0.06 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 157.6, 155.3, 147.5, 144.5, 141.7, 134.7, 131.3, 127.0, 126.5, 121.6, 117.7, 101.7, 101.5, 63.0, 55.4, 55.4, 51.1, 50.8, 45.5, 45.2, 38.7, 37.8, 36.8, 31.4, 30.6, 17.8, 17.8, –1.5 (double signals due to hindered rotation); HRMS (FAB) for C23H33N2O3Si: calculated (MH+): 413.2260, found (MH+) 413.2268. (S)–2–(Trimethylsilyl)ethyl–3–((2 S,3S)–2,3–dihydroxy–3–(6–methoxyquinolin–4–

yl)–propyl)pyrrolidine–1–carboxylate 4: Alkene (1.5 g, 3.6 mmol) was dissolved in 18 mL t–BuOH. A mixture of AD–mix α (10.4 g) and methanesulfonamide (1.7 g, 18.2 mmol) in 60 mL t–BuOH and 60 mL water was added and the resultant mixture was stirred for 24 h at 0 °C. Sodiumsulfite (15 g) was added and stirring was continued for an additional hour. Water was added and the mixture was extracted 3 times with CH2Cl2. The organic layers were combined washed with brine, dried with MgSO4 and the solvent was evaporated. The product was purified by column chromatography (EtOAc) yielding diol 4 (1.25 g, 2.8 mmol, 78%)

as an inseparable 4:1 mixture of diastereoisomers and as a white foam. IR (neat, cm–1) ν 3394, 2952, 2897, 1676, 1622, 1433, 1247, 1228, 857, 837; 1H NMR (400 MHz, CDCl3) δ 8.49 (br, 1H), 7.90 (d, 1H, J = 9.2 Hz), 7.42 (br, 1H), 7.33 (dd, 1H, J = 9.2, 2.4 Hz), 7.17 (br, 1H), 5.16 (d, 1H, J = 4.8 Hz), 4.15 (t, 2H, J = 4.1 Hz), 4.02 (m, 1H), 3.93 (s, 3H), 3.62 (m, 0.8H), 3.57 (m, 0.2H), 3.46–3.36 (m, 1H), 3.22 (m, 1H), 2.91 (q, 0.8H, J = 9.0 Hz), 2.78 (t, 0.2H, J = 9.7 Hz), 2.38 (m, 1H), 2.00 (br, 1H), 1.81 (m, 1H), 1.40 (m, 2H), 0.95 (t, 2H, J = 9.2 Hz), 0.04 (s, 9H) (the two OH groups give broad signals around 2 ppm); 13C NMR (100 MHz, CDCl3) δ 157.6, 155.2, 146.9, 146.2, 143.4, 130.8, 126.6, 121.4, 119.0, 118.9, 101.2, 73.0, 69.3, 63.0, 55.4, 51.8, 51.6, 45.3, 45.0, 36.7, 36.1, 35.3, 31.4, 30.6, 17.7, 17.6, –1.6 (double signals due to hindered rotation); HRMS (FAB) for C23H35N2O5Si: calculated (MH+): 447.2315, found (MH+) 447.2311. (S)–2–(Trimethylsilyl)ethyl–3–(((2 S,3S)–3–(6–methoxyquinolin–4–yl)oxiran–2–

yl)–methyl)pyrrolidine–1–carboxylate: Diol 4 (827 mg, 1.86 mmol) was dissolved in 11 mL anhydrous CH2Cl2. Trimethyl orthoacetate (713 μL, 5.6 mmol) and PPTS (46 mg, 0.08 mmol) were added and the mixture was stirred overnight. The product concentrated and dissolved in 11 mL anhydrous CH2Cl2. TMSCl (706 μL, 5.57 mmol) was added and stirring was continued for 24 h. The solvent was evaporated and the crude mixture was dissolved in 11 mL methanol. K2CO3 (763 mg, 5.52 mmol) was added and the resultant mixture was stirred for 2 h. The reaction was quenched with saturated NH4Cl and the mixture was extracted 3 times with CH2Cl2. The organic layer

were combined, washed with brine and dried with MgSO4. The product was purified by


117

column chromatography (EtOAc) yielding the epoxide (700 mg, 1.64 mmol, 88%) as an inseparable 4:1 mixture of diastereoisomers as a yellowish oil. IR (neat, cm–1) ν 2951, 2895, 1691, 1428, 1240, 856, 837; 1H NMR (400 MHz, CDCl3) δ 8.76 (d, 1H, J = 4.8 Hz), 8.10 (d, 1H, J = 9.6 Hz), 7.44 (dd, 1H, J = 9.6, 2.8 Hz), 7.32 (d, 1H, J = 4.4 Hz), 7.27 (d, 1H, J = 2.8 Hz), 4.19 (m, 3H), 3.98 (s, 3H), 3.72 (m, 1H), 3.58 (m, 1H), 3.37 (m, 1H), 3.12 (m, 1H), 3.00 (br, 1H), 2.47 (m, 1H), 2.18 (br, 1H), 2.02 (m, 1H), 1.88 (m, 1H), 1.69 (m, 1H), 1.03 (m, 2H), 0.06 (s, 9H);13C NMR (100 MHz, CDCl3) δ 157.8, 155.1, 147.7, 143.7, 141.3, 131.6, 127.1, 121.5, 116.5, 100.6, 63.0, 61.1, 61.0, 55.3, 55.1, 51.4, 51.0, 45.4, 45.1, 36.6, 35.6, 35.5, 35.4, 31.6, 30.9, 17.8, 17.7, –1.6 (double signals due to hindered rotation); HRMS (FAB) for C23H33N2O4Si: calculated (MH+): 429.2210, found (MH+) 429.2208. (S)–((1S,2R,4S)–1–Azabicyclo[2.2.1]heptan–2–yl)(6–methoxyquinolin –4–yl)–

methanol [2.1.2]–analogue: Epoxide (695 mg, 1.62 mmol) was dissolved in 54 mL DMF and 6 mL t–BuOH and CsF (296 mg, 1.94 mmol) was added. The mixture was heated to 110 °C and stirring was continued for 24 h. The crude NMR showed a 3:1 mixture of exo/endo cyclization. The isomers were separated by column chromatography (CH2Cl2/MeOH/NH4OH 20:1:0.2) yielding the [2.1.2]–analogue (244 mg, 0.86 mmol, 53%) as a white foam. The

endo product 5 was also obtained as white foam (81 mg, 0.29 mmol, 17%). mp 162–165 °C; [α]D= +64.6 (c = 0.5, CHCl3); IR (neat, cm–1) ν 3135, 2960, 1620, 1508, 1240, 1225, 1028, 779, 763; 1H NMR (500 MHz, CDCl3) δ 8.66 (d, 1H, J = 4.5 Hz, H–10), 7.98 (d, 1H, J = 9.0 Hz, H–12), 7.55 (d, 1H, J = 4.5 Hz, H–9), 7.28 (d, 1H, J = 9.0 Hz, H–13), 7.15 (s, 1H, H–15), 5.89 (s, 1H, H–7), 3.64 (s, 3H, H–17), 3.10 (d, 1H, J = 9.0 Hz, H–1), 2.84 (m, 1H, H–6), 2.75 (m, 1H, H–4), 2.56 (s, 1H, H–2), 2.49 (m, 1H, H–4), 2.25 (d, 1H, J = 9.0 Hz, H–1), 1.83 (m, 1H, H–5), 1.56 (m, 1H, H–3), 0.99 (m, 1H, H–3), 0.79 (t, 1H, J = 7.6 Hz, H–5) (OH is missing);13C NMR (125 MHz, CDCl3) δ 157.7 (C–14), 147.6 (C–10), 146.9 (C–8), 143.9 (C–11), 131.6 (C–12), 126.3 (C–16), 121.0 (C–13), 118.8 (C–9), 101.1 (C–15), 70.2 (C–7), 67.4 (C–6), 58.2 (C–1), 56.2 (C–4), 55.3 (C–17), 36.7 (C–2), 31.2 (C–5), 28.8 (C–3); HRMS for C17H21N2O2: calculated (MH+): 285.1603, found (MH+) 285.1608. (1S,2R,3S,5S)–2–(6–Methoxyquinolin–4–yl)–1–azabicyclo[3.2.1]oct an–3–ol 5: mp

65–68 °C; [α]D= +135.4 (c = 0.35, CH2Cl2); IR (neat, cm–1) ν 3174, 2927, 1619, 1507, 1224, 1024, 889, 864, 755, 726; 1H NMR (500 MHz, CDCl3) δ 8.74 (d, 1H, J = 4.0 Hz), 8.01 (d, 1H, J = 9.0 Hz), 7.59 (s, 1H), 7.36 (m, 2H), 4.47 (m, 1H), 4.26 (d, 1H, J = 10.0 Hz), 3.99 (s, 3H), 3.21 (d, 1H, J = 11.0 Hz), 2.89 (m, 1H), 2.80 (d, 1H, J = 11.0 Hz), 2.54 (m, 2H), 2.24 (m, 1H), 2.00 (br, 1H), 1.81 (m, 2H), 1.68 (m, 1H);13C NMR (125 MHz, CDCl3) δ 157.6, 146.7, 146.5,

144.4, 143.4, 130.9, 130.8, 129.2, 121.0, 118.8, 102.7, 102.6, 67.0, 63.3, 61.3, 55.2, 47.2, 40.3, 35.5, 35.4, 30.2; HRMS (ESI) for C17H21N2O2: calculated (MH+): 285.1598, found (MH+) 285.1601.

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(S)–2–(Trimethylsilyl)ethyl–3–(hydroxymethyl)pyrrolid ine–1–carboxylate: Triphosgene (9.0 g, 30.3 mmol), 2–TMS–ethanol (12.9 mL, 91.0 mmol) and K2CO3 (25.1 g, 182 mmol) were dissolved in 225 mL THF and stirred for 2 h. The solution was cooled to 0 °C and (S)–pyrrolidin–3–yl methanol 6 (6.13 g, 60.7 mmol) in 80 mL water was added. The mixture was allowed to come to rt and stirred overnight. The reaction was quenched with saturated NH4Cl and the layers were separated. The water layer was 3 times extracted with EtOAc.

The organic layers were combined, washed with brine, dried with MgSO4 and the crude was concentrated. The product was purified by column chromatography (PE/EtOAc 2:1) yielding the alcohol (11.4 g, 44.8 mmol, 74%) as a colorless oil. [α]D = –10.8 (c = 0.75, MeOH); Analytical data is the same as for the R–enantiomer. (S)–2–(Trimethylsilyl)ethyl–3–formylpyrrolidine–1–car boxylate 7: Oxallylchloride

(3.1 mL, 36.2 mmol) was dissolved in 290 mL CH2Cl2 and cooled to –78 °C. DMSO (5.6 mL, 78.7 mmol) was added dropwise and the mixture was stirred for 30 min. A solution of alcohol (4.0 g, 15.7 mmol) in 10 mL CH2Cl2 was added and stirring was continued for 1 h. Et3N (11.3 mL, 81.6 mmol) was added and the resulting mixture was allowed to reach rt . Water was added

and the layers were separated. The organic layer was washed with saturated NaHCO3 and brine, dried with MgSO4 and the crude was concentrated. The product purified by column chromatography (PE/EtOAc 2:1) yielding aldehyde 7 (3.7 g, 15.2 mmol, 97%) as a colorless oil [α]D = –9.3 (c = 0.63, MeOH) Analytical data is the same as for 2. (R)–2–(Trimethylsilyl)ethyl3–(2–methoxyvinyl)pyrrolid ine–1–carboxylate:

(methoxymethyl)–Triphenylphosphonium chloride (15.6 g, 45.6 mmol) was dissolved in 150 mL THF and cooled to –78 °C. NaHMDS (2 M in toluene, 20.5 mL, 41.0 mmol) was added dropwise. The resulting mixture was warmed up to 0 °C and stirred for 30 min. Aldehyde 7 (3.7 g, 15.2 mmol) in 60 mL THF was added and stirring was continued for 24 h. The reaction was quenched with saturated NH4Cl and was extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried with MgSO4 and the

solvent was evaporated. The product purified by column chromatography (PE/EtOAc 8:1) yielding the enolether (3.7 g, 13.5 mmol, 89%) as a colorless oil in a 4:1 mixture of E/Z isomers. Analytical data is the same as for the S–enantiomer. (R)–2–(Trimethylsilyl)ethyl–3–(2–oxoethyl)pyrrolidine –1–carboxylate: Enolether

(3.7 g, 13.5 mmol) was dissolved in 100 mL MeCN, CeCl3·7 H2O (1.26 g, 3.38 mmol) and NaI (252 mg, 1.69 mmol) were added. The resulting mixture was stirred overnight at 40 °C, followed by evaporation of the solvent. The product was purified by column chromatography (PE/EtOAc 4:1) yielding the aldehyde (3.14 g, 12.2 mmol, 90%) as a colorless oil. [α]D = –20.9 (c = 0.91, MeOH); Analytical data is the same as for the S–enantiomer.

NTeoc

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119

(3R)–2–(Trimethylsilyl)ethyl–3–(2–hydroxy–3–(6–methoxy quinolin–4–yl)propyl)–pyrrolidine–1–carboxylate 8: Di–isopropylamine (1.6 mL, 11.7 mmol) was dissolved in 30 mL THF and cooled to –78 oC. n–BuLi (1.6 M in hexane, 6.8 mL, 10.9 mmol) was added and the mixture was warmed to 0 °C. Stirring was continued for 15 min, followed by cooling the mixture to –78 °C. 4–Methyl 6–methoxyquinoline (2 g, 11.7 mmol) dissolved in 10 mL THF was added and the mixture was stirred for 1 h. A solution of aldehyde (2 g, 7.8 mmol) in 20 mL THF was added dropwise and stirring was continued for 3 h at –78 °C. The reaction was quenched with saturated NH4Cl and

allowed to reach rt. The resulting mixture was extracted 3 times with EtOAc. The organic layers were combined, washed with brine, dried with MgSO4 and the solvent was evaporated. The product was purified by column chromatography (EtOAc) yielding alcohol 8 (2.3 g, 5.4 mmol, 69%) as a sticky oil in a 1:1 mixture of diastereoisomers. Analytical data is the same as for 3. (S,E)–2–(Trimethylsilyl)ethyl–3–(3–(6–methoxyquinolin–4 –yl)allyl)pyrrolidine–1–

carboxylate: Alcohol 8 (2.3 g, 5.4 mmol) was dissolved in 20 mL anhydrous CH2Cl2 and cooled to 0 °C. Et3N (0.89 mL, 6.42 mmol) and methanesulfonyl chloride (0.50 mL, 6.42 mmol) were added and the resulting mixture was stirred for 1 h. The reaction was quenched with water and the mixture was warmed up to rt. The layers were separated and the water layer was extracted 2 times with CH2Cl2. The organic layers were combined, washed with brine, dried with MgSO4 and the crude was concentrated. The crude mixture was dissolved in anhydrous THF and cooled to 0 °C. KOt–Bu (720 mg, 6.42 mmol) was added and the mixture was stirred stirred for 2 h. The reaction mixture

was quenched with saturated NH4Cl and the layers were separated. The organic layer was washed with saturated NaHCO3, brine and dried with MgSO4. The solvent was evaporated and the product was purified by column chromatography (EtOAc) yielding the alkene as a brown oil (2.0 g, 4.9 mmol, 91%). [α]D = –0.6 (c = 0.27, MeOH); Analytical data is the same as for the R–enantiomer.

(R)–2–(Trimethylsilyl)ethyl–3–((2 S,3S)–2,3–dihydroxy–3–(6–methoxyquinolin–4–yl)–propyl)pyrrolidine–1–carboxylate 9: Alkene (1.3 g, 3.2 mmol) was dissolved in 16 mL t–BuOH. A mixture of AD–mix α (9.1 g) and methanesulfonamide (1.5 g, 15.8 mmol) in 53 mL t–BuOH and 53 mL water was added and the resultant mixture was stirred for 24 h at 0°C. Sodiumsulfite (13 g) was added and stirring was continued for an additional hour. Water was added and the mixture was extracted 3 times with CH2Cl2. The organic layers were combined washed with brine, dried with MgSO4 and evaporated. The product was purified by column chromatography

(EtOAc) yielding diol 9 (950 mg, 2.8 mmol, 68%) as an inseparable 4:1 mixture of diastereoisomers and as a white foam. IR (neat, cm–1) ν 3368, 2951, 2896, 1673, 1621, 1431, 1244, 1276, 856, 833; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, 1H, J = 4.8 Hz), 7.43 (d, 1H, J = 9.2 Hz), 7.37 (d, 1H, J = 4.8 Hz), 7.28 (m, 1H), 7.12 (s, 1H), 5.12 (d, 1H, J = 4.4 Hz), 4.30 (br, 2H), 4.11 (t, 2H, J = 8.0 Hz), 3.95 (m, 1H), 3.90 (s, 3H), 3.67–3.52 (m, 1H), 3.44 (m, 1H), 3.22 (m, 1H), 2.89 (t, 0.2H, J = 9.5 Hz), 2.76 (m, 0.8H), 2.42 (m, 1H), 2.02 (m, 1H), 1.88 (m, 1H), 1.50 (m, 1H), 1.38 (m, 1H), 0.96 (t, 2H, J = 8.0 Hz), 0.03 (s,

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9H);13C NMR (100 MHz, CDCl3) δ 157.5, 155.2, 146.9, 146.5, 143.4, 130.8, 126.6, 121.3, 119.0, 101.3, 72.9, 72.7, 63.1, 55.4, 51.0, 50.9, 45.6, 45.4, 37.0, 35.9, 34.9, 32.3, 31.5, 17.8, 17.7, –1.6 (double signals due to hindered rotation); HRMS (FAB) for C23H35N2O5Si: calculated (MH+): 447.2315, found (MH+) 447.2311. (R)–2–(Trimethylsilyl)ethyl–3–(((2 S,3S)–3–(6–methoxyquinolin–4–yl)oxiran–2–

yl)–methyl)pyrrolidine–1–carboxylate: Diol 9 (950 mg, 2.1 mmol) was dissolved in 10 mL anhydrous CH2Cl2. Trimethyl orthoacetate (820 μL, 6.4 mmol and PPTS (53 mg, 0.21 mmol) were added and the mixture was stirred overnight. The product concentrated and dissolved in 10 mL anhydrous CH2Cl2. TMSCl (812 μL, 6.4 mmol) was added and stirring was continued for 24 h. The solvent was evaporated and the crude mixture was dissolved in 10 mL methanol. K2CO3 (885 mg, 6.4 mmol) was added and the resultant mixture was stirred for 2 h. The reaction was quenched with saturated NH4Cl and the mixture was

extracted 3 times with CH2Cl2. The organic layer were combined, washed with brine, dried with MgSO4 and the solvent was evaporated. The product was purified by column chromatography (EtOAc) yielding the epoxide (860 mg, 2.0 mmol, 94%) as a yellowish oil as an inseparable 4:1 mixture of diastereoisomers. IR (neat, cm–1) ν 2951, 2895, 1690, 1620, 1427, 1240, 1228, 856, 836; 1H NMR (400 MHz, CDCl3) δ 8.76 (d, 1H, J = 4.4 Hz), 8.09 (d, 1H, J = 9.2 Hz), 7.43 (dd, 1H, J = 9.2, 2.4 Hz), 7.31 (d, 1H, J = 4.4 Hz), 7.27 (d, 1H, J = 2.4 Hz), 4.20 (m, 3H), 4.00 (s, 3H), 3.75 (m, 1H), 3.57 (m, 1H), 3.43 (m, 1H), 3.15 (m, 1H), 3.00 (br, 1H), 2.46 (m, 1H), 2.18 (m, 1H), 2.02 (m, 1H), 1.88–1.60 (m, 2H), 1.02 (m, 2H), 0.05 (s, 9H);13C NMR (100 MHz, CDCl3) δ 157.7, 155.0, 147.6, 143.6, 141.2, 131.5, 127.1, 121.6, 121.4, 116.4, 100.5, 62.9, 61.2, 61.1, 55.4, 55.3, 55.2, 55.0, 51.3, 51.0, 45.4, 45.1, 36.5, 35.7, 35.6, 35.4, 31.7, 30.9, 17.6, –1.6 (double signals due to hindered rotation); HRMS (FAB) for C23H33N2O4Si: calculated (MH+): 429.2210, found (MH+) 429.2208. (S)–((1R,2R,4R)–1–Azabicyclo[2.2.1]heptan–2–yl)(6–methoxyquinolin –4–yl)–

methanol [2.2.1]–analogue: Epoxide (860 mg, 2.0 mmol) was dissolved in 63 mL DMF and 7 mL t–BuOH. CsF (365 mg, 2.4 mmol) was added, the mixture was heated to 110 °C and stirring was continued for 24 h. The crude NMR showed a 3.5:1 mixture of exo/endo cyclization. The isomers were separated with by column chromatography (CH2Cl2/MeOH/NH4OH 20:1:0.2) yielding the [2.2.1]–analogue (312 mg, 1.1 mmol, 55%) as a white foam. The endo product could not be obtained as a pure compound. mp 108–

109 °C; [α]D= +77.9 (c = 0.5, CHCl3); IR (neat, cm–1) ν 3170, 2962, 1619, 1507, 1239, 1225, 1028, 876; 1H NMR (500 MHz, CDCl3) δ 8.46 (d, 1H, J = 4.0 Hz, H–10), 7.89 (d, 1H, J = 9.0 Hz, H–12), 7.39 (m, 2H, H–9 and 15), 7.28 (m, 1H, H–13), 5.74 (br, 1H), 5.38 (d, 1H, J = 3.5 Hz, H–7), 3.90 (s, 3H, H–17), 3.26 (m, 2H, H–1 and 6), 2.51 (s, 1H, H–3), 2.44 (m, 1H, H–1), 2.34 (d, 1H, J = 9.0 Hz, H–4), 2.21 (d, 1H, J = 9.0 Hz, H–4), 1.48 (m, 2H, H–2 and 7), 1.38 (m, 1H, H–2), 1.27 (m, 1H, H–7); 13C NMR (125 MHz, CDCl3) δ 157.7 (C–14), 148.1 (C–8), 147.3 (C–10), 144.0 (C–11), 131.2 (C–12), 126.5 (C–16), 121.2 (C–13), 118.7 (C–9), 101.8 (C–15), 69.2 (C–7), 66.7 (C–6), 61.5 (C–4), 55.8 (C–17), 47.7 (C–1), 38.0 (C–3), 30.4 (C–5), 30.3 (C–2); HRMS (FAB) for C17H21N2O2: calculated (MH+): 285.1603, found (MH+) 285.1608.


121

2–(Trimethylsilyl)ethyl–4–formylpiperidine–1–carbox ylate: (methoxymethyl)–Triphenylphosphonium chloride (7.2 g, 21 mmol) was dissolved in 50 mL THF and cooled to –78 °C. NaHMDS (2 M in toluene, 8.5 mL, 17 mmol) was added dropwise. The resulting mixture was warmed to 0 °C and stirred for 30 min. Piperidone 12 (1.7 g, 7.0 mmol) in 10 mL THF was added and stirring was continued for 24 h. The reaction was quenched with saturated NH4Cl and extracted 3 times with EtOAc. The combined organic layers were washed with

brine, dried with MgSO4 and the solvent was evaporated. The residue was filtrated over silica to yield the enolether as a colorless oil and used directly in the next step. The enolether was dissolved in 50 mL acetonitrile. CeCl3·7 H2O (650 mg, 1.75 mmol) and NaI (131 mg, 0.88 mmol) were added and the resulting mixture was stirred overnight at 40 °C, followed by evaporation of the solvent. The product was purified by column chromatography (PE/EtOAc 4:1) yielding the aldehyde (1.39 g, 5.4 mmol, 77% over 2 steps) as a colorless oil. IR (neat, cm–1) ν 2951, 2856, 1726, 1692, 1433, 1222, 838; 1H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 4.20 (t, 2H, J = 3.6 Hz), 4.04 (d, 2H, J = 10.4 Hz), 3.03 (m, 2H), 2.45 (m, 1H), 1.92 (d, 2H, J = 11.2 Hz), 1.60 (m, 2H), 1.03 (t, 2H, J = 3.6 Hz), 0.02 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 202.6, 155.3, 63.6, 47.7, 42.7, 24.9, 17.6, –1.6; HRMS (FAB) for C12H24NO3Si: calculated (MH+): 258.1525, found (MH+) 258.1526. 2–(Trimethylsilyl)ethyl–4–(1–hydroxy–2–(6–methoxyqu inolin–4–yl)ethyl)–

piperidine–1–carboxylate 13: Di–isopropylamine (840 μL, 6.0 mmol) was dissolved in 20 mL THF and cooled to –78 °C. n–BuLi (1.6 M in hexane, 3.6 mL, 5.8 mmol) was added and the mixture was warmed to 0 °C. Stirring was continued for 15 min and followed by cooling the mixture to –78 °C. 4–Methyl–6–methoxyquinoline (1.0 g, 5.8 mmol) dissolved in 5 mL THF was added and stirring was continued for 1 h. A solution of aldehyde (1.04 g, 4.0 mmol) in 10 mL THF was added dropwise and stirring was continued for 3 h at –78 °C. The reaction was quenched with

saturated NH4Cl and allowed to reach rt . The resulting mixture was extracted 3 times with EtOAc. The organic layers were combined, washed with brine, dried with MgSO4 and the solvent was evaporated. The product was purified by column chromatography (EtOAc) yielding alcohol 13 (1.3 g, 3.01 mmol, 75%) as a sticky oil. IR (neat, cm–1) ν 3400, 2951, 2857, 1692, 1620, 1510, 1433, 1248, 839; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, 1H, J = 4.4 Hz), 7.51 (d, 1H, J = 9.2 Hz), 7.07 (dd, 1H, J = 9.2, 2.8 Hz), 7.01 (d, 1H, J = 2.8 Hz), 6.91 (d, 1H, J = 4.8 Hz), 5.04 (br, 1H), 4.16 (br, 2H), 4.07 (t, 2H, J = 3.6 Hz), 3.78 (s, 3H), 3.71 (t, 1H, J = 6.8 Hz), 3.12 (d, 1H, J = 13.2 Hz), 2.76–2.62 (m, 3H), 1.95 (d, 1H, J = 12.4 Hz), 1.75 (d, 1H, J = 12.4 Hz), 1.61 (m, 1H), 1.42–1.30 (m, 2H), 0.93 (t, 2H, 3.6 Hz), –0.03 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 157.1, 155.3, 146.4, 144.2, 143.1, 130.4, 128.2, 122.4, 120.1, 101.6, 73.9, 63.1, 55.1 43.7, 42.5, 28.2, 17.5, –1.7; HRMS (FAB) for C23H35N2O4Si: calculated (MH+):431.2366, found (MH+) 431.2359.

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(E)–2–(Trimethylsilyl)ethyl–4–(2–(6–methoxyquinolin–4 –yl)vinyl)piperidine–1–carboxylate: Alcohol 13 (1.2 g, 2.79 mmol) was dissolved in 15 mL anhydrous CH2Cl2 and cooled to 0 °C. Et3N (0.46 mL, 3.34 mmol) and methanesulfonyl chloride (0.26 mL, 3.34 mmol) were added and the resulting mixture was stirred for 1 h. The reaction was quenched with water and the mixture was warmed to rt. The layers were separated and the water layer was extracted 2 times with CH2Cl2. The organic layers were combined, washed with brine, dried with MgSO4 and the crude was concentrated. The crude mixture was dissolved in 15 mL CH2Cl2 and cooled to 0 °C. KOt–Bu

(1M in t–BuOH, 3.3 mL, 3.34 mmol) was added and the mixture stirred for 2 h. The reaction mixture was quenched with saturated NH4Cl and the layers were separated. The organic layer was washed with saturated NaHCO3 and brine and dried with MgSO4. The solvent was evaporated and the product was purified by column chromatography (EtOAc) yielding the alkene (1.16 g, 2.79 mmol, 99%) as a brown oil. IR (neat, cm–1) ν 2951, 2852, 1693, 1620, 1471, 1250, 1225, 838; 1H NMR (400 MHz, CDCl3) δ 8.71 (d, 1H, J = 4.4 Hz), 8.02 (d, 1H, J = 9.2 Hz), 7.40 (m, 2H), 7.30 (d, 1H, J = 2.8 Hz), 7.02 (d, 1H, J = 15.6 Hz), 6.21 (dd, 1H, J = 15.6, 6.8 Hz), 4.31–4.20 (m, 4H), 3.98 (s, 3H), 2.91 (m, 2H), 2.52 (m, 1H), 1.90 (d, 2H, J = 12.8 Hz), 1.50 (m, 2H), 1.05 (t, 2H, J = 3.6 Hz), 0.07 (s, 9H) 13C NMR (100 MHz, CDCl3) δ 157.5, 155.5, 147.5, 144.5, 141.8, 140.7, 131.3, 127.1, 123.5, 121.4, 117.6, 101.5, 63.4, 55.4, 43.5, 39.6, 31.4, 17.7, –1.6 ; HRMS (FAB) for C23H33N2O3Si: calculated (MH+): 413.2260, found (MH+): 413.2259. 2–(Trimethylsilyl)ethyl–4–((1 S,2S)–1,2–dihydroxy–2–(6–methoxyquinolin–4–yl)–

ethyl)–piperidine–1–carboxylate 14: Alkene (1.16 g, 2.8 mmol) was dissolved in 10 mL t–BuOH. A mixture of AD–mix α (8 g) and methanesulfonamide (1.3 g, 14.0 mmol) in 18 mL t–BuOH and 18 mL water was added and the resultant mixture was stirred for 24 h at 0 °C. Sodiumsulfite (10 g) was added and stirring was continued for an additional hour. Water was added and the mixture was extracted 3 times with CH2Cl2. The organic layers were combined washed with brine, dried with MgSO4 and evaporated. The product was purified by column chromatography

(CH2Cl2/MeOH/Et3N 20:1:0.5) yielding diol 14 (860 mg,1.9 mmol, 69%) as a white foam. (ee = 97%) (ee determined by HPLC Chiral Daicel ODH, i–PrOH/n–heptane 15:85 (0.50 mL/min, λ = 220 nm), tr major = 29.7 min and tr minor = 23.8 min) mp 68–71°C; [α]D= –12.0 (c = 0.5, MeOH); IR (neat, cm–1) ν 3369, 2952, 1673, 1593, 1510, 1472, 1278, 1248, 1227, 835, 731; 1H NMR (400 MHz, CDCl3) δ 8.23 (br, 1H), 7.54 (dd, 1H, J = 9.2, 6.8 Hz), 7.38 (d, 1H, J = 3.2 Hz), 7.14 (d, 1H, J = 9.2 Hz), 6.88 (s, 1H), 5.40 (s, 1H), 4.26 (br, 2H), 4.19 (t, 2H, J = 8.0 Hz), 3.87 (s, 3H), 3.72 (d, 1H, J = 7.2 Hz), 2.78 (m, 2H), 2.15 (d, 1H, J = 12.8 Hz), 1.99 (m, 2H), 1.46 (m 1H), 1.26 (m, 1H), 1.01 (t, 2H, J = 8.0 Hz), 0.06 (s, 9H) (OH–groups are missing); 13C NMR (100 MHz, CDCl3) δ 157.4, 155.6, 146.9, 142.8, 130.4, 125.8, 121.0, 118.9, 100.8, 76.2, 68.7, 63.5, 55.4, 43.8, 38.9, 28.7, 17.7, –1.5; HRMS (FAB) for C23H35N2O5Si: calculated (MH+): 447.2315, found (MH+) 447.2321.


123

2–(Trimethylsilyl)ethyl–4–((2 S,3S)–3–(6–methoxyquinolin–4–yl)oxiran–2–yl)–piperidine–1–carboxylate: Diol 14 (350 mg, 0.78 mmol) was dissolved in 5 mL anhydrous CH2Cl2. Trimethyl orthoacetate (300 μL, 2.53 mmol) and PPTS (19 mg, 0.078 mmol) were added and the mixture was stirred overnight. The product concentrated and dissolved in 5 mL anhydrous CH2Cl2. TMSCl (320 μL, 2.53 mmol) was added and stirring was continued for 24 h. The solvent was evaporated and the crude mixture was dissolved in 5 mL methanol. K2CO3 (539 mg, 3.9 mmol) was added and the resultant mixture was stirred for 2 h. The reaction was quenched with saturated NH4Cl and the mixture was extracted 3 times with CH2Cl2. The organic

layers were combined, washed with brine and dried with MgSO4. The product was purified by column chromatography (CH2Cl2/MeOH 40:1) yielding the epoxide (285 mg, 0.66 mmol, 85%) as a yellowish oil. [α]D= –19.5 (c = 1.0, MeOH); IR (neat, cm–1) ν 2951, 1687, 1621, 1363, 1177, 1030, 855, 833; 1H NMR (400 MHz, CDCl3) δ 8.74 (d, 1H, J = 4.4 Hz), 8.06 (d, 1H, J = 9.2 Hz), 7.42 (dd, 1H, J = 9.2, 2.8 Hz), 7.31 (d, 1H, J = 4.4 Hz), 7.22 (d, 1H, J = 2.8 Hz), 4.32–4.22 (m, 5H), 3.96 (s, 3H), 2.88–2.80 (m, 3H), 1.98 (d, 1H, J = 13.2 Hz), 1.87 (d, 1H, J = 12.8 Hz), 1.76 (m, 1H), 1.48 (m, 2H), 1.02 (t, 2H, J = 8.4 Hz), 0.05 (s, 9H);13C NMR (100 MHz, CDCl3) δ 157.8, 155.4, 147.8, 143.6, 141.1, 131.6, 127.0, 121.3, 116.7, 100.7, 65.3, 63.4, 55.4, 54.2, 43.2, 38.5, 27.9, 17.6, –1.6; HRMS (FAB) for C23H33N2O4Si: calculated (MH+): 429.2210, found (MH+) 429.2212. (S)–((1S,4S,7R)–1–Azabicyclo[2.2.1]heptan–7–yl)(6–methoxyquinolin –4–yl)–

methanol [1.2.2]–analogue: Epoxide (240 mg, 0.56 mmol) was dissolved in 18 mL DMF and 2 mL t–BuOH. CsF (126 mg, 0.84 mmol) was added, the mixture was heated to 110 °C and stirring was continued for 24 h. The product was concentrated and purified by column chromatography (CH2Cl2/MeOH/NH4OH 10:1:0.1) yielding the [1.2.2]–analogue (120 mg, 0.42 mmol, 75%) as a white solid. mp 75–77 °C; [α]D= +23.3 (c = 1.0, CHCl3); IR (neat, cm–1) ν

3329, 2962, 1621, 1509, 1242, 1227; 1H NMR (400 MHz, CDCl3) δ 8.71 (d, 1H, J = 4.4 Hz, H–10), 7.87 (d, 1H, J = 9.2 Hz, H–12), 7.57 (d, 1H, J = 4.4 Hz, H–9), 7.22 (s, 1H, H–15), 7.17 (dd, 1H, J = 9.2, 2.4 Hz, H–13), 5.95 (br, 1H, H–7), 3.80 (br, 1H, H–1), 3.74 (s, 3H, H–17), 3.22 (d, 1H, J = 4.0 Hz, H–6), 3.18 (m, 1H, H–5), 2.76 (m, 2H, H–1 and 5), 2.67 (s, 1H, H–3), 2.58 (m, 1H, H–2), 1.74 (m, 1H, H–4), 1.48 (m, 1H, H–2), 1.38 (m, 1H, H–4) (OH is missing); 13C NMR (100 MHz, CDCl3) δ 157.7 (C–14), 147.0 (C–10), 146.5 (C–8), 143.8 (C–11), 130.9 (C–12), 126.2 (C–16), 121.7 (C–13), 118.7 (C–9), 101.0 (C–15), 73.5 (C–6), 65.7 (C–7), 56.0 (C–17), 54.3 (C–5), 52.2 (C–1) 35.8 (C–3), 29.8 (C–4), 28.4 (C–2); HRMS (FAB) for C17H21N2O2: calculated (MH+): 285.1603, found (MH+) 285.1600. 2–(Trimethylsilyl)ethyl–4–(2–ethoxy–2–oxoethylidene )azepane–1–carboxylate: To

a solution of triethyl phosphonoacetate (1.97 mL, 9.9 mmol) in 28 mL THF, NaH (397 mg, 9.91 mmol, 60% in mineral oil) was added and the suspension was stirred for 1 h at rt . A solution of protected azepinone 16 (1.7 g, 6.6 mmol) in 8 mL THF was added and the mixture was stirred for 4 h. The reaction was quenched with saturated NH4Cl and the aqueous layer was extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried with MgSO4, and the crude was concentrated. The residue was purified by column chromatography (PE/EtOAc 8:1) to yield the alkene (1.89 g, 5.77 mmol, 87%)

N

OH

N

OMe

12

34

57

68

910

11

1213

14

1516

17

CHAPTER 4

124

as an inseparable mixture of 4 isomers. IR (neat, cm–1) ν 2952, 1692, 1643, 1420, 1326, 1298, 1191, 1173, 1144, 857, 834; 1H NMR (400 MHz, CDCl3) δ 5.45 (m, 1H), 3.84 (m, 4H), 3.10 (m, 4H), 2.76 (m, 1.5H), 2.54 (m, 0.5H), 2.23 (m, 0.5H), 2.10 (m, 1.5H), 1.45 (m, 2H), 0.97 (t, 3H, J = 7.2Hz), 0.71 (t, 2H, J = 8.4 Hz), –0.25 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 166.8, 161.5, 161.4, 155,8, 117.7, 117.5, 63.2, 59.4, 58.2, 48.6, 48.2, 47.1, 46.4, 46.2, 45.5, 44.6, 39.5, 39.0, 37.5, 32.2, 32.1, 29.8, 29.6, 28.1, 27.9, 26.8, 26.5, 17.7, 17.6, 14.1, –1.5; HRMS (FAB) for C16H30NO4Si: calculated (MH+): 328.1944, found (MH+) 328.1945. 2–(Trimethylsilyl)ethyl–4–(2–ethoxy–2–oxoethyl)azep ane–1–carboxylate 17: To a

solution of alkene (1.89 g, 5.8 mmol) in MeOH (40 mL), was added Pd/C (10% wt) (31 mg, 0.3 mmol). The reaction was stirred under H2 atmosphere for 1 h. The mixture was filtered over Celite and the product was concentrated to yield ester 17 (1.90 g, 5.8 mmol, 100%) as a colorless oil. IR (neat, cm–1) ν 2951, 1733, 1693, 1248, 1186, 1155, 937, 859; 1H NMR (400 MHz, CDCl3) δ 4.16 (m, 4H), 3.69 (m, 1H), 3.46 (m, 2H), 3.21 (m, 1H), 2.17 (d, 2H, J = 4.8 Hz), 1.98 (m, 1H), 1.85 (m, 2H), 1.77 (m, 1H), 1.61 (m, 1H), 1.40 (m, 1H) 1.29 (m,

4H), 1.03 (dd, 2H, J = 8.4, 4.0 Hz), 0.06 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.4, 156.2, 63.0, 59.9, 46.4, 46.1, 44.6, 44.2, 41.7, 35.9, 35.7, 34.6, 34.4, 33.0, 32.8, 26.7, 26.4, 17.6, 14.0, –1.9 (double signals due to hindered rotation); HRMS (FAB) for C16H32NO4Si: calculated (MH+): 330.2101, found (MH+) 330.2114. 2–(Trimethylsilyl)ethyl–4–(3–(6–methoxyquinolin–4–y l)–2–oxopropyl)azepane–1–

carboxylate: Di–isopropylamine (0.11 mL, 0.76 mmol) in 2 mL anhydrous THF was cooled to –78 °C. n–BuLi (0.48 mL, 0.76 mmol, 1.6M in hexane) was added dropwise and the reaction mixture was warmed to 0 °C. After stirring for 15 min, the reaction was cooled to –78 °C. 4–Methyl 6–methoxquinoline (0.13 g, 0.76 mmol) in 1 mL THF was added and the reaction was stirred for 1 h. A solution of ester 17 (100 mg, 0.30 mmol) in 1 mL THF was added dropwise and stirring was continued for 12 h at –78 °C. The reaction was quenched with saturated NH4Cl and the mixture was allowed to reach rt . The

resulting mixture was extracted 3 times with EtOAc. The organic layers were combined, washed with brine, dried with MgSO4 and the crude was concentrated. The product was purified with column chromatography (EtOAc/PE 1:1) to yield the ketone (101 mg, 0.22 mmol, 74%) as a yellow oil. IR (neat, cm–1) ν 2950, 1687, 1621, 1422, 1242, 1229, 857, 837; 1H NMR (400 MHz, CDCl3) δ 8.69 (d, 1H, J = 4.4 Hz), 7.99 (d, 1H, J = 9.2 Hz), 7.34 (d, 1H, J = 9.2 Hz), 7.21 (d, 1H, J = 4.4 Hz), 7.06 (s, 1H), 4.12 (t, 2H, J = 8.4 Hz), 4.01 (s, 2H), 3.88 (s, 3H), 3.69–3.47 (m, 1H), 3.33 (m, 2H), 3.08 (m, 1H), 2.37 (d, 2H, J = 6.8 Hz), 1.98 (m, 1H), 1.86–1.61 (m, 2H), 1.53 (m, 2H), 1.24 (m, 1H), 1.06 (m, 1H), 0.92 (t, 2H, J = 8.4 Hz), 0.02 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 205.8, 158.0, 156.3, 147.5, 144.4, 138.7, 131.6, 128.4, 122.9, 121.8, 101.6, 63,1, 55.4, 49.0, 48.8, 48.2, 46.1, 46.0, 44.7, 44.3, 34.8, 34.6, 34.4, 34.3, 33.0, 32.9, 26.7, 26.4, 17.7, –1.6 (double signals due to hindered rotation); HRMS (FAB) for C25H37N2O4Si: calculated (MH+): 457.2523, found (MH+) 457.2522.


125

2–(Trimethylsilyl)ethyl–4–(2–hydroxy–3–(6–methoxyqu inolin–4–yl)propyl)–azepane–1–carboxylate: Ketone (1.15 g, 2.5 mmol) was dissolved in 15 mL MeOH and the mixture was cooled to 0˚C. NaBH4 (290 mg, 7.6 mmol) was slowly added and the mixture was warmed to rt . After stirring for 2 h, water was added and the mixture was extracted 3 times with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4 and concentrated to yield the alcohol (1.1 g, 2.4 mmol, 95%) as a sticky oil. IR (neat, cm–1) ν 3421, 2926, 1682, 1242, 1228, 833, 730; 1H NMR (400 MHz, CDCl3) δ 8.63 (br, 1H), 8.09 (br, 1H), 7.34 (d, 1H, J = 8.8 Hz), 7.30 (m, 2H), 4.18 (m, 3H), 3.98 (s, 3H), 3.79–3.60 (m, 1H), 3.46 (m, 2H), 3.29–3.05 (m, 3H), 1.98–1.10 (m, 10H), 1.00 (t, 2H, J = 8.4 Hz), 0.08 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 157.0,

156.0, 146.3, 143.9, 143.2, 130.3, 128.3, 122.1, 120.8, 101.5, 68.1, 62.7, 55.0, 54.9, 46.0, 45.9, 45.7, 45.6, 45.5, 45.0, 44.7, 44.6, 44.3, 44.1, 41.1, 41.0, 35.9, 35.4, 35.3, 35.2, 35.0, 34.2, 34.0, 33.7, 33.4, 32.1, 31.7, 26.6, 26.4, 17.6, –2.0 (double signals due to hindered rotation); HRMS (FAB) for C25H39N2O4Si: calculated (MH+): 459.2679, found (MH+) 459.2681. (E)–2–(Trimethylsilyl)ethyl–4–(3–(6–methoxyquinolin–4 –yl)allyl)azepane–1–

carboxylate 18: Alcohol (1.1 g, 2.4 mmol) was dissolved in 13 mL CH2Cl2 and the cooled to 0 °C. Et3N (0.40 mL, 2.88 mmol) and methanesulfonyl chloride (0.22 mL, 2.9 mmol) were added. After 1 h the reaction was quenched with water and the reaction mixture was allowed to warm to rt. The layers were separated and the water layer was 3 times extracted with CH2Cl2. The organic layers were combined, washed with brine, dried with MgSO4 and the solvent was evaporated. The crude was dissolved in 13 mL CH2Cl2 and the reaction mixture was cooled to 0 °C. KOt–Bu (377 mg, 3.36 mmol) was added and the reaction mixture stirred for 2 h. The reaction was quenched with water and the mixture was

allowed to warm to rt . The layers were separated and the water layer was 3 times extracted with CH2Cl2. The organic layers were combined, washed with brine, dried with MgSO4 and the solvent was evaporated. The product was purified by column chromatography (EtOAc) to yield alkene 18 (0.80 g, 1.82 mmol, 76%) as a brown oil. IR (neat, cm–1) ν 2922, 1686, 1420, 1299, 1249, 1226, 832; 1H NMR (400 MHz, CDCl3) δ 8.45 (d, 1H, J = 4.0 Hz), 7.77 (dd, 1H, J = 9.2, 1.6 Hz), 7.12 (m, 2H), 7.03 (s, 1H), 6.71 (d, 1H, J = 15.6 Hz), 6.14 (m, 1H), 4.00 (t, 2H, J = 8.4 Hz), 3.69 (s, 3H), 3.49–2.91 (m, 4H), 2.06 (br, 2H), 1.65 (m, 3H), 1.40 (m, 2H), 1.19 (m, 1H), 1.02 (m, 1H), 0.82 (t, 2H, J = 8.4 Hz), –0.16 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 157.0, 155.8, 147.0, 144.1, 141.3, 135.2, 130.8, 126.5, 125.8, 121.0, 117.1, 101.0, 62,6, 59.6, 54.8, 45.9, 45.7, 44.5, 44.2, 40.7, 40.6, 38.6, 38.3, 34.4, 34.0, 32.8, 32.4, 26.6, 26.3, 17.3, –2.0 (double signals due to hindered rotation); HRMS (FAB) for C25H37N2O3Si: calculated (MH+): 441.2573, found (MH+) 441.2572.

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2–(Trimethylsilyl)ethyl–4–((2 S,3S)–2,3–dihydroxy–3–(6–methoxyquinolin–4–yl)–propyl)–azepane–1–carboxylate: To a mixture of AD–mix α (4.9 g) and methanesulfonamide (810 mg, 8.5 mmol) in 12 mL water and 12 mL t–BuOH, alkene 18 (750 mg, 1.7 mmol) in 8 mL t–BuOH was added and the solution was cooled to 0 °C. The resultant mixture stirred for 18 h. Sodiumsulfite (6.0 g) was added and the reaction was allowed to warm to rt and stirred for an additional hour. Water was added and the mixture was extracted 3 times with CH2Cl2. The organic layers were combined, washed with brine, dried with MgSO4 and concentrated. The product was purified by column chromatography (CH2Cl2/MeOH/Et3N 20:1:0.5) to yield the diol (680

mg, 1.43 mmol, 84%) in 1:1 mixture of diastereoisomers as a white foam. (ee for both diastereoisomers = 98%) (determined by HPLC analysis Chiralpak OD–H, i–PrOH/heptane 10:90 (0.7 mL, λ = 220 nm); tr major = 29.0 and 31.0 min, tr minor = 23.4 min (both minor enantiomers have the same retention time)) IR (neat, cm–1) ν 3368, 2929, 1673, 1243, 1228, 856, 834; 1H NMR (400 MHz, CDCl3) δ 8.48 (d, 1H, J = 4.4 Hz), 7.86 (d, 1H, J = 9.2 Hz), 7.45 (d, 1H, J = 4.0 Hz), 7.37 (d, 1H, J = 9.2 Hz), 7.19 (s, 1H), 5.16 (d, 1H, J = 4.4 Hz), 4.18–4.04 (m, 3H), 3.94 (s, 3H), 3.71–3.06 (m, 4H), 1.88–1.56 (m, 9H), 1.32–1.01 (m, 2H), 0.98 (t, 2H, J = 8.4 Hz), 0.03 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 157.0, 156.0, 146.8, 146.5, 143.0, 130.3, 126.4, 121.0, 118.9, 101.0, 72.7, 71.3, 62.8, 54.9, 45.9, 45.8, 45.6, 45.5, 45.3, 44.5, 44.2, 44.0, 41.1, 41.0, 40.7, 36.0, 35.5, 35.2, 35.0, 34.8, 34.2, 33.8, 33.7, 33.1, 31.7, 31.3, 26.5, 26.2, 17.7, 9.0, –1.9 (double signals due to hindered rotation); HRMS (FAB) for C25H39N2O5Si: calculated (MH+): 475.2628, found (MH+) 475.2626. 2–(Trimethylsilyl)ethyl4–(((2 S,3S)–3–(6–methoxyquinolin–4–yl)oxiran–2–yl)–

methyl)–azepane–1–carboxylate 19: To a solution of diol (630 mg, 1.3 mmol) in 10 mL CH2Cl2, trimethylorthoacetate (0.85 mL, 6.7 mmol) and PPTS (33 mg, 0.13 mmol) were added and the reaction mixture stirred for 18 h. The solvent was evaporated and the crude was dissolved in 10 mL CH2Cl2. TMSCl (0.90 mL, 6.7 mmol) was added and the mixture was stirred for 2 h. The solvent was evaporated and the crude was dissolved in 10 mL MeOH. K2CO3 (920 g, 6.7 mmol) was added and the reaction mixture was stirred for 2 h. The reaction was quenched with saturated NH4Cl and the resulting mixture was extracted 3 times with CH2Cl2. The organic layers were combined, washed with brine, dried with MgSO4 and

concentrated. The residue was purified by column chromatography (EtOAc) to yield epoxide 19 (520 mg, 1.14 mmol, 86%) as a yellow oil. IR (neat, cm–1) ν 2927, 1685, 1620, 1235, 1179, 853, 833; 1H NMR (400 MHz, CDCl3) δ 8.60 (d, 1H, J = 4.4 Hz), 7.91 (d, 1H, J = 9.2 Hz), 7.26 (d, 1H, J = 9.2 Hz), 7.13 (m, 2H), 4.04 (m, 3H), 3.82 (s, 3H), 3.58 (m, 1H), 3.37 (m, 2H), 3.09 (m, 1H), 2.84 (br, 1H), 1.92–1.62 (m, 6H), 1.51 (m, 1H), 1.39 (m, 1H), 1.22 (m, 1H), 0.88 (t, 2H, J = 8.4 Hz), –0.07 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 157.7, 156.1, 147.6, 143.6, 141.4, 131.4, 129.6, 127.0, 121.5, 121.3, 116.3, 100.5, 62,9, 61.4, 61.2, 61.1, 61.1, 59.9, 55.2, 55.1, 46.2, 46.0, 45.9, 45.8, 44.5, 44.4, 44.2, 39.8, 39.7, 39.6, 37.3, 37.1, 37.0, 36.8, 34.8, 34.4, 33.3, 33.1, 33.0, 32.8, 26.1, 26.0, 17.9, –2.0 (double signals due to hindered rotation); HRMS (FAB) for C25H37N2O4Si: calculated (MH+): 457.2523, found (MH+) 457.2522. Epoxide 19 (483 mg, 1.06 mmol) was dissolved in 40 mL of NMP and t–BuOH (9:1). CsF (193 mg, 1.27 mmol) was added and the reaction mixture stirred for 24 h at 110 °C.


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The mixture was cooled to rt and 100 mL EtOAc was added. The mixture was washed 5 times with brine to remove the NMP. The organic layer was dried with MgSO4 and concentrated. The residue was purified by column chromatography (CH2Cl2/MeOH/Et3N 95:5:1) to yield the [2.2.3]–analogue (92 mg, 0.29 mmol, 28%) as fraction 1 (Rf = 0.28) and the [2.3.2]–analogue (76 mg, 0.23 mmol, 23%) as fraction 2 (Rf = 0.14). (S)–((1R,5S,7R)–1–Azabicyclo[3.2.2]nonan–7–yl)(6–methoxyquinolin– 4–yl)–

methanol [2.3.2]–analogue: mp 146–148 °C; [α]D= +108.2 (c = 0.53, CHCl3) IR (neat, cm–1) ν 3213, 2925, 1619, 1239, 1227; 1H NMR (500 MHz, CDCl3) δ 8.49 (d, 1H, J = 4.5 Hz, H–12), 7.83 (d, 1H, J = 9.5 Hz, H–14), 7.50 (d, 1H, J = 4.5 Hz, H–11), 7.21 (d, 1H, J = 2.5 Hz, H–17), 7.18 (dd, 1H, J = 2.5, 9.5 Hz, H–15), 5.75 (br, 1H, H–9), 3.81 (s, 3H, H–19), 3.75 (m, 1H, H–1), 3.12 (m, 1H, H–8) 3.04 (m, 1H, H–6), 2.97 (m, 1H, H–6), 2.88 (m, 1H, H–1), 2.12 (br, 1H, H–4), 2.04 (m, 1H, H–7), 1.84 (m, 1H, H–2), 1.76 (m, 2H,

H–3), 1.67 (m, 1H, H–2), 1.57 (m, 1H, H–5), 1.50 (m, 1H, H–5), 1.44 (m, 1H, H–7) (OH is missing);13C NMR (100 MHz, CDCl3) δ 157.6 (C–16), 147.6 (C–10), 147.1 (C–12), 143.8 (C–13), 131.0 (C–14), 126.4 (C–18), 121.4 (C–15), 118.5 (C–11), 101.3 (C–17), 70.7 (C–9), 59.8 (C–8), 56.0 (C–19), 51.5 (C–1), 49.6 (C–6), 34.1 (C–3), 27.4 (C–4), 27.2 (C–7), 25.6 (C–5), 23.2 (C–2); HRMS (FAB) for C19H25N2O2: calculated (MH+): 313.1916, found (MH+) 313.1920. (S)–((1S,5R,7R)–1–Azabicyclo[3.2.2]nonan–7–yl)(6–methoxyquinolin– 4–yl)–

methanol [2.2.3]–analogue: mp 129–131 °C; [α]D= +51.7 (c = 1.0, CHCl3); IR (neat, cm–1) ν 3196, 2914, 1620, 1240, 1227; 1H NMR (500 MHz, CDCl3) δ 8.63 (d, 1H, J = 4.5 Hz, H–12), 7.68 (d, 1H, J = 9.5 Hz, H–14), 7.59 (d, 1H, J = 4.5 Hz, H–11), 6.99 (d, 1H, J = 2.5 Hz, H–15), 6.83 (s, 1H, H–17), 6.41 (br, 1H, H–9), 4.20 (m, 1H, H–1), 3.64 (s, 3H, H–19), 3.44 (m, 1H, H–8) 3.36 (m, 1H, H–6), 3.27 (m, 1H, H–6), 3.10 (m, 1H, H–1), 2.26 (br, 1H, H–3), 2.13 (m, 1H, H–7), 2.04 (m, 1H, H–2), 1.89–1.72 (m, 3H, H–2, 4 and

5), 1.66 (m, 1H, H–5), 1.61 (m, 1H, H–4), 1.11 (m, 1H, H–7) (OH is missing); 13C NMR (125 MHz, CDCl3) δ 157.7 (C–16), 147.0 (C–12), 145.0 (C–10), 143.5 (C–13), 131.1 (C–14), 125.4 (C–18), 121.8 (C–15), 118.5 (C–11), 99.7 (C–17), 68.1 (C–9), 61.3 (C–8), 60.0 (C–6), 56.4 (C–19), 45.3 (C–1), 31.5 (C–4), 26.4 (C–3), 24.0 (C–2), 23.5 (C–7), 20.8 (C–5); HRMS (FAB) for C19H25N2O2: calculated (MH+): 313.1916, found (MH+) 313.1920. 2–(Trimethylsilyl)ethyl–4–(2–(1,3–dioxolan–2–yl)eth ylidene)piperidine–1–

carboxylate: Wittig reagent 20 (15.0 g, 33.8 mmol) was dissolved in 150 mL THF and the mixture was cooled to –78 °C. NaHMDS (2M, 15.8 mL, 31.6 mmol) was added dropwise, the resulting mixture was warmed to 0 °C and stirred for 30 min. Teoc–protected 4–Piperidinone 12 (3.04 g, 12.5 mmol) in 25 mL THF was added dropwise and the resulting mixture stirred for 24 h. The reaction was quenched with saturated NH4Cl and the mixture was extracted 3 times with EtOAc. The organic layers were combined, washed with brine, dried with MgSO4 and the solvent was evaporated. The product was purified

by column chromatography (PE/EtOAc 4:1) yielding the alkene (3.7 g, 11.5 mmol, 92%) as a colorless oil. IR (neat, cm–1) ν 2952, 2895, 1698, 1276, 1249, 1224; 1H NMR (400 MHz, CDCl3) δ 5.23 (t, 1H, J = 7.2 Hz), 4.79 (t, 1H, J = 4.8 Hz), 4.12 (t, 2H, J = 8.4 Hz),

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3.91 (m, 2H), 3.79 (m, 2H), 3.39 (br, 4H), 2.34 (dd, 2H, J = 4.8, 7.2 Hz), 2.17–2.11 (m, 4H), 0.95 (t, 2H, J = 8.4 Hz), 0.00 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.3, 137.9, 116.9, 103.8, 64.7, 63.2, 45.3, 44.4, 35.6, 31.9, 28.3, 17.5, 1.7. 2–(Trimethylsilyl)ethyl–4–(2–(1,3–dioxolan–2–yl)eth yl)piperidine–1–carboxylate:

Alkene (2.00 g, 6.1 mmol) was dissolved in 40 mL MeOH. Pd/C (10 wt%) (325 mg, mmol) and Et3N (1 mol%) were added and the reaction was stirred under H2 atmosphere for 2 h. The mixture was filtered over Celite and the product was concentrated on reduced pressure to yield the acetal (2.0 g, 6.1 mmol, 99%) as a yellow oil. IR (neat, cm–1) ν 2949, 2855, 1693, 1431, 1276, 1247, 859, 836; 1H NMR (400 MHz, CDCl3) δ 4.78 (t, 1H, J = 4.8 Hz), 4.11 (t, 2H, J = 8.4 Hz), 4.09 (br, 2H), 3.90 (m, 2H), 3.79 (m, 2H), 2.66 (br, 2H), 1.62 (m, 4H), 1.33 (m, 3H), 1.04 (br, 2H), 0.94 (t, 2H, J = 8.4 Hz), 0.00 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.4, 104.4, 64.7, 63.0, 43.8, 35.6, 31.8, 30.8,

30.3, 17.6, 1.6; HRMS (FAB) for C16H32NO4Si: calculated (MH+): 330.2101, found (MH+) 330.2102. 2–(Trimethylsilyl)ethyl–4–(3–oxopropyl)piperidine–1 –carboxylate 21: Acetal (1.77

g, 5.4 mmol) was dissolved in 40 mL of acetone/water (3:1) and 1 mL concentrated H2SO4 was added. The resulting mixture stirred overnight at rt. The reaction was quenched with saturated NaHCO3 and the mixture was extracted 3 times with EtOAc. The organic layers were combined, washed with brine, dried with MgSO4 and the solvent was evaporated to yield aldehyde 21 (1.53 g, 5.4 mmol, 100%) as a yellow oil. IR (neat, cm–1) ν 2951, 2927, 1726, 1695, 1470, 1248, 861, 838; 1H NMR (400 MHz, CDCl3) δ 9.68 (s, 1H), 4.07 (t, 2H, J = 8.4 Hz), 4.04 (br, 2H), 2.62 (br, 2H), 2.38 (t, 2H, J =

7.2 Hz), 1.58 (br, 2H), 1.49 (q, 2H, J = 7.2 Hz), 1.34 (m, 1H), 1.04 (br, 2H), 0.90 (t, 2H, J = 8.4 Hz), 0.06 (s, 9H13C NMR (100 MHz, CDCl3) δ 201.8, 155.3, 64.5, 63.0, 43.6, 40.8, 35.1, 31.5, 28.1, 17.4, 1.7; HRMS (FAB) for C14H28NO3Si: calculated (MH+): 286.1838, found (MH+) 286.1844. 2–(Trimethylsilyl)ethyl–4–(3–hydroxy–4–(6–methoxyqu inolin–4–yl)butyl)–

piperidine–1–carboxylate: Di–isopropylamine (1.21 mL, 8.6 mmol) was dissolved in 30 mL THF and the solution was cooled to –78 °C. After cooling n–BuLi (1.6M in hexane, 5.2 mL, 8.3 mmol) was added dropwise and the reaction mixture was warmed to 0 °C. After stirring for 15 min the reaction was cooled to –78 °C. 4–Methyl 6–methoxquinoline (1.44 g, 8.3 mmol) in 7.5 mL THF was added dropwise and the reaction was stirred for 1 h. A solution of aldehyde 21 (1.58 g, 5.5 mmol) in 15 mL THF was added slowly to the reaction mixture and stirring was continued for 3 h at –78 °C. The reaction was quenched with saturated

NH4Cl and the reaction mixture was allowed to warm to rt. The layers were separated and the aqueous layer was extracted 3 times with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4 and the crude product was concentrated. The product was purified with column chromatography (EtOAc) to yield the alcohol (1.73 g, 3.8 mmol, 68%) as a yellow oil. IR (neat, cm–1) ν 3421, 2931, 2851, 1692, 1242, 1230, 858, 837; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, 1H, J = 4.4 Hz), 7.67 (d, 1H, J = 9.2 Hz), 7.17–7.13 (m, 2H), 7.01 (d, 1H, J = 4.4 Hz), 4.12–3.97 (m, 5H), 3.83 (s, 3H), 3.09 (dd, 1H, J = 3.2, 13.6 Hz), 2.94 (dd, 1H, 8.8, 13.6 Hz), 2.64 (br, 2H), 1.61


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(br, 4H), 1.55 (m, 1H), 1.34 (br, 2H), 1.05 (br, 2H), 0.93 (t, 2H, J = 8.4 Hz), –0.02 (s, 9H) (OH is missing); 13C NMR (100 MHz, CDCl3) δ 157.2, 155.4, 146.6, 144.0, 143.4, 130.6, 128.4, 122.3, 120.9, 101.9, 71.0, 63.1, 55.2, 43.8, 40.6, 35.8, 34.7, 32.6, 31.9, 17.5, 1.7; HRMS (FAB) for C25H39N2O4Si: calculated (MH+): 459.2679, found (MH+) 459.2681. (E)–2–(Trimethylsilyl)ethyl–4–(4–(6–methoxyquinolin–4 –yl)but–3–en–1–yl)–

piperidine–1–carboxylate 22: Alcohol (1.36 g, 3.0 mmol) in 15 mL CH2Cl2 was added and the mixture was cooled to 0 °C . Et3N (0.5 mL, 3.6 mmol) and methanesulfonyl chloride (0.28 mL, 3.6 mmol) were added. After 1 h the reaction was quenched with water and the reaction mixture was allowed to warm to rt. The layers were separated and the water layer was extracted 3 times with CH2Cl2. The organic layers were combined, washed with brine, dried with MgSO4 and the solvent was evaporated. The crude was dissolved in 15 mL CH2Cl2 and the mixture was cooled to 0 °C. KOt–Bu (510 mg, 4.2 mmol) was added and the reaction

mixture stirred for 2 h. The reaction was quenched with water and the reaction mixture was allowed to warm to rt. The layers were separated and the water layer was extracted 3 times with CH2Cl2. The organic layers were combined, washed with brine, dried with MgSO4 and the solvent was evaporated. The product was purified by column chromatography (EtOAc) to yield alkene 22 (1.11 g, 2.52 mmol, 85%) as a yellow oil. IR (neat, cm–1) ν 2918, 2849, 1688, 1299, 1275, 855, 833; 1H NMR (400 MHz, CDCl3) δ 8.46 (d, 1H, J = 4.4 Hz), 7.79 (d, 1H, J = 9.2 Hz), 7.15–7.11 (m, 2H), 7.04 (d, 1H, J = 2.4 Hz), 6.73 (d, 1H, J = 15.6 Hz), 6.17 (dt, 1H, J = 7.2, 15.6 Hz), 4.03–3.91 (m, 4H), 3.70 (s, 3H), 2.53 (br, 2H), 2.14 (br, 2H), 1.51 (br, 2H), 1.14 (br, 3H), 0.95 (br, 2H), 0.82 (t, 2H, J = 8.4 Hz), –0.14 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 157.0, 155.0, 147.0, 144.1, 141.4, 136.8, 130.8, 126.5, 124.3, 120.9, 117.0, 101.0, 62.7, 54.8, 43.4, 35.2, 35.0, 31.5, 30.0, 17.2, –1.9; HRMS (FAB) for C25H37N2O3Si: calculated (MH+): 441.2573, found (MH+) 441.2572. 2–(Trimethylsilyl)ethyl–4–((3 S,4S)–3,4–dihydroxy–4–(6–methoxyquinolin–4–yl)–

butyl)–piperidine–1–carboxylate: To a mixture of AD–mix α (6.6 g) and methanesulfonamine (1.1 g, 11.6 mmol) in 16 mL water and 16 mL t–BuOH, alkene 22 (1.02 g, 2.3 mmol) in 10 mL t–BuOH was added and the solution was cooled to 0 °C. The resultant mixture stirred for 18 h. Sodiumsulfite (8.2 g) was added and the reaction was allowed to warm to rt and stirred for an additional hour. The reaction mixture was extracted 3 times with CH2Cl2. The organic layers were combined, washed with brine, dried with MgSO4 and the crude was concentrated. The product was purified by column chromatography (CH2Cl2/MeOH/Et3N

20:1:0.5) to yield the diol (920 mg, 1.8 mmol, 84%) as a white foam. (ee was not determined because the cyclization to the [3.2.2]–analogue was not successful) IR (neat, cm–1) ν 3369, 2934, 2850, 1674, 1240, 857, 835; 1H NMR (400 MHz, CDCl3) δ 8.34 (d, 1H, J = 4.4 Hz), 7.77 (d, 1H, J = 9.2 Hz), 7.36 (d, 1H, J = 4.4 Hz), 7.23 (dd, 1H, J = 2.8, 9.2 Hz), 7.13 (d, 1H, J = 2.8 Hz), 5.11 (d, 1H, J = 4.4 Hz), 4.10 (t, 2H, J = 8.4 Hz), 4.01 (br, 2H), 3.88 (m, 1H), 3.85 (s, 3H), 2.60 (br, 2H), 1.43–1.68 (m, 5H), 1.29 (br, 2H), 0.98 (m, 4H), 0.02 (s, 9H) (OH–groups are missing); 13C NMR (100 MHz, CDCl3) δ 157.4, 155.6, 147.0, 146.6, 143.5, 130.8, 126.7, 121.2, 119.1, 101.5, 74.1, 72.5, 63.3,

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55.4, 43.8, 35.7, 32.7, 32.1, 32.0, 30.7, 17.6, –1.6; HRMS (FAB) for C25H39N2O5Si: calculated (MH+): 475.2628, found (MH+) 475.2626. 2–(Trimethylsilyl)ethyl–4–(2–((2 S,3S)–3–(6–methoxyquinolin–4–yl)oxiran–2–yl)–

ethyl)–piperidine–1–carboxylate 23: Diol (0.92 g, 1.9 mmol) was dissolved in 15 mL CH2Cl2. Trimethylorthoacetate (1.13 mL, 8.8 mmol) and PPTS (44 mg, 0.18 mmol) were added and the reaction mixture was stirred for 18 h. The solvent was evaporated and the crude was dissolved in 15 mL CH2Cl2. TMSCl (1.19 mL, 8.8 mmol) was added and the mixture was stirred for 2 h. The solvent was evaporated and the crude was dissolved in 15 mL MeOH. K2CO3 (1.22 g, 8.8 mmol) was added and stirring was continued for 2 h. The reaction was quenched with saturated NH4Cl and the mixture was extracted 3 times with CH2Cl2. The

organic layers were combined, dried with MgSO4 and concentrated. The product was purified by column chromatography (CH2Cl2/MeOH 40:1) to yield epoxide 23 (850 mg, 1.86 mmol, 96%) as a yellow oil. IR (neat, cm–1) ν 2919, 2850, 1688, 1234, 854, 835; 1H NMR (400 MHz, CDCl3) δ 8.58 (d, 1H, J = 4.4 Hz), 7.89 (d, 1H, J = 9.2 Hz), 7.24 (dd, 1H, J = 2.8, 9.2 Hz), 7.13 (d, 1H, J = 4.4 Hz), 7.07 (d, 1H, J = 2.8 Hz), 4.09–3.97 (m, 5H), 3.79 (s, 3H), 2.78 (m, 1H), 2.61 (br, 2H), 1.71 (m, 2H), 1.59 (br, 2H), 1.38 (m, 2H), 1.02 (br, 2H), 0.89 (t, 2H, J = 4.0 Hz), –0.08 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 157.5, 155.2, 147.5, 143.4, 141.4, 131.2, 126.9, 121.2, 116.3, 100.5, 62.9, 62.1, 55.1, 55.0, 43.5, 35.3, 32.4, 32.6, 29.1, 17.4, –1.8; HRMS (FAB) for C25H37N2O4Si: calculated (MH+): 457.2523, found (MH+) 457.2522. (Z)–2–((6–Methoxyquinolin–4–yl)methylene)quinuclidin– 3–one 26: NaH (2.2 g,

55.6 mmol, 60% in mineral oil) was dissolved in 40 mL of ethanol and stirred for 30 min. Next quinuclidinone hydrochloride 24 (6.9 g, 42.8 mmol) and 6–methoxyquinoline–4–carbaldehyde 25 (8.0 g, 42.8 mmol) were added and the mixture was heated to 35 °C and stirred for 10 min. The solution was allowed to cool down to rt and stirring was continued for 4 h. Crystallization of the product was accomplished by slowly adding water (150 mL). The product

was filtered, washed 3 times with water and was dried over night by air yielding the aldol condensation product 26 (11.3 g, 38.5 mmol, 90%) as a yellow powder. mp 152–153 °C; IR (neat, cm–1) ν 2944, 1707, 1619, 1505, 1228, 1099, 1031, 729; 1H NMR (500 MHz, CDCl3) δ 8.82 (d, 1H, J = 4.5 Hz), 8.10 (d, 1H, J = 4.5 Hz), 8.04 (d, 1H, J = 9.5 Hz), 7.71 (s, 1H), 7.41 (dd, 1H, J = 9.0, 2.5 Hz), 7.32 (d, 1H, J = 2.5 Hz), 3.99 (s, 3H), 3.23 (m, 2H), 3.05 (m, 2H), 2.75 (m, 1H), 2.11 (m, 4H);13C NMR (125 MHz, CDCl3) δ 202.5, 158.1, 148.1, 147.3, 144.7. 136.2, 131.7, 128.1, 123.1, 121.9, 119.3, 101.1, 55.6, 47.6, 40.0, 25.4; HRMS (ESI) for C18H19N2O2 calculated (MH+): 295.1441, found (MH+): 295.1450.


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2–((6–Methoxyquinolin–4–yl)methyl)–1–azabicyclo[3.2 .2]non–2–en–4–one 27: n–BuLi (1.6M in hexane, 33 mL, 52.4 mmol) was dissolved in 150 mL Et2O and cooled to –78 °C. TMS–diazomethane (2 M in hexanes, 24.3 mL, 48.6 mmol) was added and the mixture was stirred for 30 min. A solution of the aldol condensation product 26 (11 g, 37.4 mmol) in 140 mL THF was added dropwise over a period of 15 min. The dark red solution was stirred for 15 min and then slowly quenched with MeOH (2.5 mL, 74.8 mmol) in 70 mL THF. The reaction mixture was allowed to come to rt, diluted with 250 mL of

EtOAc and washed with water and brine. The organic layer was dried with Na2SO4 and then 100 g of silica gel was added. The solution was stirred for 30 min followed by filtrating the solution over sand. The filtrate was washed two times with methanol and the crude product was concentrated. Purification with column chromatography (EtOAc/Et3N 100:1) gave the ring expanded product 27 (5.1 g, 16.6 mmol, 43%) as a dark red sticky oil. IR (neat, cm–1) ν 2935, 1656, 1619, 1508, 1368, 1239, 1228; 1H NMR (500 MHz, CDCl3) δ 8.70 (d, 1H, J = 4.5 Hz), 8.02 (d, 1H, J = 9.0 Hz), 7.36 (dd, 1H, J = 9.0, 2.5 Hz), 7.24 (d, 1H, J = 4.5 Hz), 7.17 (d, 1H, J = 2.5 Hz), 5.92 (s, 1H), 3.92 (s, 2H), 3.89 (s, 3H), 3.19 (m, 2H), 2.94 (m, 2H), 2.79 (m, 1H), 1.88 (m, 2H), 1.78 (m, 2H);13C NMR (125 MHz, CDCl3) δ 205.7, 173.4, 157.8, 147.6, 144.5, 141.0, 131.7, 130.0, 128.4, 123.1, 121.6, 101.7, 55.4, 48.2, 46.7, 41.3, 24.3; HRMS (ESI) for C19H21N2O2 calculated (MH+): 309.1598, found (MH+): 309.1580. 2–((6–Methoxyquinolin–4–yl)methyl)–1–azabicyclo[3.2 .2]non–2–en–4–ol: 27 (3.32

g, 10.7 mmol) was dissolved in 60 mL MeOH and cooled to 0 °C. NaBH4 (1.21 g, 32.1 mmol) was added in portions and the mixture was stirred at rt for 2 h. The crude was concentrated, dissolved in EtOAc, extracted 3 times with water and one time with brine. The product was dried with Na2SO4 and concentrated. The crude was dissolved in 20 mL THF and was added to a 143 mL solution of THF/t–BuOH (10:1) containing KOt–Bu (3.6 g, 32.1 mmol) at –40 °C. The mixture was allowed to come to rt and stirred overnight. The

mixture was quenched with saturated NH4Cl and extracted 3 times with EtOAc. The organic layers were combined, dried with Na2SO4 and the crude was concentrated providing a 5:1 mixture of Z:E–isomers. The Z–isomer could be obtained as pure compound via means of purification by column chromatography (CH2Cl2/MeOH/Et3N 100:2:1). During the evaporation of the solvent a small portion of the Z–isomer isomerized towards the E–alkene, providing a 10:1 mixture of Z:E–isomers of product 28 (2.4 g, 7.79 mmol, 73% over 2 steps) as a white foam. IR (neat, cm–1) ν 3314, 2918, 1619, 1508, 1228; 1H NMR (500 MHz, CDCl3) δ 8.65 (d, 0.9H, J = 4.5 Hz), 8.58 (d, 0.1H, J = 4.5 Hz), 8.14 (d, 0.9H, J = 5.0 Hz), 8.00 (m, 1.1H), 7.35 (m, 2H), 6.63 (s, 0.1H), 6.13 (s, 1H), 4.04 (m, 1H), 3.94 (s, 2.7H), 3.91 (s, 0.3H), 3.32 (m, 0.1H), 3.17 (m, 0.9H), 3.00–2.90 (m, 3H), 2.82–2.71 (m, 3H), 2.17 (m, 1H), 2.07 (br, 1H), 1.70 (m, 2H), 1.59 (m, 1H);13C NMR (125 MHz, CDCl3) δ 157.5, 157.3, 154.0, 147.3, 147.1, 144.1, 130.9, 130.8, 127.1, 122.1, 121.2, 120.9, 119.4, 115.9, 108.6, 102.5, 102.2, 74.7, 74.2, 55.7, 55.5, 51.4, 48.7, 47.8, 47.7, 46.5, 42.9, 35.9, 35.6, 25.6, 24.9, 19.6, 19.5; HRMS (ESI) for C19H23N2O2 calculated (MH+): 311.1754, found (MH+): 311.1740.

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O–(2–((6–Methoxyquinolin–4–yl)methyl)–1–azabicyclo[3 .2.2]nonan–4–yl)1 H–imidazole–1–carbothioate: Alkene 28 (2.4 g, 7.8 mmol) was dissolved in 40 mL solution of 0.4M HCl in MeOH, Pd/C (10 wt%) (410 mg, 0.44 mmol) was added and the resulting mixture was stirred under an H2–atmosphere for 3 h. The solvent was removed and the crude was dissolved in water and the pH was adjusted to 12 by adding a concentrated solution of NH4OH. The mixture was 3 times extracted with CH2Cl2. The organic layers were combined, dried with Na2SO4 and concentrated. Providing the product as a 2.5:1 mixture of diastereoisomers, which was dissolved in 25 mL dry THF, followed by

the addition of thiocarbonyldiimidazole (1.8 g, 9.4 mmol) and the resulting mixture was refluxed overnight. The reaction was cooled to rt, diluted with EtOAc and extracted 3 times with water and 3 times with saturated NaHCO3. The organic layer was dried with Na2SO4 and the crude was concentrated. The product was purified with column chromatography (EtOAc/Et3N 100:1) yielding 29 (2.1 g, 5.0 mmol, 64% over two steps) in a 2:1 mixture of diastereoisomers as a white foam. IR (neat, cm–1) ν 2937, 1756, 1620, 1509, 1473, 1240, 1229; 1H NMR (400 MHz, CDCl3) δ 8.68 (d, 1H, J = 4.4 Hz), 8.32 (s, 0.67H), 8.27 (s, 0.33H), 8.04 (d, 0.33H, J = 3.0 Hz), 8.02 (d, 0.67H, J = 3.0 Hz), 7.62 (d, 0.67H, J = 1.2 Hz), 7.53 (d, 0.33H, J = 1.2 Hz), 7.39 (m, 1H), 7.24 (m, 2H), 7.03 (d, 1H, J = 7.6 Hz), 5.82 (m, 0.33H), 5.56 (dd, 0.67H, J = 10.7, 5.6 Hz), 3.97 (s, 2H), 3.94 (s, 1H), 3.43 (m, 0.67H), 3.25 (m, 2H), 3.13 (m, 1.33H), 3.01–2.85 (m, 3H), 2.62 (br, 0.67H), 2.32 (br, 0.33H), 2.27 (br, 1H), 2.10 (m, 1H), 1.94 (m, 1H), 1.82–1.65 (m, 3H) ;13C NMR (100 MHz, CDCl3) δ 182.7, 157.4, 147.3, 144.2, 144.0, 143.9, 131.5, 130.7, 130.5, 18.5, 128.4, 122.0, 121.1, 121.0, 117.7, 101.8, 101.7, 87.7, 84.4, 61.0, 59.5, 55.3, 49.5, 40.2, 39.4, 38.7, 35.9,34.8, 32.8, 29.6, 24.8, 23.7, 22.3, 22.0; HRMS (ESI) for C23H27N4O2S calculated (MH+): 423.1849, found (MH+): 423.1830. 1–Azabicyclo[3.2.2]nonan–2–yl)(6–methoxyquinolin–4– yl)methanol racemic

[3.2.2]–analogue: 29 (2.1 g, 5.0 mmol) was dissolved in 70 mL dry toluene, followed by the addition of n–Bu3SnH (4.0 mL, 15.0 mmol) and AIBN (205 mg, 1.25 mmol). The resulting mixture was refluxed for 3 h and then allowed to cool to rt. The mixture was 3 times extracted with 1M HCl. The water layers were combined and the pH was adjusted to 12 by the addition of an NH4OH solution. The basic solution was extracted 3 times with CH2Cl2. The organic

layers were combined, washed with brine, dried with Na2SO4, concentrated and directly used in the next step. NaH (387 mg, 9.7 mmol, 60% in mineral oil) was dissolved in 35 mL dry DMSO and heated to 70 °C. Stirring was continued for 45 min, next the racemic deoxy–[3.2.2]–analogue (1.3 g, 4.3 mmol) in 15 mL of DMSO was added and after 1 min stirring a dark red solution was formed. Oxygen was bubbled through the solution for 45 min, the reaction was quenched with 30 mL saturated NaHCO3 under cooling. The mixture was extracted 3 times with EtOAc, the organic layers were combined, 3 times washed with brine and dried with Na2SO4. The solvent was removed yielding a 2.5:1 mixture of the racemic [3.2.2]–analogue and its epi–isomer. The racemic analogue was obtained via purification with column chromatography (CH2Cl2/MeOH/NH4OH 100:3:1) providing the racemic [3.2.2]–analogue (550 mg, 1.76 mmol, 35% over two steps) as a white foam. mp 68–71 °C; IR (neat, cm–1) ν 3168, 2908, 2858, 1620, 1507, 1240, 1225, 1172, 1150, 792, 773; 1H NMR (500 MHz, CDCl3) δ 8.71 (d, 1H, J = 4.0 Hz, H–12), 8.01 (d, 1H, J = 9.0 Hz, H–14), 7.51 (d, 1H, J = 4.0 Hz, H–11), 7.35 (d, 1H, J = 9.0 Hz, H–15), 7.19 (s, 1H, H–17), 5.39 (d, 1H, J = 4.5 Hz, H–9), 4.98 (br, 1H, OH), 3.91

N

OH

N

OMe

1

2

4

5

67

89

1011

12

13

1415

16

1718

19

3


133

(s, 3H, H–19), 3.21 (d, 1H, J = 12.0 Hz, H–8), 3.02 (m, 1H, H–5), 2.93 (m, 1H, H–5), 2.76 (m, 2H, H–1), 1.96 (br, 1H, H–3), 1.84 (m, 2H, H–4 and 6), 1.66 (m, 2H, H–4 and 7), 1.46–1.31 (m, 4H, H–2 (2x), 6 and 7); 13C NMR (125 MHz, CDCl3) δ 157.3 (C–16), 147.7 (C–10), 147.5 (C–12), 147.4 (C–12), 144.0 (C–13), 131.6 (C–14), 131.5 (C–14), 127.3 (C–18), 121.2 (C–15), 119.4 (C–11), 101.7 (C–17), 101.6 (C–17), 70.7 (C–9), 70.7 (C–8), 67.6 (C–19), 55.5 (C–5), 50.9 (C–1), 44.1 (C–4), 34.8 (C–2), 29.9 (C–3), 26.9 (C–7), 24.9 (C–7), 24.8 (C–6), 24.6 (C–6) (double signals due to hindered rotation); HRMS (ESI) for C19H25N2O2 calculated (MH+): 313.1911, found (MH+): 313.1892. (2S)–(1S)–((2R)–1–Azabicyclo[3.2.2]nonan–2–yl)(6–methoxyquinolin– 4–yl)methyl–2–methoxy–2–phenylacetate and ( S)–(R)–((1R,2S,5R)–1–azabicyclo[3.2.2]nonan–2–yl)(6–methoxyquinolin–4–yl )methyl–2–methoxy–2–

phenylacetate 30 and 31: 10 mL CH2Cl2 was cooled to 0 °C and (S)–(+)–α–methoxyphenylacetic acid (162 mg, 0.98 mmol), EDC (201 mg, 0.98 mmol) and HOBt (132 mg, 0.98 mmol) were added. Next racemic [3.2.2]–analogue (190 mg, 0.61 mmol) was added and the resulting mixture was stirred at 0 °C overnight. The solution was filtrated over celite and washed 3 times with saturated

Na2CO3. The solution was dried with Na2SO4, concentrated and the formed diastereoisomers were separated with column chromatography (EtOAc/PE 3:2), providing the quinidine analogue 30 (80 mg, 0.18 mmol, 29%) as a single isomers and as an oil. The quinine analogue 31 (148 mg, 0.33 mmol, 54%) was isolated as a 4:1 mixture of diastereoisomers as a white solid. Data for 30: [α]D= +24.0 (c = 0.3, CH2Cl2); IR (neat, cm–1) ν 2929, 2866, 1747, 1621, 1508, 1240, 1171, 731; 1H NMR (400 MHz, CDCl3) δ 8.66 (d, 1H, J = 4.4 Hz), 8.01 (d, 1H, J = 9.2 Hz), 7.51 (d, 2H, J = 6.6 Hz), 7.38 (m, 4H), 7.15 (d, 1H, J = 4.4 Hz), 6.35 (d, 1H, J = 5.2 Hz), 4.85 (s, 1H), 3.94 (s, 3H), 3.41 (s, 3H), 3.08 (m, 1H), 2.75 (m, 1H), 2.63 (m, 2H), 2.48 (m, 1H), 1.83 (br, 1H), 1.73 (m, 1H), 1.64 (m, 1H) 1.57–1.41 (m, 5H), 1.27 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 169.5, 157.7, 147.2, 144.5, 144.1, 136.0, 131.6, 128.9, 128.7, 127.3, 127.1, 121.9, 118.1, 101.5, 82.8, 76.8, 67.8, 57.5, 55.5, 50.2, 42.2, 34.1, 30.3, 29.7, 26.9, 25.0, 24.1; Data for 31: IR (neat, cm–1) ν 2929, 2866, 1748, 1621, 1508, 1240, 1171, 731; 1H NMR (400 MHz, CDCl3) δ 8.65 (d, 0.2H, J = 4.4 Hz), 8.44 (d, 0.8H, J = 4.5 Hz), 7.99 (m, 1H), 7.51 (d, 0.2H, J = 6.6H), 7.37 (m, 4.8H), 7.23 (s, 1H), 7.15 (d, 0.2H, J = 4.4 Hz), 6.69 (d, 0.8H, J = 4.0 Hz), 6.35 (d, 1H, J = 4.7 Hz), 4.87 (s, 0.8H, 4.85 (s, 0.2H), 3.94 (s, 0.6H), 3.92 (s, 2.4H), 3.43 (s, 2.4H), 3.41 (s, 0.6H), 3.18 (m, 1H). 3.07 (m, 1H), 2.82 (m, 1H), 2.69 (m, 2H), 2.68 (m, 2H), 1.98–1.92 (m, 2H), 1.71–1.20 (m, 7H);13C NMR (100 MHz, CDCl3) δ 169.4, 157.5, 147.1, 147.0, 144.2, 144.0, 143.8, 135.8, 131.5, 131.4, 128.8, 128.6, 127.2, 127.2, 127.0, 121.8, 121.6, 117.7, 101.3, 82.7, 82.6, 76.7, 67.6, 67.4, 57.4, 55.3, 50.2, 42.6, 42.1, 34.1, 34.0, 30.2, 26.8, 26.8, 26.6, 25.0, 24.9, 24.3, 24.0; HRMS (ESI) for C28H33N2O4 calculated (MH+): 461.2435, found (MH+): 461.2434. (1S)–((2R)–1–Azabicyclo[3.2.2]nonan–2–yl)(6–methoxyquinolin– 4–yl)methanol

[3.2.2]–analogue: 30 (58 mg, 0.13 mmol) was dissolved in 2 mL of methanol and cooled to 0 °C. K2CO3 (53 mg, 0.38 mmol) was added and the resulting mixture was stirred at rt for 2 h. The mixture was diluted with CH2Cl2, washed 2 times with water and 1 time with brine. The organic layer was dried with Na2SO4, the crude product was concentrated and the product was purified with column

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chromatography (CH2Cl2/MeOH/NH4OH 100:3:1) yielding the [3.2.2]–analogue (36 mg, 0.12 mmol, 89%) as a white foam. (ee = 96%) (ee determined by HPLC Chiral Daicel AD, i–PrOH/n–heptane/Et2HN 15:85:0.1 (1.00 mL/min, λ = 220 nm), tr major = 7.1 min and tr minor = 18.8 min). [α]D= +109.8 (c = 0.21, CH2Cl2). Analytical data is the same as for the racemic [3.2.2]–analogue. (S)–((1S,2R,4S)–5–Formylquinuclidin–2–yl)(6–methoxyquinolin–4–yl) methyl–

acetate 43: Quindine 41 (2.0 g, 6.2 mmol) was dissolved in 20 mL of a 1:1 mixture of acetic anhydride and pyridine. DMAP (122 mg, 1 mmol) was added and the resulting mixture was stirred overnight. The solvent was removed and the crude was dissolved in CH2Cl2 and was extracted with saturated NaHCO3. The water layer was extracted 3 times with CH2Cl2. The organic layers were combined, washed with brine, dried with Na2SO4 and the solvent was evaporated. The crude was dissolved in 20 mL of t–BuOH and added to a 80 mL solution of t–BuOH and water containing AD–mix α (18.0

g) and methanesulfonamide (2.94 g, 31.0 mmol). The mixture was stirred overnight and quenched with sodiumsulfite (15 g). 200 mL Water and 200 mL of CH2Cl2 were added and the layers were separated. The water layer was extracted 3 more times with CH2Cl2. The organic layers were combined, dried with Na2SO4 and concentrated. The crude was dissolved in 20 mL solution of a 1:1 mixture of acetone/water and cooled to 0 °C. NaIO4 (1.32 g, 6.1 mmol) was added and stirring was continued at rt for 2 h. The acetone was removed and saturated NaHCO3 and CH2Cl2 were added. The layers were separated and the water layer was extracted 2 times with CH2Cl2. The organic layers were combined, dried with Na2SO4 and concentrated. Purification with column chromatography (CH2Cl2/MeOH 100:5) provided aldehyde 43 (2.0 g, 5.5 mmol, 88% over 3 steps) as 9:1 mixture of isomers as a white solid. IR (neat, cm–1) ν 2940, 1743, 1719, 1621, 1228, 1028, 731; 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 0.9H), 9.82 (s, 0.1H), 8.74 (d, 1H, J = 4.6 Hz), 8.03 (d, 1H, J = 9.2 Hz), 7.52 (d, 1H, J = 2.5 Hz), 7.40 (dd, 1H, J = 9.2, 2.5 Hz), 7.31 (d, 1H, J = 4.5 Hz), 6.56 (d, 1H, J = 6.5 Hz), 4.03 (s, 2.7H), 3.97 (s, 0.3H), 3.66 (m, 1H), 3.26 (m, 1H), 2.91 (m, 1H), 2.76 (m, 2H), 2.49 (m, 2H), 2.17 (s, 3H), 1.83 (br, 1H), 1.68–1.54 (m, 3H);13C NMR (100 MHz, CDCl3) δ 203.4, 203.3, 169.7, 157.8, 147.2, 144.4, 143.6, 131.5, 126.7, 121.9, 121.7, 118.3, 118.1, 101.0, 73.4, 58.5, 55.5, 50.2, 48.8, 42.1, 25.7, 24.6, 23.2, 20.8; HRMS (ESI) for C21H25N2O4 calculated (MH+): 369.1809, found (MH+): 369.1813. Des–vinyl–quinidine 44: Argon was bubbled through 30 mL of diglyme for 30 min, next

((COD)RhCl)2 (39 mg, 0.05 mmol) and dppp (90 mg, 0.22 mmol) were added and the bubbling of argon was continued for 15 min. Aldehyde 43 (800 mg, 2.17 mmol) was added and the mixture was refluxed overnight. The solution was cooled to rt and 200 mL water and 200 mL of CH2Cl2 were added. The layers were separated and the water layer was extracted 2 times with CH2Cl2. The organic layers were combined, washed with brine, dried with Na2SO4 and

concentrated. The crude was dissolved in 10 mL of MeOH and cooled to 0 °C. K2CO3 (1.5 g, 10.9 mmol) was added and the mixture was stirred at rt for 2 h. The reaction was quenched with water and the mixture was extracted 3 times with CH2Cl2. The organic layers were combined, washed with brine, dried with Na2SO4 and concentrated. Purification with column chromatography (CH2Cl2/MeOH/NH4OH 100:3:1) provided des–vinylquinidine 44 (518 mg, 1.74 mmol, 81%) as a white solid. mp 81–82 °C; [α]D=


135

+126.6 (c = 0.37, CH2Cl2); IR (neat, cm–1) ν 3076, 2935, 1621, 1508, 1259, 1241, 729; 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 7.99 (d, 1H, J = 9.2 Hz), 7.55 (d, 1H, J = 4.4 Hz), 7.32 (d, 1H, J = 9.2 Hz), 7.21 (s, 1H), 5.65 (d, 1H, J = 3.8 Hz), 3.87 (s, 3H), 3.53 (m, 1H), 3.17 (m, 1H), 2.88 (m, 2H), 2.75 (m, 1H), 2.20 (br, 1H), 1.86 (m, 2H), 1.63 (m, 1H), 1.48 (m, 3H), 1.32 (m, 1H);13C NMR (100 MHz, CDCl3) δ 157.4, 148.2, 147.1, 143.6, 130.9, 126.3, 121.2, 118.4, 101.2, 71.2, 59.4, 55.5, 50.5, 43.8, 26.1, 25.4, 25.2, 21.7; HRMS (ESI) for C18H23N2O2 calculated (MH+): 299.1754, found (MH+): 299.1749. (R)–Methyl–3–(benzylthio)–2–(1,3–dioxoisoindolin–2–yl )propanoate 34: Catalyst

(6.0 µmol, 5.0 mol %) and methyl 2–(1,3–dioxoisoindolin–2–yl)acrylate 32 (29 mg, 0.125 mmol) were dissolved in 1.0 mL toluene and the mixture was cooled to 0 °C. Phenylmethanethiol 33 (16 µL, 0.14 mmol) was added and the mixture stirred for 24 h. The mixture was filtrated over silica and concentrated to obtain

addition product 34. (ee determined by HPLC Chiral Daicel AD, i–PrOH/n–heptane 10:90 (1.00 mL/min, λ = 220 nm), tr major = 20.5 min and tr minor = 16.8 min) (S)–3–((4–(tert–Butyl)phenyl)thio)cyclohexanone 37: Catalyst (6.4 µmol, 1.0 mol %)

and cyclohex–2–enone 35 (65 µL, 0.67 mmol) were dissolved in 1.28 mL toluene. 4–tert–butylthiophenol 36 (133 µL, 0.77 mmol) was added and the mixture stirred overnight. The mixture was filtrated over silica and concentrated to obtain thioether 37. (ee determined by HPLC Chiral Daicel AD, i–PrOH/n–heptane 2:98

(1.00 mL/min, λ = 220 nm), tr major = 6.9 min and tr minor = 8.5 min. (R)–Methyl–1–oxo–2–(3–oxobutyl)–2,3–dihydro–1 H–indene–2–carboxylate 40:

Catalyst (5.0 µmol, 1.0 mol %) and methyl 1–oxo–2–indanecarboxylate 39 (95 mg, 0.5 mmol) were dissolved in 2.0 mL toluene. 3–Buten–2–one 38 (81 µL, 1.0 mmol) was added and the mixture stirred overnight. The mixture was filtrated over silica and concentrated to obtain 40. (ee determined by HPLC Chiral Daicel

AD–H, i–PrOH/n–heptane 15:85 (1.00 mL/min, λ = 220 nm), tr major = 12.8 min, tr minor = 11.3 min). (R)–2–(3–Oxo–1,3–diphenylpropyl)malononitrile 47: Catalyst (10.0 µmol, 10.0 mol

%) and trans–chalcone 45 (21 mg, 0.1 mmol) were dissolved in 1 mL of toluene. Malononitrile 46 (8 mg, 0.12 mmol) was added and the mixture was stirred overnight. The mixture was filtrated over silica and

concentrated to obtain 47. (ee determined by HPLC Chiral Daicel AD, i–PrOH/n–heptane 20:80 (1.00 mL/min, λ = 220 nm), tr major = 10.2 min, tr minor = 13.6 min). General procedure of the determination of the catal yst activity. For the determination of the activity of the catalysts the Perkin Elmer 241 polarimeter was used. The polarimeter was equipped with a cooling unit maintaining the temperature at 18 °C throughout the whole measurement. The measurements were carried out in a 10 cm jacketed cell, the polarimeter was coupled to a computer by a Labjack and the software provided by Labjack recorded the optical rotations every 10 seconds. Before the reaction, the catalyst was dissolved in 1 M HCl and three times extracted with dichloromethane. The pH was adjusted with NH4OH to 12 and the water layer was 3

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times extracted with CH2Cl2. The organic layers were combined, washed with brine, dried with Na2SO4 and concentrated. 1H NMR was taken to check the purity. Cyclohexenone and 4–tert–butylthiophenol were freshly distilled before use. Cyclohexenone (505 μL, 5.23 mmol) and Cinchona catalyst (0.0523 mmol) were dissolved in 5 mL toluene. A 5 mL solution of toluene containing 4–tert–butylthiophenol (1.01 mL, 6.01 mmol) was added and the mixture was shaken. The reaction solution was placed in the cuvet and the optical rotation was measured as a function of time. The time was measured between the addition of 4–tert–butylthiophenol and the placement of the cuvet in the polarimeter and the time was later corrected. All the reaction rates of the catalysts were measured twice and the conversion for both experiments were averaged. The conversion was plotted as a function of time. The 50% (t½) conversion point was taken as a fixed point to compare the reaction rates of the catalysts. pKAH–determination Procedure: Cinchona alkaloid was dissolved in DMSO (10 μmol/mL). From that solution 5 μL was dissolved in 2.5 mL of 0.1M NaOH solution into a sample cuvette. An absorption spectrum was measured between 260 and 450 nm. The concentration of the sample was adjusted so that the maximum absorption was below 0.1. Next, the pH value was measured and then the emission spectrum was measured between 325 and 550 nm with 310 nm excitation. A small amount of HCl solution (different concentrations of HCl solutions were used) was added and then the procedure was repeated until the sample solution reached the pH of 7 or below. The emission spectra were intergraded and corrected for the dilution factor. The corrected integrated emissions (Itot) were plotted as a function of pH. The pKAH’s were determined by curve fitting to the equation on page 111. All the samples were measured in twice, the pKAH’s were averaged and standard deviations were used as the error. 4.8 References

1) a) Marcelli, T.; Hiemstra, H. Synthesis 2010, 1229–1279. b) Ingemann, S.; Hiemstra, H. Comprehensive Enantioselectivity Organocatalysis, Vol 1, Dalko, P. I. Ed.; Wiley–VCH: Weinheim, 2013, 119–160.

2) Hammar, P.; Marcelli, T.; Hiemstra, H.; Himo, F. Adv. Synth. Catal. 2007, 349, 2537–2548. 3) Merschaert, A.; Delbeke, P.; Dalozeb, D.; Dive, G. Tetrahedron Lett. 2004, 45, 4697–4701. 4) Hintermann, L.; Ackerstaff, J.; Boeck, F. Chem. Eur. J. 2013, 19, 2311–2321. 5) Lygo, B.; Crosby, J.; Lowdon, T. R.; Wainwright, P. G. Tetrahedron 2001, 57, 2391–2402. 6) Grob, C. A. Helv. Chim. Acta 1985, 68, 882–886. 7) Prankerd, R. J. Profiles of Drug Substances, Excipients and Related Methodology, Vol 33, Brittain, H.

G. Ed.; Elsevier Inc., 2007, 354–356. 8) a) Raheem, I. T.; Goodman, S. N.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 706–707 b) Igarashi,

J.; Katsukawa, M.; Wang, Y. G.; Acharya, H. P.: Kobayashi, Y. Tetrahedron Lett. 2004, 45, 3783–3786 b) Igarashi, J.; Kobayashi, Y. Tetrahedron Lett. 2005, 46, 6381–4638 d) Furukawa, K.; Katsukawa, M.;Nuruzzaman, M.; Kobayashi, Y. Heterocycles 2007, 74, 159–166

9) Kolb, H. C.; van Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547. 10) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515–10530. 11) Nielsen, L.; Brehm, L.; Krogsgaard–Larsen, P. J. Med. Chem. 1990, 33, 71–77. 12) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651–1660. 13) a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–736 b) Baldwin, J. E.; Thomas, R. C.;

Kruse, L. I.; Silberman, L. J. Org. Chem. 1977, 42, 3846–3852. 14) Fairweather, K. A.; Mander, L. N. Org. Lett. 2006, 8, 3395–3398. 15) Dubinina, G. G.; Yoshida, W. Y.; Chain, W. J. Tetrahedron Lett. 2010, 51, 5325–5327. 16) This was also reported in: Gupta, K. A.; Saxena, A. K.; Jain, P. C.; Anand, N. Ind. J. Chem. 1987,

26B, 344–347.


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17) Sarkar, S. M.; Taira, Y.; Nakano, A.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Tetrahedron Lett. 2011, 52, 923–927.

18) Al Batal, M.; Jones, P. G.; Lindel, T. Eur. J. Org. Chem. 2013, 2533–2536. 19) Webber, P.; Krische, M. J. J. Org. Chem. 2008, 73, 9379–9387. 20) Bhanushali, M. J.; Nandurkar, N. S.; Bhor, M. D.; Bhanage, B. M. Tetrahedron Lett. 2008, 49, 3672–

3676. 21) Bender, D. R.; Coffen, D. L. J. Org. Chem. 1968, 33, 2504–2509. 22) Liu, H.; Sun, C.; Lee, N.–K.; Henry, R. F.; Lee, D. Chem. Eur. J. 2012, 18, 11889–11893. 23) Sotter, P. L.; Friedman, M. D. J. Org. Chem. 1985, 50, 29–31. 24) Stork, G.; Niu, D.; Fujimoto, A.; Koft, E. R.; Balkovec, J. M.; Tata, J. R.; Duke, G. R. J. Am. Chem.

Soc. 2001, 123, 3239–3242. 25) When the esterification was performed without HOBt and at rt, epimerization of (S)–(+)–α–

methoxyphenylacetic acid occurred and the [3.2.2]–analogues was obtained in 80% ee. 26) Pracejus, H.; Wilcke, F. W.; Hanemann, K. J. Prakt. Chem. 1977, 319, 219–229. 27) a) Helder. R.; Arends, R.; Bolt, W.; Hiemstra, H.; Wynberg, H. Tetrahedron Lett. 1977, 18, 2181–2182

b) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417–430. 28) Wynberg, H.; Helder, R. Tetrahedron Lett. 1975, 16, 4057–4060. 29) Fristrup, P.; Kreis, M.; Palmelund, A.; Norrby, P.–O.; Madsen, R. J. Am. Chem. Soc. 2008, 130, 5206–

5215. 30) Russo, A.; Perfetto, A.; Lattanzi, A. Adv. Synth. Catal. 2009, 351, 3067–3071. 31) Hine, J.; Chen. Y.–J. J. Org. Chem. 1987, 52, 2091–2094. 32) Principles of Fluorescence Spectroscopy, Lakowicz, J. R. Ed.; Springer, 2006. 33) Wilcox, J. L.; Bevilacqua, P. C. J. Am. Chem. Soc. 2013, 135, 7390–7393. 34) a) Qin, W.; Vozza, A.; Brouwer, A. M. J. Phys. Chem. C, 2009, 113, 11790–11795 b) Kumpulainen,

T.; Brouwer, A. M. Phys. Chem. Chem. Phys. 2012, 14, 13019–13026. 35) a) Rosenberg, L. S.; Wions, J.; Schulma, S. G. Talanta 1979, 26, 867–871 b) Melo, M. J.; Bernardo,

M. A.; Melob, E. C.; Pina, F. J . Chem. Soc., Furaduy Trans. 1996, 92, 957–968. 36) Berkessel, A.; Seelig, B.; Schwengberg, S; Hescheler, J.; Sachinidis, A. ChemBioChem. 2010, 11,

208–217.

Synthesis of Quinuclidines by Intramolecular Silver-Catalyzed Hydroamination

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CHAPTER 5

Synthesis of Quinuclidines by Intramolecular Silver –Catalyzed

Hydroamination of Alkynes *

Abstract: A new method was developed for the synthesis of 2–alkylidenequinuclidines based on the cyclization of the piperidine NH onto an alkyne at the 4–position, catalyzed by silver triflate. Di–cis–substituted piperidines reacted faster than the mono–substituted piperidines because of the requirement for the propynyl group to occupy an axial position. Internal alkynes as well as terminal alkynes were tolerated. The process was selective for an alkyne even in the presence of a vinyl group. With this novel silver catalyzed cyclization, a short procedure was developed for the relay synthesis of the Cinchona alkaloids dihydroquinidine and dihydroquinine.

*The research in this chapter will be published in:

Breman, A. C.; Ruiz–Olalla, A.; van Maarseveen, J. H.; Ingemann, S.; Hiemstra, H. Eur. J. Org. Chem.

submitted

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5.1 Introduction

5.1.1 2–Alkylidenequinuclidines

2–Alkylidenequinuclidines are valuable intermediates for the development of pharmaceutical compounds.1–6 They are usually prepared in good yields under basic conditions via aldol condensation between 3–quinuclidinone hydrochloride and an aldehyde (scheme 1).7 The α,β–unsaturated system can be further functionalized by means of 1,2–additions,1 1,4–additions,2 hydrogenation3 and deoxygenating reactions4. Chirality can be introduced through tautomerization using chiral acids5 or via asymmetric carbonyl reduction6. By using this approach it is difficult to introduce functional groups at other positions than the α,β–unsaturated system. The only known procedure to functionalize the quinuclidine system is hydroxylation with enzymes.8

Scheme 1. Synthetic possibilities of 2–alkylidenequinuclidines.

It can be anticipated, that 2–alkylidenequinuclidines are suitable intermediates for drug discovery and can serve as valuable intermediates in the synthesis of analogues of Cinchona alkaloids. As demonstrated in chapter 4 synthetic analogues can be used to gain more insight into the mechanism of Cinchona alkaloids catalyzed reactions. However, in order to obtain these analogues lengthy syntheses were needed. To develop this approach in organocatalysis further new and shorter synthetic routes should be developed. The intramolecular addition of secondary amines to alkynes would be a valuable strategy to obtain substituted 2–alkylidenequinuclidines which then can be functionalized to analogues of Cinchona alkaloids (scheme 2). In order to achieve this, enantiomerically pure 3,4–cis–substituted piperidines with a propynyl substituent at the 4–position are needed. The terminal alkyne can be modified easily to internal alkynes by Sonogashira couplings9 and alkylation reactions10.


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Scheme 2. Synthetic approach for the synthesis of 2–alkylidenequinuclidines.

5.1.2 Hydroamination

The intramolecular hydroamination of alkynes11, allenes12 and alkenes13 is a powerful method for constructing nitrogen containing heterocycles. These heterocycles are often used as intermediates for natural product synthesis and drug discovery.14 The hydroamination has been studied intensively and a variety of different types of catalysts such as metals15, acids16 and even bases17 have been reported. Catalysts containing late transition metals like palladium18, platinum19, silver20 and gold21 are often used because of the high functional group tolerance and low oxophilicity. In addition, late transition metals tend to coordinate strongly to multiple bonds and activate such bonds for nucleophilic attack with formation of the trans addition products.

Scheme 3 . Formation of nitrogen containing bridge systems by a gold–catalyzed hydroamination.

Only a few studies are known in which a late transition metal–catalyzed hydroamination process provided nitrogen containing bicycles. Recently, the group of Fiksdahl reported an example of the formation of a nitrogen containing bridged system by a gold–catalyzed addition of a secondary amine to an internal alkyne (scheme 3).22 Treatment of the pyrrolidine with a catalytic amount of a gold complex in the presence of AgSbF6 gave a mixture of the 5–exo–dig and 6–endo–dig cyclization products. By using triethylphoshine a 33:67 ratio of 5–exo–dig and 6–endo–dig was observed, while the more bulky ligand A led to complete cyclization with the formation of the 6–endo–dig product (4:96).

A similar cyclization process was applied in the total synthesis of communesin B (scheme 4). The group of Funk reported a gold–catalyzed process involving a 7–exo–dig cyclization leading to the nitrogen–containing bridged system (in 89% yield) in communesin B.23 This cyclization occurred spontaneously albeit slowly at room temperature, so apparently the nitrogen and the alkyne were in close proximity. Based on these findings, it was proposed that a gold–catalyzed process would be a good strategy to explore the formation of 2–alkylidenequinuclidines.

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Scheme 4. Gold–catalyzed hydroamination in the total synthesis of communesin B.

In this chapter, a new synthetic strategy towards analogues of Cinchona alkaloids is described. The key step in this approach is a transition metal–catalyzed intramolecular hydroamination of alkynes yielding 2–alkylidenequinuclidines. The difference in reactivity between mono– and di–substituted piperidines will be studied also. After the cyclization follow–up chemistry will be described for the synthesis of di–hydroquinidine and di–hydroquinine.


To obtain enantiomerically pure 3,4–cis–di–substituted piperidines, quinidine (1) was oxidized according to a known procedure providing 3,4–di–substituted piperidine 2 in good yield over two steps (scheme 5).24 Subsequently, the vinyl group was hydrogenated with 5 mol% Pd/C in methanol to give the ethyl–substituted piperidine 3 in 95% yield.

Scheme 5. Oxidation of quinidine (1).

Alkynes 5 and 7 were obtained in four steps starting from 2 and 3 (scheme 6).

Scheme 6. Synthesis of di–substituted 4–(prop–2–yn–1–yl)piperidines 5 and 7.

First the tert–butyl esters were reduced with LiAlH4 to their corresponding alcohols, followed by protection of the amines with a Boc–group to provide 4 and 6 both in good yields over two steps. A Swern oxidation of the alcohols gave both aldehydes in excellent yields. Finally, these aldehydes were converted to the alkynes 5 and 7 by using


143

Seyferth–Gilbert homologation conditions25 using trimethylsilyldiazomethane and n–butyllithium in THF.

Scheme 7. Synthesis of mono–substituted 4–(prop–2–yn–1–yl)piperidine 11.

4–Propynylpiperidine 11 was prepared in order to compare the reactivity of mono–substituted species with cis–di–substituted piperidines. The synthesis of 11 started from commercially available N–Boc protected piperidone 8 (scheme 7). A Horner–Wadsworth–Emmons olefination reaction was performed with triethyl phosphonoacetate and NaH giving a 1:2.5 mixture of exo/endo isomers 9 in 81% yield.26 Next, the mixture of isomers was hydrogenated by 5 mol% Pd/C in EtOH to provide the ester which was reduced to alcohol 10 with LiAlH4 in THF in quantitative yield over two steps. The Swern oxidation provided the aldehyde in 89% yield and with the use of the Seyferth–Gilbert homologation conditions, alkyne 11 was obtained in 71%.

Table 1. Formation of aromatic alkynes.

entry compound R = ArX product yield (%)a product yield (%)b

1 5 ethyl

12 91 13 88

2 5 ethyl

14 72 15 78

3 5 ethyl

16 80 17 97

4 5 ethyl

18 88 19 95

5 7 vinyl

20 92 21 91

6 11 H

22 95 23 75

7 11 H

24 74 25 99

a) Yield after the Sonogashira coupling b) Yield after Boc–deprotection.

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To obtain the corresponding aromatic alkynes a modified Sonogashira coupling developed by Hoffmann was applied (table 1).27 First ethyl–substituted alkyne 5 was reacted with a series of aryl halides (entries 1–4). The corresponding aromatic alkynes were obtained in good yields (72–91%). Also the vinyl–substituted piperidine 7 proved compatible with the reaction conditions (entry 5) providing the corresponding product 20 in 92% yield. Piperidine 11 gave the corresponding aromatic products 22 and 24 in 95% and 74% yield, respectively (entries 6 and 7). After the Sonogashira coupling, the Boc–groups were removed with a 1:10 mixture of TFA and CH2Cl2. All free amines were obtained in good to excellent yields after stirring overnight.

The Boc–group of alkyne 5 was also removed in excellent yield using the same conditions as given in table 1 (scheme 8). Alkyne 5 was methylated by deprotonation with n–butyllithium followed by reacting with methyl iodide in THF to provide the methylated alkyne in 80%.10 Subsequently, the Boc–group was cleaved to provide 27 in excellent yield. Benzyl ether 28 was prepared in a three step procedure. First, alkyne 5 was reacted with n–butyllithium and para–formaldehyde to give the alcohol in 80% yield. Next, the alcohol was deprotonated with NaH and benzylated with benzyl chloride in DMF in 88%. Finally, the Boc–group was removed to obtain alkyne 28 quantitatively.

Scheme 8. Formation of terminal alkyne 26 and aliphatic substituted alkynes 27 and 28.


The screening started with ClAuPPh3 as catalyst and AgSbF6 as the additive (table 2, entry 1) in CH2Cl2 at room temperature. After 16 h only a small amount of product 29 was formed. In view of a report by Muller indicating that the counter anion can be crucial for good conversion, AgOTf was also examined as an additive, but no improvement in conversion was observed (entry 2).28 Recently, the group of Xu reported that the rate of gold–catalyzed hydroamination reactions of alkynes can be increased by using more electron rich ligands coordinated to gold.29 Therefore, gold catalysts with electron rich ligands were examined (entries 3–5). By using triethylphosphine (L2) fast degradation of the catalyst was observed and only a small amount of product was obtained (entry 3). The use of a more bulky ligand (L3) did not improve the results (entry 4). Next, an NHC–ligand (L4) was introduced, due to the higher electron donating effect and the possibility to provide some reactivity to the reaction (entry 5).30 However, this complex gave no conversion. Elevated temperature appeared to be more helpful (entries 6 and 7). L1 was tested in toluene at 100 °C and after 6 h full conversion was obtained (entry 6). As a


145

control experiment, AgOTf was used in absence of any gold–complex and this time full conversion was observed after only 2 h at 100 °C (entry 7).

Table 2. Catalyst screening for the hydroamination of 13.

entrya Ligand additive solvent temperature (°C) time (h) conversion (%)b

1c L1 AgSbF6 CH2Cl2 rt 16 <10 2c L1 AgOTf CH2Cl2 rt 16 <10 3c L2 AgOTf CH2Cl2 rt 16 <10 4c L3 AgOTf CH2Cl2 rt 16 <10 5 L4 AgOTf CH2Cl2 rt 16 0 6 L1 AgOTf toluene 100 6 100 7 – AgOTf toluene 100 2 100

a) Reaction performed at 0.3M of substrate b) Conversion determined by 1H–NMR c) Longer reaction times did not give more conversion

The likely mechanism of this hydroamination process is depicted in scheme 9. Activation of the alkyne occurs by complexation with the metal and results in attack of the secondary amine on the alkyne. The formed intermediate undergoes demetalation through proton transfer from the protonated quinuclidine to the double bond providing the Z–isomer. Xu reported that demetalation is the rate determining step in the hydroamination of alkynes catalyzed by gold complexes.29 Any acid present in the reaction mixture is mostly or completely neutralized by the presence of a relative large amount of basic amines. This results in a slower demetalation step.

Scheme 9. Mechanism of transition metal catalyzed hydroamination of alkynes.

Because gold and silver are not very different, it can be presumed that the demetalation step is also rate determining for silver complexes. Possible differences in the reactivity of gold and silver complexes are commonly attributed to lanthanide contraction and relativistic effects.31 These two quantum chemical properties are more pronounced for

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gold than for silver, which makes gold more electron negative than silver (EN Ag = 1.9 vs Au = 2.4). This results in stronger interactions between ligands and gold as compared to silver. As a result, cleavage of a carbon–gold bond is more difficult than a carbon–silver bond.

The structure analysis of 29 by 13C NMR showed that the double bond has some enamine character, even though the overlap between the nitrogen lone pair and the π–orbital of the double bond is likely to be small. The quaternary carbon next to the nitrogen has a chemical shift of 154.97 ppm whereas the other double bond carbon has a chemical shift of only 101.87 ppm. In the 1H NMR spectra a large chemical shift (6.88 ppm) for the hydrogen atom of the alkene is observed, which is quite unusual for a Z–alkene. Thus, NOE–experiments were performed in order to determine the configuration of the double bond (scheme 10).

Scheme 10. Isomerization of the Z–isomer to the E–isomer.

The irradiation of the double bond hydrogen of the Z–isomer should show an NOE correlation with the two hydrogen atoms (2.57 and 2.28 ppm) of the quinuclidine ring. However, this correlation was not observed for 29, but instead a correlation with one of the hydrogen atoms (7.30 ppm) of the quinoline ring was detected. Irradiation of the hydrogen atoms (2.57 and 2.28 ppm) of the quinuclidine ring gave only a correlation with the bridge hydrogen atom (1.90 ppm) of the quinuclidine ring. It was concluded from these experiments, that after cyclization the Z–isomer isomerizes to the more stable E–isomer.

5.4 Reaction scope

With the optimized conditions the reaction scope was investigated (scheme 11). The product 29 of the cyclization detailed in table 3 was obtained in 95% yield. Also, the pyridine analogue 30 could be isolated in high yield (93%). 1H NMR analysis showed the double bond proton at 5.79 ppm, so there is a difference of 1 ppm compared with compound 29. NOE–experiments showed this time the correlation between the double bond hydrogen atom and the hydrogen atoms (2.57 and 2.24 ppm) of the quinuclidine ring, revealing that isomerization to the E–isomer is not occurring. This was also observed for the phenyl compound 31 (NOE: 5.83 ppm correlation with 2.57 and 2.23 ppm) and the naphthalene species 32 (NOE: 6.51 ppm correlation with 2.74 and 2.41 ppm). The compounds were obtained as pure Z–isomers in high yields. To further


147

demonstrate the difference in reactivity of a gold or silver catalyzed process, (with the reaction conditions given in table 2, entry 6) only 40% conversion to the bicyclic system 31 was observed after 40 h with the triphenylphosphine gold complex.

Scheme 11. Reaction scope for the silver catalyzed hydroamination.

Also the terminal alkyne 26 gave the corresponding ring system 33 in good yield (78%). Aliphatic alkynes cyclized to the corresponding methyl (34) and benzyl ether (35) substituted ring systems in 70% and 80% yield, respectively, and in both cases pure Z–isomers were obtained. In addition, the cyclization to 35 was tested at lower temperature. At room temperature only 8% conversion was observed after 8 h, while at 50 °C almost full conversion (>90%) was observed after 8 h. The vinyl–substituted piperidine 21 also cyclized cleanly to product 36, and no attack of the vinyl group onto the alkyne was observed. Nevertheless, 50 mol% of AgOTf was needed to obtain full conversion. The product 36 was obtained as a 5:1 mixture of Z– and E–isomers. The non–substituted piperidines 23 and 25 cyclized much more slowly than the corresponding ethyl or vinyl substituted substrates. For the cyclization to 37 an extra 5 mol% of AgOTf was added after 24 h to obtain full conversion and the product was isolated in 73% yield as the E–isomer. For the cyclization of 25, 20 mol% of catalyst was used and after stirring for 60 h only a 50% conversion was observed. The addition of more AgOTf did not improve the conversion, but 38 could be isolated in 42% as 9:1 mixture of Z– and E–isomers.

The longer reaction time for the non–substituted piperidine can be explained by the fact that the alkyne should be in the axial position for the cyclization to occur (scheme 12). For the di–substituted piperidines the conformational preference of the propynyl group

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for the axial position is likely to be greater than for the mono–substituted piperidines which results in shorter reaction times.

Scheme 12. Reactivity difference between di– and mono–substituted piperidines.

5.5 Follow up chemistry

Dihydroquinidine (40) and dihydroquinine (41) were successfully obtained in two steps after the silver catalyzed cyclization (scheme 13). The double bond of 29 was hydrogenated with Pd/C in methanol to provide 4:1 inseparable mixture of the diastereoisomers 39a and 39b. Oxidation of the diastereoisomers by molecular oxygen in DMSO provided a 10:2.5:3:0.5 mixture of dihydroquinidine (40), dihydroquinine (41), epi–dihydroquinidine and epi–dihydroquinine, respectively.32 After separation a mixture of dihydroquinidine (40) and dihydroquinine (41) was obtained in 53%.

Scheme 13. Synthesis of dihydroquinidine (40) and dihydroquinine (41).

5.6 Conclusion

In conclusion, a new approach to substituted 2–alkylidenequinuclidines has been developed. The key step is a silver triflate catalyzed intramolecular hydroamination reaction of 4–(prop–2–yn–1–yl)piperidines. These piperidines were easily prepared by


149

a Seyferth–Gilbert homologation followed by Sonogashira coupling or alkylation reactions. 2–Alkylidenequinuclidines were obtained in moderate to excellent yield and in most examples as the Z–isomers. If the alkyne was substituted with a quinoline complete isomerization to the E–isomer was observed. Cis–disubstituted piperidines reacted much faster than mono–substituted piperidines because the propynyl group prefers the axial position in di–substituted piperidines. After the cyclization the Cinchona alkaloids dihydroquinidine and dihydroquinine could be obtained by a two step procedure.

5.7 Acknowledgments

Andrea Ruiz–Olalla is acknowledged for starting the project and Elwin Jansen of the VU University is acknowledged for carrying out the exact mass measurements.


tert–Butyl–2–((3 R,4S)–3–ethylpiperidin–4–yl)acetate 3: 2 (8.4 g, 37.3 mmol) was dissolved in 200 mL of MeOH. Pd/C (10 wt%) (1.98 g, 1.86 mmol) was added and the mixture was stirred under a H2 atmosphere overnight. The resulting mixture was filtered over celite and the solvent was evaporated under reduced pressure giving ester 3 (8.1 g, 35.6 mmol, 95%) as a yellowish oil. [α]D = +0.71 (c = 0.57 , MeOH); IR (neat, cm–1) ν 2963, 2930, 2874, 1725, 1392, 1255, 1149; 1H NMR (400 MHz, CDCl3) δ 2.89–2.92 (m, 1H), 2.84–2.70

(m, 3H), 2.20 (br s, 3H), 1.50–1.48 (m, 4H), 1.45 (s, 9H), 1.39–1.23 (m, 2H), 0.91 (t, 3H, J = 7.36 Hz); 13C NMR (100 MHz, CDCl3) δ 172.4, 79.8, 47.8, 44.5, 39.5, 36.9, 35.0, 29.0, 27.9, 19.4, 11.8; HRMS (FAB) for C13H26NO2: calculated (MH+): 228.1964, found (MH+): 228.1967. (3R,4S)–tert–Butyl–3–ethyl–4–(2–hydroxyethyl)piperidine–1–carbo xylate 4: To a

mixture of LiAlH4 (1.6 g, 42.8 mmol) in 200 mL THF at 0 °C was dropwise added a solution of ester 3 (8.1 g, 35.6 mmol) in 50 mL THF. The resulting mixture was allowed to come to room temperature and stirred for 1 h. 250 mL of THF was added, followed by carefully quenching with 2.1 mL of water (1.3 g / g LiAlH4), 2.1 mL of 15% NaOH (1.3 g / g LiAlH4) and 5.2 mL of water (3.25 g / g LiAlH4). The resulting mixture was stirred vigorously for 15 min. Next, the mixture was filtrated and the filtrate was washed 3

more times with Et2O. The solvent was removed under reduced pressure and the crude mixture was dissolved in 120 mL of methanol, (Boc)2O (9.3 g, 42.7 mmol) and NaOH (1.7 g, 42.7 mmol) were added and the resulting mixture was stirred overnight. The crude material was concentrated and dissolved in EtOAc and prior to the addition water. After separation of the layers, the water layer was 2 times extracted with EtOAc. The organic layers were combined, washed with brine and dried with MgSO4. The crude was concentrated under reduced pressure and the product was purified by flash column chromatography (PE/EtOAc 2:1) to give alcohol 4 (7.5 g, 29.2 mmol, 82% over 2 steps) as a yellowish oil. [α]D = +17.1 (c = 0.44, MeOH); IR (neat, cm–1) ν 3428, 2966, 2931, 2873, 1693, 1669, 1430, 1391, 1245, 1167; 1H NMR (400 MHz, CDCl3) δ 4.02–3.94 (br, 2H), 3.69 (br, 2H), 2.98 (br, 1H), 2.89–2.86 (m, 1H), 1.80 (m, 1H), 1.62–1.52 (m, 2H), 1.47 (s, 9H), 1.44 (m, 3H), 1.27–1.16 (m, 2H), 0.97 (t, 3H, J = 7.3 Hz) (proton of the

NBoc

OH

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alcohol was not observed); 13C NMR (100 MHz, CDCl3) δ 155.2, 79.1, 60.2, 46.3, 43.1, 39.9, 35.5, 34.9, 28.3, 27.2, 16.8, 12.2; HRMS (FAB) for C14H28NO3: calculated (MH+): 258.2069, found (MH+): 258.2064. (3R,4S)–tert–Butyl–3–ethyl–4–(2–oxoethyl)piperidine–1–carboxyla te: Oxalyl

chloride (4.1 mL, 48.3 mmol) was dissolved in 250 mL of CH2Cl2 and cooled to –78 °C. DMSO (7.5 mL, 105 mmol) was added dropwise and the resulting mixture was stirred for 30 min. Next a solution of 4 (5.4 g, 21.0 mmol) in 35 mL CH2Cl2 was added dropwise and stirring was continued for 1 h. Et3N (15 mL, 109 mmol) was added and the resulting mixture was allowed to reach room temperature. Next, water was added and the layers were separated. The organic layer was washed with saturated NaHCO3 and brine. The solution was dried with MgSO4 and the

crude product was concentrated. The product was purified by flash column chromatography (PE/EtOAc 4:1) to give the aldehyde (5.2 g, 20.4 mmol, 97%) as a colorless oil. [α]D = +18.3 (c = 0.57, MeOH); IR (neat, cm–1) ν 2964, 2931, 2874, 1692, 1670, 1429, 1391, 1365, 1244, 1140, 1124; 1H NMR (400 MHz, CDCl3) δ 9.77 (d, 1H, J = 1.68 Hz), 3.92–2.84 (m, 1H), 3.59 (br, 1H), 3.13 (br, 1H), 2.97–2.94 (m, 1H), 2.40 (t, 2H, J = 8.8 Hz), 2.32 (br, 1H), 1.51–1.38 (br m, 12H), 1.28–1.57 (m, 2H), 0.94 (t, 3H, J = 7.5 Hz); 13C NMR (100 MHz, CDCl3) δ 201.2, 154.5, 78.2, 47.2, 45.8, 42.2, 39.4, 33.0, 27.9, 26.9, 17.2, 11.7; HRMS (FAB) for C14H26NO3: calculated (MH+): 256.1913, found (MH+): 256.1910. (3R,4R)–tert–Butyl–3–ethyl–4–(prop–2–yn–1–yl)piperidine–1–carbo xylate 5:

TMS–diazomethane (15 mL, 2 M in hexane, 30.5 mmol) was dissolved in 100 mL of THF and cooled to –78 °C. Next, n–BuLi (18 mL, 1.6 M in hexane, 28.4 mmol) was added and the mixture was stirred for 30 min. A solution of aldehyde (5.2 g, 20.3 mmol) in 20 mL THF was added and stirring was continued for 30 min at –78 °C. Then the mixture was allowed to come to room temperature and the mixture was quenched with

saturated NH4Cl. The layers were separated and the water layer was extracted 2 times with EtOAc. The organic layers were combined, dried with MgSO4 and the solvent was evaporated. The product was purified by flash column chromatography (PE/EtOAc 15:1) to give alkyne 5 (3.6 g, 14.3 mmol, 71%) as a withe solid. mp = 55–56 °C; [α]D = +30.0 (c = 0.38, CH2Cl2); IR (neat, cm–1) ν 2967, 2931, 2872, 2247, 1686, 1391, 1242, 1164, 1137, 629; 1H NMR (400 MHz, CDCl3) δ 4.02–3.94 (br, 1H), 3.79–3.65 (br, 1H), 3.01 (br, 1H), 2.87–2.75 (m, 1H), 2.14 (d, 2H, J = 7.6 Hz), 1.97 (t, 1H, J = 2.6 Hz), 1.86 (m, 1H), 1.60 (m, 1H), 1.51 (m, 1H), 1.45 (s, 9H), 1.40 (m, 1H), 1.23–1.13 (m, 2H), 0.97 (t, 3H, J = 7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 154.1, 81.8, 78.2, 69.1, 45.5 42.3, 38.6, 38.3, 27.7, 26.4, 21.3, 16.0, 11.6; HRMS (FAB) for C15H26NO2: calculated (MH+): 252.1964, found (MH+): 252.1964. (3R,4S)–tert–Butyl–4–(2–hydroxyethyl)–3–vinylpiperidine–1–carbo xylate 6: To a

mixture of LiAlH4 (0.91 g, 24.0 mmol) in 100 mL THF at 0 °C was added dropwise a solution of 2 (3.45 g, 20 mmol) in 25 mL THF. The resulting mixture was allowed to reach room temperature and stirred for 1 h. 100 mL of THF was added, followed by carefully quenching with 1.2 mL of water (1.3 g / g LiAlH4), 1.2 mL of 15% NaOH (1.3 g / g LiAlH4) and 3.0 mL of water (3.25 g / g LiAlH4). The resulting mixture was stirred vigorously for 15 min. Next the mixture was filtrated and the filtrate was washed 3


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more times with Et2O. The solvent was removed under reduced pressure and the crude mixture was dissolved in 70 mL of methanol, (Boc)2O (5.2 g, 24 mmol) and NaOH (0.96 g, 24 mmol) were added and the resulting mixture was stirred overnight. The crude material was concentrated and dissolved in EtOAc and water was added. After separation of the layers the water layer was 2 times extracted with EtOAc. The organic layers were combined, washed with brine and dried with MgSO4. The crude was concentrated under reduced pressure and the product was purified by flash column chromatography (PE/EtOAc 2:1) to give alcohol 6 (4.2 g, 16.4 mmol, 82% over 2 steps) as a sticky colorless oil. [α]D = +58.0 (c = 0.51, CH2Cl2); IR (neat, cm–1) ν 3428, 2975, 2929, 2862, 1693, 1670, 1430, 1392, 1246, 1167; 1H NMR (400 MHz, CDCl3) δ 5.82 (m, 1H), 5.15 (s, 1H), 5.12 (d, 1H, J = 4.2 Hz), 4.15 (br, 1H), 3.98 (d, 1H, J = 12.6 Hz), 3.71 (d, 2H, J = 2.8 Hz), 3.02 (dd, 1H, J = 13.2, 2.9 Hz), 2.93–2.78 (br, 1H), 2.30 (br, 1H), 1.83 (m, 1H), 1.63–1.52 (m, 3H), 1.47 (s, 10H), 1.39 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 154.9, 135.7, 116.6, 79.2, 59.7, 43.2, 43.0, 39.8, 35.7, 34.9, 28.2, 27.3; HRMS (FAB) for C14H26NO3: calculated (MH+): 256.1907, found (MH+): 256.1895. (3R,4S)–tert–Butyl–4–(2–oxoethyl)–3–vinylpiperidine–1–carboxyla te: Oxalyl

chloride (2.2 mL, 25.2 mmol) was dissolved in 150 mL of CH2Cl2 and cooled to –78 °C. DMSO (3.9 mL, 55.0 mmol) was added dropwise and the resulting mixture was stirred for 30 min. Next a solution of 6 (2.8 g, 11.0 mmol) in 25 mL CH2Cl2 was added and stirring was continued for 1 h. Et3N (8.0 mL, 57.2 mmol) was added and the resulting mixture was allowed to come to room temperature. Subsequently, water was added and the layers were separated. The organic layer was washed with

saturated NaHCO3 and brine. The solution was dried with MgSO4 followed by evaporation of the solvent. The product was purified by flash column chromatography (PE/EtOAc 4:1) to give aldehyde (2.6 g, 10.4 mmol, 95%) as a colorless oil. [α]D = +50.1 (c = 1.05, CH2Cl2); IR (neat, cm–1) ν 2975, 2929, 2861, 1723, 1688, 1424, 1365, 1244, 1169, 1146; 1H NMR (400 MHz, CDCl3) δ 9.79 (d, 1H, J = 5.1 Hz), 5.80 (m, 1H), 5.16 (d, 1H, J = 10.4 Hz), 5.09 (d, 1H, J = 18.0 Hz), 4.12 (br, 1H), 3.93 (dd, 1H, J = 13.2, 1.4 Hz), 3.09 (dd, 1H, J = 13.2, 2.8 Hz), 2.98–2.81 (br, 1H), 2.49 (m, 1H), 2.31 (m, 3H), 1.53–1.40 (m, 11H); 13C NMR (100 MHz, CDCl3) δ 200.8, 154.3, 134.9, 117.0, 78.8, 48.3, 46.8, 42.2, 41.9, 32.7, 27.9, 27.0; HRMS (ESI) for C14H23NO3Na: calculated (MNa+): 276.1570, found (MNa+): 276.1561. (3R,4R)–tert–Butyl–4–(prop–2–yn–1–yl)–3–vinylpiperidine–1–carbo xylate 7:

TMS–diazomethane (1 mL, 2 M in hexane, 2 mmol) was dissolved in 10 mL of THF and cooled to –78 °C. Next, n–BuLi (1.25 mL, 1.6 M in hexane, 2 mmol) was added and the mixture was stirred for 30 min. A solution of aldehyde (506 mg, 2 mmol) in 3 mL THF was added and stirring was continued for 30 min at –78 °C. Then the mixture was allowed to reach room temperature and the mixture was quenched with saturated NH4Cl.

The layers were separated and the water layer was extracted 2 times with EtOAc. The organic layers were combined, dried with MgSO4 and the solvent was evaporated. The product was purified by flash column chromatography (PE/EtOAc 15:1) to give alkyne 7 (330 mg, 1.3 mmol, 66%) as a colorless oil. [α]D = +63.9 (c = 0.57, CH2Cl2); IR (neat, cm–1) ν 2975, 2928, 2861, 2042, 1689, 1423, 1392, 1244, 1166, 1142; 1H NMR (400 MHz, CDCl3) δ 5.77 (dt, 1H, J = 17.2, 9.9 Hz), 5.22 (dd, 1H, J = 16.0, 2.0 Hz), 5.16 (dd, 1H, J = 10.4, 1.8 Hz), 4.18 (br, 1H), 4.02 (d, 1H, J = 12.8 Hz), 3.00 (dd, 1H, J = 13.3, 3.0 Hz), 2.81 (br, 1H), 2.50 (br, 1H), 2.17 (dd, 2H, J = 7.8, 2.6 Hz), 2.00 (t, 1H, J = 2.6 Hz),

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1.90–1.81 (m, 1H), 1.64 (m, 1H), 1.47 (s, 9H), 1.42 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 154.7, 134.4, 117.3, 82.4, 79.0, 69.4, 43.0, 41.7, 38.5, 28.1, 26.9, 22.4 (one carbon next to the NBoc was not observed); HRMS (ESI) for C15H23NO2Na: calculated (MNa+): 272.1621, found (MNa+): 272.1616. tert–Butyl–4–(2–ethoxy–2–oxoethylidene)piperidine–1–car boxylate and tert–

butyl–4–(2–ethoxy–2–oxoethyl)–5,6–dihydropyridine–1 –(2H)–carboxylate 9: A solution of triethyl phosphono acetate (9.13 mL, 46 mmol) and NaH (2.9 g, 73.6 mmol, 60% in mineral oil) in 75 mL THF was stirred at room temperature under nitrogen atmosphere. After 1 h, 8 (6.50 g, 32.84 mmol) was added and the resulting mixture was stirred at ambient temperature for 2 h. NH4Cl was added and the layers were separated. The aqueous

layer was extracted 2 times with CH2Cl2. The organic layers were combined, washed with brine and dried over MgSO4. Evaporation under reduced pressure provided the crude which was subjected to purification by flash chromatography. The mixture product of endo and exo alkenes were separated by flash chromatography (PE/EtOAC 6:1) to yield 9 (7.15 g, 26.2 mmol, 81%) in a 1:2.5 exo:endo ratio The exo isomer was obtained as a white solid and the endo isomer as a colorless oil. Exo–isomer 9: mp = 68–71ºC; IR (neat, cm–1) ν 2978, 1696, 1652, 1477, 1394, 1253, 1164, 1140, 1115, 1038, 997; 1H NMR (400 MHz, CDCl3) δ 5.73 (s, 1H), 4.17 (q, 2H, J = 7.1 Hz), 3.58–3.41 (m, 4H), 2.95 (t, 2H, J = 5.5 Hz), 2.35–2.25 (m, 2H), 1.49 (s, 9H), 1.30 (t, 3H, J = 7.1 Hz); 13C NMR (400 MHz, CDCl3): δ 166.1, 157.6, 154.4, 115.1, 79.6, 59.5, 36.2, 29.3, 28.2, 14.1. Endo–isomer 9: IR (neat, cm–1): 2977, 1734, 1693, 1413, 1365, 1284, 1239, 1170, 1149, 1108, 1031; 1H NMR (400 MHz, CDCl3) δ 5.49 (s, 1H), 4.10 (q, 2H, J = 7.1 Hz), 3.86 (d, 2H, J = 1.2 Hz), 3.47 (t, 2H, J = 5.7 Hz), 2.98 (s, 2H), 2.10 (d, 2H, J = 1.1 Hz), 1.42 (s, 9H), 1.22 (t, 3H, J = 7.1 Hz); 13C NMR (400 MHz, CDCl3): δ 171.0, 154.6, 129.8, 122.2, 79.3, 60.4, 43.0, 42.5, 28.2, 28.1, 14.0 (one carbon next to NBoc was not observed); HRMS (FAB) for C14H24NO4: calculated (MH+): 269.1627, found (MH+): 269.1621. tert–Butyl–4–(2–ethoxy–2–oxoethyl)piperidine–1–carboxyl ate: A mixture of 9 (7.02

g, 25.89 mmol) was dissolved in 50mL of EtOH. Pd/C (10 wt%) (1.33 g, 1.29 mmol) was added and the reaction was let to stir until completion under H2 atmosphere. The reaction mixture was filtered through a pad of celite and solvent evaporated under reduced pressure to provide the ester (6.28 g, 23.18 mmol, 90%) as a colorless oil. IR (neat, cm–1) ν 2977, 2930, 1732, 1688, 1419, 1365, 1286, 1237, 1154, 1119, 1030; 1H NMR (400 MHz,

CDCl3) δ 4.15 (q, 2H, J = 7.1 Hz), 4.09 (d, 2H, J = 13.3 Hz), 2.73 (dt, 2H, J = 13.3, 2.5 Hz), 2.24 (d, 2H, J = 7.1 Hz), 2.05–1.84 (m, 1H), 1.70 (d, 2H, J = 12.7 Hz), 1.47 (s, 9H), 1.27 (t, 3H, J = 7.1 Hz), 1.17 (m, 2H); 13C NMR (400 MHz, CDCl3): δ 172.3, 154.6, 79.2, 60.1, 41.0, 32.9, 31.6, 29.5, 28.3, 14.1; HRMS (FAB) for C14H26NO4: calculated (MH+): 271.1784, found (MH+): 271.1783. tert–Butyl–4–(2–hydroxyethyl)piperidine–1–carboxylate 1 0: To a 0°C solution of

ester (6.28 g, 23.18 mmol) in 150 mL THF was added a solution of LiAlH4 in THF (23.28 mL, 1.0 M). The reaction was allowed to warm to room temperature for 1 h, then cooled to 0°C and carefully quenched by a sequential addition of water (50mL), aq NaOH 3M (50 mL), then water (100 mL) and stirred at the same temperature for 30 minutes. The resulting mixture was filtered over a pad of celite to remove solids. Then, the layers were separated


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and the aqueous layer was extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried and the solvent was evaporated giving 10 (5.45 g, 23.81 mmol, 100%) as a colorless oil. IR (neat, cm–1) ν 3419, 2924, 2853, 1691, 1666, 1421, 1365, 1276, 1245, 1161, 1057, 975, 867, 769; 1H NMR (400 MHz, CDCl3) δ 4.08 (br, 2H), 3.70 (dt, 2H, J = 10.8, 5.5 Hz), 2.69 (t, 2H, J = 11.4 Hz), 1.74 (br, 1H), 1.67 (d, 2H, J = 13.3 Hz), 1.64–1.56 (m, 1H), 1.52 (dd, 2H, J = 13.1, 6.5 Hz), 1.45 (s, 9H), 1.12 (m, 2H); 13C NMR (400 MHz, CDCl3): δ 154.6, 79.1, 60.0, 39.1, 32.4, 31.9, 28.3 (carbons next to NBoc were not observed); HRMS (FAB) for C12H24NO3: calculated (MH+): 229.1678, found (MH+): 229.1680. tert–Butyl–4–(2–oxoethyl)piperidine–1–carboxylate: DMSO (8.4 mL, 119 mmol) was

added dropwise to oxalyl chloride (4.6 mL, 54.7 mmol) in CH2Cl2 at –78°C. After 30 minutes, alcohol 10 (5.45 g, 23.81 mmol) in CH2Cl2 was added slowly. After 1 h, Et3N (17 mL, 123 mmol) was added and the mixture was allowed to reach room temperature. Then, water was added and the reaction mixture was extracted with CH2Cl2. The combined organic layers were dried (MgSO4), evaporated and purified by flash chromatograph (PE/EtOAc 2:1) to give the aldehyde (4.79 g, 21.1 mmol, 89%) as an orange solid. mp 37–38

ºC; IR (neat, cm–1) ν 2975, 2925, 2852, 2719, 1723, 1688, 1421, 1365, 1280, 1245, 1167, 1135; 1H NMR (400 MHz, CDCl3) δ 9.79 (t, 1H, J = 1.7 Hz), 4.10 (br, 2H), 2.76 (t, 2H, J = 11.9 Hz), 2.40 (dd, 2H, J = 6.7, 1.7 Hz), 2.20–1.94 (m, 1H), 1.70 (d, 2H, J = 13.7 Hz), 1.46 (s, 9H), 1.19 (m, 2H); 13C NMR (400 MHz, CDCl3): δ 201.3, 154.6, 79.3, 50.2, 43.5, 31.7, 30.5, 28.3; HRMS (FAB) for C12H22NO3: calculated (MH+): 227.1521, found (MH+): 227.1526. tert–Butyl–4–(prop–2–yn–1–yl)piperidine–1–carboxylate 1 1: n–BuLi (8.9 mL, 1.6 M

in hexane, 14.3 mmol) was added at –78°C to a solution of trimethylsilyldiazomethane (8.25 mL, 2 M in hexane, 16.5 mmol) in 50 mL of THF. The reaction was stirred for 45 minutes. A solution of aldehyde (2.5 g, 11.0 mmol) in 10 mL THF was added and stirring was continued for 1 h. The reaction mixture was allowed to warm up to room temperature and was quenched with saturated NH4Cl. The layers were separated and the water

layer was extracted with Et2O. The organic layers were combined, dried with MgSO4 and the crude was concentrated. Purification by flash chromatography (PE/EtOAC 6:1) yielded alkyne 11 (1.75 g, 7.82 mmol, 71%) as a yellowish oil. IR (neat, cm–1) ν 3304, 3250, 2976, 2929, 2853, 1687, 1419, 1365, 1279, 1243, 1164, 1124, 632; 1H NMR (400 MHz, CDCl3) δ 4.12 (d, 2H, J = 13.4 Hz), 2.70 (dt, 2H, J = 13.2, 2.6 Hz), 2.16 (dd, 2H, J = 6.7, 2.7 Hz), 2.00 (t, 1H, J = 2.7 Hz), 1.77 (d, 2H, J = 15.3 Hz), 1.64 (m, 1H), 1.47 (s, 9H), 1.21 (m, 2H); 13C NMR (400 MHz, CDCl3): δ 154.7, 82.2, 79.2, 69.5, 43.6, 35.3, 31.2, 28.3, 25.3; HRMS (FAB) for C13H22NO2: calculated (MH+): 223.1572, found (MH+): 223.1564. General procedure for the Sonogashira coupling A solution of THF/Et3N (1:1) under an argon atmosphere was prepared and argon was bubbled through the mixture for 15 min. Pd(Cl)2(PPh3)2 (5 mol%) and CuI (10 mol%) were added and the bubbling of argon was continued for 15 min more. Next the aryl halide (1.5 equiv.) was added followed by the addition of the alkyne (0.1M). The corresponding mixture was stirred overnight at room temperature and then quenched with saturated NaHCO3. The layers were separated and the water layer was extracted 2 times with EtOAc. The organic layers were combined, dried with MgSO4 and the crude

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was concentrated under reduced pressure. The product was purified by flash column chromatography General procedure for Boc–deprotection Boc–protected piperidine (0.1M) was dissolved in CH2Cl2 and cooled to 0 °C. TFA (a solution of 10 v/v % of TFA in CH2Cl2 was made) was added dropwise, the mixture was allowed to come to room temperature and stirred overnight. The solution was 3 times diluted with Et2O, saturated K2CO3 was added and the layers were separated. The water layer was extracted 2 more times with Et2O, the organic layers were combined and dried with Na2SO4. The product was concentrated under reduced pressure to yield the free amine. (3R,4R)–tert–Butyl–3–ethyl–4–(3–(6–methoxyquinolin–4–yl)prop–2– yn–1–yl)–

piperidine–1–carboxylate 12: According to the general procedure for the Sonogashira coupling alkyne 5 (252 mg, 1 mmol) reacted with 4–bromo–6–methoxy–quinoline (355 mg, 1.5 mmol), Pd(Cl)2(PPh3)2 (35 mg, 0.05 mmol) and CuI (19 mg, 0.1 mmol) in 10 mL of THF/Et3N. The product was purified by flash column chromatography (PE/EtOAc 3:1) to give 12 (371 g, 0.91 mmol, 91%) as a sticky orange oil. [α]D = +18.2 (c = 0.67, CH2Cl2); IR (neat, cm–1) ν 2966, 2931, 2874, 2224, 1690, 1618, 1503, 1428, 1242, 1228, 1167; 1H NMR (400 MHz, CDCl3) δ

8.71 (d, 1H, J = 4.4 Hz), 8.01 (d, 1H, J = 12.8 Hz), 7.50, (d, 1H, J = 2.8 Hz), 7.44–7.38 (m, 2H), 4.15–4.00 (br, 1H), 3.97 (s, 3H), 3.87–3.79 (br, 1H), 3.10 (br, 1H), 2.97–2.93 (m, 1H), 2.59 (d, 2H, J = 7.8 Hz), 2.10 (br, 1H), 1.79–1.59 (br, 3H), 1.49 (s, 9H), 1.40–1.27 (m, 2H), 1.04 (t, 3H, J = 7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 158.2, 154.9, 147.0, 144.0, 131.1, 129.1, 128.7, 123.8, 122.3, 103.4, 98.3, 79.2, 78.0, 55.4, 46.1, 42.8, 39.3, 39.1, 28.3, 27.2, 22.9, 16.9, 12.2. 4–(3–((3R,4R)–3–Ethylpiperidin–4–yl)prop–1–yn–1–yl)–6–methoxy–q uinoline 13:

According to the general procedure for the Boc–deprotection, Boc–protected piperidine 12 (332 mg, 0.81 mmol) was dissolved in 8 mL of CH2Cl2 and 0.8 mL of TFA was added. After work up the free amine 13 (220 mg, 0.71 mmol, 88%) was obtained as an orange oil. [α]D = +8.2 (c = 0.38, CH2Cl2); IR (neat, cm–1) ν 3286, 2956, 2924, 2872, 2222, 1689, 1501, 1471, 1428, 1225, 910, 721; 1H NMR (400 MHz, CDCl3) δ 8.68 (d, 1H, J = 4.4 Hz), 7.97 (d, 1H, J = 9.2 Hz), 7.49 (d, 1H, J = 2.6 Hz),

7.40–7.35 (m, 2H), 3.95 (s, 3H), 3.03 (d, 1H, J = 12.0 Hz), 2.93 (d, 1H, J = 11.9 Hz), 2.73 (d, 2H, J = 12.2 Hz), 2.57 (d, 2H, J = 7.2 Hz), 2.11 (m, 2H), 1.71 (br, 3H), 1.48–1.25 (m, 2H), 0.98 (t, 3H, J = 7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 157.8, 146.7, 143.8, 130.8, 128.8, 128.5, 123.4, 122.0, 103.1, 98.7, 77.5, 55.0, 47.6, 44.6, 39.4, 37.8, 28.6, 21.3, 18.6, 11.7; HRMS (ESI) for C20H25N2O: calculated (MH+): 309.1961, found (MH+): 309.1970.

NH

N

OMe


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(3R,4R)–tert–Butyl–3–ethyl–4–(3–(pyridin–4–yl)prop–2–yn–1–yl)pi peridine–1–carboxylate 14 : According to the general procedure for the Sonogashira coupling alkyne 5 (500 mg, 1.98 mmol) reacted with 4–bromopyridine (469 mg, 2.97 mmol), Pd(Cl)2(PPh3)2 (69 mg, 0.1 mmol) and CuI (38 mg, 0.2 mmol) in 20 mL of THF/Et3N. The product was purified by flash column chromatography (PE/EtOAc 4:1) to give 14 (470 mg, 1.43 mmol, 72%) as a sticky orange oil. [α]D = +25.4 (c = 0.26, CH2Cl2); IR (neat, cm–1) ν 2968, 2930, 2873, 2224, 1686, 1592, 1391, 1343, 1242, 1164, 821; 1H NMR

(400 MHz, CDCl3) δ 8.57 (br, 2H), 7.26 (d, 2H, J = 3.3 Hz), 4.06–3.99 (m, 1H), 3.76, (br, 1H), 3.07 (br, 1H), 2.92–2.83 (m, 1H), 2.41 (d, 2H, J = 7.8 Hz), 1.99 (br, 1H), 1.64–1.53 (m, 3H), 1.48 (s, 9H), 1.33–1.20 (m, 2H), 1.02 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 154.8, 149.4, 131.8, 93.8, 79.4, 79.0, 46.0, 42.7, 39.2, 38.7, 28.8, 27.0, 23.1, 22.5, 16.6, 12.0. 4–(3–((3R,4R)–3–Ethylpiperidin–4–yl)prop–1–yn–1–yl)pyridine 15: According to the

general procedure for the Boc–deprotection, Boc–protected piperidine 14 (460 mg, 1.4 mmol) was dissolved in 15 mL of CH2Cl2 and 1.5 mL of TFA was added. After work up the free amine 15 (245 mg, 1.07 mmol, 78%) was obtained as an orange oil. [α]D = +7.6 (c = 0.51, CH2Cl2); IR (neat, cm–1) ν 3301, 2958, 2926, 2873, 2223, 1678, 1488, 1463, 821; 1H NMR (400 MHz, CDCl3) δ 8.53 (d, 2H, J = 4.4 Hz), 7.25 (d, 2H, J = 4.4Hz), 3.02–2.97 (m, 1H), 2.91 (dd, 1H, J = 12.6, 5.4 Hz), 2.73–2.69 (m, 2H), 2.42 (dd, 2H, J = 8.5, 2.5 Hz), 2.05–2.00 (m, 1H), 1.80 (br, 1H),

1.67–1.59 (m, 3H), 1.46–1.41 (m, 1H), 1.39–1.28 (m, 1H), 0.96 (t, 3H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 149.3, 131.8, 125.4, 94.3, 79.1, 47.6, 44.5, 39.3, 37.4, 28.5, 21.0, 18.7, 11.7. HRMS (ESI) for C15H21N2: calculated (MH+): 229.1699, found (MH+): 229.1710. (3R,4R)–tert–Butyl–3–ethyl–4–(3–phenylprop–2–yn–1–yl)piperidine –1–

carboxylate 16: According to the general procedure for the Sonogashira coupling alkyne 5 (500 mg, 1.98 mmol) reacted with phenyl iodide (0.33 mL, 2.97 mmol), Pd(Cl)2(PPh3)2 (69 mg, 0.1 mmol) and CuI (38 mg, 0.2 mmol) in 20 mL of THF/Et3N. The product was purified by flash column chromatography (PE/EtOAc 20:1) to give 16 (520 mg, 1.58 mmol, 80%) as an orange oil. [α]D = +24.6 (c = 0.39, CH2Cl2); IR (neat, cm–1) ν 2968, 2930, 2873, 2222, 1689, 1426, 1365, 1242, 1137, 756; 1H NMR (400 MHz, CDCl3) δ

7.40 (m, 2H), 7.33–7.21 (m, 3H), 4.06–3.99 (m, 1H), 3.76 (br, 1H), 3.08 (br, 1H), 2.90 (m, 1H), 2.39 (d, 2H, J = 7.5 Hz), 1.98 (br, 1H), 1.71 (br, 1H), 1.61–1.54 (br, 2H), 1.48 (s, 9H), 1.32–1.20 (m, 2H), 1.02 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 155.0, 131.4, 128.5, 127.5, 123.7, 88.3, 81.7, 79.1, 46.2, 42.9, 39.3, 39.1, 28.3, 27.1, 23.1, 16.7, 12.2; HRMS (FAB) for C21H30NO2: calculated (MH+): 328.2277, found (MH+): 328.2273.

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(3R,4R)–3–Ethyl–4–(3–phenylprop–2–yn–1–yl)piperidine 17: According to the general procedure for the Boc–deprotection, Boc–protected piperidine 16 (484 mg, 1.48 mmol) was dissolved in 15 mL of CH2Cl2 and 1.5 mL of TFA was added. After work up the free amine 17 (326 mg, 1.43 mmol, 97%) was obtained as an orange oil. [α]D

= +11.3 (c = 0.56, CH2Cl2); IR (neat, cm–1) ν 3279, 2957, 2922, 2872, 2227, 1571, 1490, 1462, 1263, 755, 719; 1H NMR (400 MHz, CDCl3) δ 7.43–7.39 (m, 2H), 7.33–7.28 (m, 3H), 3.00 (dd, 1H, J = 12.1, 4.0 Hz), 2.94 (dd, 1H, J = 12.1, 4.2 Hz), 2.71 (dd, 2H, J =

12.3, 3.2 Hz), 2.40 (dd, 2H, J = 8.5, 3.0 Hz), 2.02 (m, 1H), 1.69–1.61 (m, 4H), 1.46–1.35 (m, 2H), 0.96 (t, 3H, J = 7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 131.3, 128.0, 127.3, 123.8, 88.8, 81.4, 47.8, 44.7, 39.6, 37.8, 23.3, 21.1, 18.8, 11.9; HRMS (ESI) for C16H22N: calculated (MH+): 228.1752, found (MH+): 228.1750. (3R,4R)–tert–Butyl–3–ethyl–4–(3–(naphthalen–1–yl)prop–2–yn–1–yl )piperidine–

1–carboxylate 18: According to the general procedure for the Sonogashira coupling alkyne 5 (500 mg, 1.98 mmol) reacted with 1–iodo naphthalene (0.43 mL, 2.97 mmol), Pd(Cl)2(PPh3)2 (69 mg, 0.1 mmol) and CuI (38 mg, 0.2 mmol) in 20 mL of THF/Et3N. The product was purified by flash column chromatography (PE/EtOAc 20:1) to give 18 (654 g, 1.73 mmol, 88%) as an orange oil. [α]D = +25.6 (c = 0.41, CH2Cl2); IR (neat, cm–1) ν 2969, 2930, 2872, 2229, 1688, 1426, 1325, 1166, 829, 799; 1H NMR (400 MHz, CDCl3) δ 8.32 (dd, 1H, J = 8.1, 0.7 Hz),

7.86 (d, 1H, J = 7.3 Hz), 7.81 (d, 1H, J = 8.2 Hz), 7.62 (dd, 1H, J = 7.1, 1.0 Hz), 7.58 (m, 1H), 7.54 (m, 1H) 7.43 (dd, 1H, J = 8.2, 7.2 Hz), 4.15–4.04 (m, 1H), 3.86 (br, 1H), 3.12 (br, 1H), 3.01–2.87 (m, 1H), 2.56 (d, 2H, J = 7.9 Hz), 2.08 (m, 1H), 1.81 (m, 1H), 1.66–1.55 (m, 2H), 1.49 (s, 9H), 1.47–1.40 (m, 1H), 1.33–1.26 (m, 1H), 1.06 (t, 3H, J = 7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 154.8, 133.2, 132.9, 129.9, 128.0, 127.8, 127.4, 126.0, 125.9, 125.0, 121.3, 93.2, 79.6, 78.9, 53.6, 46.0, 42.9, 39.2, 28.2, 27.1, 22.9, 16.5, 12.1; HRMS (FAB) for C25H32NO2: calculated (MH+): 378.244, found (MH+): 378.2433. (3R,4R)–3–Ethyl–4–(3–(naphthalen–1–yl)prop–2–yn–1–yl)pipe ridine 19: According

to the general procedure for the Boc–deprotection, Boc–protected piperidine 18 (130 mg, 0.34 mmol) was dissolved in 3 mL of CH2Cl2 and 0.3 mL of TFA was added. After work up the free amine 19 (90 mg, 0.32 mmol, 95%) was obtained as an orange oil. [α]D = +9.1 (c = 0.33, CH2Cl2); IR (neat, cm–1) ν 3057, 2957, 2924, 2871, 2223, 1688, 1460, 1439, 1200, 1175, 1135, 799, 774; 1H NMR (400 MHz, CDCl3) δ 8.33 (d, 1H, J = 8.8 Hz), 7.85 (d, 1H, J = 8.4 Hz), 7.80 (d, 1H, J = 8.3 Hz), 7.63 (dd, 1H,

J = 7.1, 1.0 Hz), 7.59–7.50 (m, 2H), 7.42 (dd, 1H, J = 8.2, 7.2 Hz), 3.10–3.05 (m, 1H), 2.98 (dd, 1H, J = 12.8, 5.6 Hz), 2.82–2.76 (m, 2H), 2.59 (dd, 2H, J = 10.8, 2.0 Hz), 2.15 (m, 1H), 1.80–1.70 (m, 3H), 1.53–1.42 (m, 3H), 1.00 (t, 3H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 133.3, 133.0, 128.3, 127.1, 126.4, 125.1, 124.2, 121.5, 93.8, 79.5, 47.7, 44.7, 39.4, 37.9, 30.2, 28.7, 23.8, 21.4, 18.8, 11.9; HRMS (ESI) for C20H24N: calculated (MH+): 278.1903, found (MH+): 278.1924.

NH


157

(3R,4R)–tert–Butyl–4–(3–phenylprop–2–yn–1–yl)–3–vinylpiperidine –1–carboxylate 20: According to the general procedure for the Sonogashira coupling alkyne 7 (328 mg, 1.32 mmol) reacted with phenyl iodide (0.22 mL, 1.98 mmol), Pd(Cl)2(PPh3)2 (46 mg, 0.067 mmol) and CuI (25 mg, 0.13 mmol) in 13 mL of THF/Et3N. The product was purified by flash column chromatography (PE/EtOAc 20:1) to give 20 (394 mg, 1.21 mmol, 92%) as an orange oil. [α]D

= +81.7 (c = 0.43, CH2Cl2); IR (neat, cm–1) ν 2975, 2926, 2858, 2231, 1688, 1422, 1391, 1165; 1H NMR (400 MHz, CDCl3) δ 7.42

(m, 2H), 7.31 (m, 3H), 5.82 (m, 1H), 5.25 (dd, 1H, J = 17.2, 1.2 Hz), 5.19 (dd, 1H, J = 10.4, 1.2 Hz), 4.12 (br, 1H), 4.05 (d, 1H, J = 12.2 Hz), 3.02 (dd, 1H, J = 13.2, 2.9 Hz), 2.83 (br, 1H), 2.56 (br, 1H), 2.23 (d, 2H, J = 7.6 Hz), 1.95 (m, 1H), 1.63 (m, 1H), 1.50 (s, 10H); 13C NMR (100 MHz, CDCl3) δ 155.0, 134.7, 131.4, 128.1, 127.5, 123.7, 117.5, 88.3, 81.8, 79.3, 42.9, 42.0, 39.4, 39.0, 28.3, 27.2, 23.5. (3R,4R)–4–(3–Phenylprop–2–yn–1–yl)–3–vinylpiperidine 21: According to the

general procedure for the Boc–deprotection, Boc–protected piperidine 20 (240 mg, 0.74 mmol) was dissolved in 7 mL of CH2Cl2 and 0.7 mL of TFA was added. After work up the free amine 21 (152 mg, 0.67 mmol, 91%) was obtained as an orange oil. [α]D = +80.5 (c = 0.76, CH2Cl2); IR (neat, cm–1) ν 3293, 2920, 2225, 1689, 1490, 1441, 756, 692; 1H NMR (400 MHz, CDCl3) δ 7.40 (m, 2H), 7.30 (m, 3H), 6.11 (ddd, 1H, J = 19.5, 17.1, 9.2 Hz), 5.20 (m, 2H), 3.15 (dt, 1H, J = 12.4, 5.0 Hz), 3.06 (dd, 1H J = 12.4, 3.2 Hz), 2.92

(dd, 1H, J = 12.4, 3.2 Hz), 2.85 (br, 1H), 2.75 (m, 1H), 2.54 (m, 1H), 2.32 (d, 2H, J = 8.0 Hz), 1.97 (m, 1H), 1.72 (m, 1H), 1.53 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 136.0, 131.3, 128.0, 127.4, 123.7, 117.0, 88.5, 81.6, 50.9, 45.8, 42.2, 38.4, 28.2, 23.5. HRMS (ESI) for C16H20N: calculated (MH+): 226.1590, found (MH+): 226.1600. tert–Butyl–4–(3–(6–methoxyquinolin–4–yl)prop–2–yn–1–yl) piperidine–1–

carboxylate 22 : According to the general procedure for the Sonogashira coupling alkyne 11 (283 mg, 1.27 mmol) reacted with 4–bromo–6–methoxy–quinoline (450 mg, 1.91 mmol), Pd(Cl)2(PPh3)2 (35 mg, 0.064 mmol) and CuI (25 mg, 0.13 mmol) in 13 mL of THF/Et3N. The product was purified by flash column chromatography (PE/EtOAc 4:1) to give 22 (0.45 g, 1.2 mmol, 95%) as an orange oil. IR (neat, cm–1) ν 2974, 2928, 2851, 2223, 1688, 1618, 1580, 1423, 1365, 1243, 1226, 1164, 848; 1H NMR (400 MHz,

CDCl3) δ 8.71 (d, 1H, J = 4.0 Hz), 8.01 (d, 1H, J = 9.2 Hz), 7.51 (d, 1H, J = 2.8 Hz), 7.42–7.38 (m, 2H), 4.17 (br, 2H), 3.97 (s, 3H), 2.77 (t, 2H, J = 11.6 Hz), 2.59 (d, 2H, J = 6.4 Hz), 1.92 (d, 2H, J = 11.5 Hz), 1.85 (m, 1H), 1.48 (s, 9H), 1.44–1.31 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 158.2, 154.7, 146.9, 144.0, 131.1, 128.6, 123.7, 122.3, 103.4, 97.7, 79.3, 78.3, 55.3, 35.6, 31.4, 28.3, 26.6 (carbons next to NBoc were not observed); HRMS (FAB) for C23H29N2O3: calculated (MH+): 381.2178, found (MH+): 381.2175.

NBoc

N

OMe

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6–Methoxy–4–(3–(piperidin–4–yl)prop–1–yn–1–yl)quino line 23: According to the general procedure for the Boc–deprotection, Boc–protected piperidine 22 (166 mg, 0.44 mmol was dissolved in 4 mL of CH2Cl2 and 0.4 mL of TFA was added. After work up the free amine 23 (93 mg, 0.33 mmol, 75%) was obtained as an orange oil. IR (neat, cm–

1) ν 3314, 2924, 2580, 2237, 1618, 1581, 1503, 1472, 1446, 1268, 1254, 1228, 848; 1H NMR (400 MHz, CDCl3) δ 8.67 (d, 1H, J = 4.4 Hz), 7.97 (d, 1H, J = 9.2 Hz), 7.51 (d, 1H, J = 2.8 Hz), 7.39–7.35 (m, 2H), 3.95 (s, 3H), 3.12 (d, 2H, J = 12.0 Hz), 2.65 (dd, 2H, J = 12.0,

10.8 Hz), 2.53 (d, 2H, J = 6.8 Hz), 2.22 (br, 1H),1.92 (d, 2H, J = 12.8 Hz), 1.78 (m, 1H), 1.43–1.32 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 158.1, 147.3, 144.1, 131.1, 129.1, 123.6, 122.3, 103.5, 98.3, 78.1, 55.3, 46.3, 35.9, 32.8, 29.5, 27.7; HRMS (FAB) for C18H21N2O: calculated (MH+): 281.1654, found (MH+): 281.1650. tert–Butyl 4–(3–phenylprop–2–yn–1–yl)piperidine–1–carbo xylate 24: According to

the general procedure for the Sonogashira coupling alkyne 11 (236 mg, 1.06 mmol) reacted with phenyl iodide (0.18 mL, 1.59 mmol), Pd(Cl)2(PPh3)2 (37 mg, 0.05 mmol) and CuI (20 mg, 0.11 mmol) in 10 mL of THF/Et3N. The product was purified by flash column chromatography (PE/EtOAc 30:1) to give 24 (220 mg, 0.74 mmol, 74%) as an orange oil. IR (neat, cm–1) ν 2975, 2929, 2851, 2226, 1690, 1469, 1421, 1130, 1166, 756, 692; 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 2H), 7.30 (m, 3H), 4.15 (br, 2H), 2.74 (t, 2H, J = 11.8 Hz), 2.39 (d, 2H, J =

6.6 Hz), 1.83 (d, 2H, J = 13.2 Hz), 1.75 (m, 1H), 1.48 (s, 9H), 1.33–1.27 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 154.7, 131.4, 128.0, 127.5, 123.6, 87.8, 81.9, 79.2, 35.7, 31.4, 28.3, 26.2 (carbons next to NBoc were not observed). 4–(3–Phenylprop–2–yn–1–yl)piperidine 25: According to the general procedure for

the Boc–deprotection, Boc–protected piperidine 24 (220 mg, 0.73 mmol) was dissolved in 7 mL of CH2Cl2 and 0.7 mL of TFA was added. After work up the free amine 25 (144 mg, 0.73 mmol, 99%) was obtained as an orange oil. IR (neat, cm–1) ν 3309, 2922, 2848, 2227, 1688, 1546, 1489, 1263, 1133, 756, 692; 1H NMR (400 MHz, CDCl3) δ 7.41 (m, 2H), 7.30 (m, 3H), 3.18 (d, 2H, J = 12.3 Hz), 2.84 (br, 1H), 2.69 (t, 2H, J = 12.3 Hz), 2.38 (d, 2H, J = 6.7 Hz), 1.89 (d, 2H, J = 13.4 Hz), 1.76–1.69 (m, 1H), 1.40–1.28 (m, 2H); 13C NMR (100 MHz, CDCl3) δ

131.4, 128.0, 127.4, 123.7, 88.0, 81.8, 45.8, 35.5, 32.0, 26.6. HRMS (ESI) for C14H18N: calculated (MH+): 200.1434, found (MH+): 200.1441. (3R,4R)–3–Ethyl–4–(prop–2–yn–1–yl)piperidine 26: According to the general

procedure for the Boc–deprotection, Boc–protected piperidine 5 (252 mg, 1 mmol was dissolved in 10 mL of CH2Cl2 and 1 mL of TFA was added. After work up the free amine 26 (142 g, 0.93 mmol, 93%) was obtained as an colorless oil. [α]D = +21.1 (c = 1.06, CH2Cl2); IR (neat, cm–1) ν 3309, 2961, 2928, 2874, 1677, 1463, 1441, 909, 732, 641; 1H NMR (400 MHz, CDCl3) δ 3.00–2.95 (m, 1H), 2.89 (dd, 1H, J = 12.6, 5.5 Hz), 2.74–2.68

(m, 2H), 2.28 (br, 1H), 2.20 (m, 2H), 1.98 (t, 1H, J = 2.5 Hz), 1.93 (m, 1H), 1.65–1.56 (m, 3H), 1.41–1.36 (m, 1H), 1.36–1.24 (m, 1H), 0.95 (t, 3H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 82.9, 68.9, 47.5, 44.5, 39.2, 37.4, 28.3, 19.9, 18.5, 11.6; HRMS (ESI) for C10H18N: calculated (MH+): 152.1434, found (MH+): 152.1439.

NH


159

(3R,4R)–tert–Butyl–4–(but–2–yn–1–yl)–3–ethylpiperidine–1–carbox ylate: Alkyne 5 (252 mg, 1 mmol) was dissolved in 3 mL of THF and cooled to –78 °C. n–BuLi (0.69 mL, 1.6 M in hexane, 1.1 mmol) was dropwise added and stirring was continued for 30 min. Next methyl iodide (0.16 mL, 2.5 mmol) was added and the resulting mixture was allowed to come to room temperature and stirred overnight. Saturated NH4Cl was added and the layers were separated. The water layer was extracted two times with EtOAc. The organic layers were combined, dried with

MgSO4 and the crude mixture was concentrated under reduced pressure. The product was purified by flash column chromatography (PE/EtOAc 20:1) to give the methylated alkyne (212 mg, 0.8 mmol, 80%) as a colorless oil (10% of the alkyne 5 remained in the product, which could not be separated by flash column chromatography). [α]D = +29.3 (c = 0.42, CH2Cl2); IR (neat, cm–1) ν 2967, 2922, 2863, 1689, 1424, 1391, 1241, 1165, 1135; 1H NMR (400 MHz, CDCl3) δ 4.00 (br, 1H), 3.71 (br, 1H), 3.04 (br, 1H), 2.89–2.79 (m, 1H), 2.10 (d, 2H, J = 7.6 Hz), 1.80 (m, 4H), 1.55–1.48 (m, 12H), 1.31–1.13 (m, 2H), 0.99 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 154.9, 78.9, 76.4, 69.3, 46.2, 42.8, 39.3, 39.1, 28.3, 26.9, 22.4, 16.7, 12.1, 3.3. (3R,4R)–4–(But–2–yn–1–yl)–3–ethylpiperidine 27: According to the general

procedure for the Boc–deprotection, Boc–protected piperidine (118 mg, 0.44 mmol was dissolved in 5 mL of CH2Cl2 and 0.5 mL of TFA was added. After work up the free amine 27 (72 g, 0.43 mmol, 99%) was obtained as an orange oil. (10% of the ‘free’ alkyne remained in the product) [α]D = +18.3 (c = 0.71, CH2Cl2); IR (neat, cm–1) ν 3308, 2958, 2919, 2872, 1463, 1420, 1201, 808; 1H NMR (400 MHz, CDCl3) δ 2.96 (m, 1H), 2.88 (dd, 1H, J = 12.6, 5.4 Hz), 2.73–2.66 (m, 2H),

2.11 (m, 2H), 2.07 (m, 1H), 1.86 (m, 1H), 1.80 (t, 3H, J = 2.5 Hz), 1.62–1.53 (m, 3H), 1.38–1.32 (m, 1H), 1.32–1.26 (m, 1H), 0.94 (t, 3H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 77.7, 76.1, 47.8, 44.7, 39.5, 37.9, 28.6, 20.3, 18.8, 11.8, 3.3; HRMS (ESI) for C11H20N: calculated (MH+): 166.1590, found (MH+): 166.1596. (3R,4R)–tert–Butyl–3–ethyl–4–(4–hydroxybut–2–yn–1–yl)piperidine –1–

carboxylate: Alkyne 5 (340 mg, 1.34 mmol) was dissolved in 2 mL of THF and cooled to –78 °C. n–BuLi (0.92 mL, 1.6 M in hexane, 1.47 mmol) was drop wise added and stirring was continued for 30 min. Next a solution of para–formaldehyde (101 mg, 3.37 mmol) in 2 mL of THF was added and the resulting mixture was allowed to come to room temperature and stirred overnight. Saturated NH4Cl was added and the layers were separated. The water layer was extracted two times with EtOAc. The organic layers were combined, dried with

MgSO4 and the crude mixture was concentrated under reduced pressure. The product was purified by flash column chromatography (PE/EtOAc 4:1) to give alcohol (305 mg, 1.08 mmol, 81%) as an colorless oil. [α]D = +23.6 (c = 0.33, CH2Cl2); IR (neat, cm–1) ν 3243, 2968, 2930, 2868, 2223, 1689, 1668, 1428, 1343, 1244, 1165; 1H NMR (400 MHz, CDCl3) δ 4.28 (dt, 2H, J = 6.0, 2.1 Hz), 4.00 (br, 1H), 3.73 (br, 1H), 3.03 (br, 1H), 2.89 (m, 1H), 2.20 (d, 2H, J = 7.9 Hz), 1.87 (m, 1H), 1.62–1.50 (m, 4H), 1.47 (s, 9H), 1.25–1.15 (m, 2H), 0.98 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 155.0, 83.7, 79.7, 79.2, 50.7, 46.2, 42.8, 39.2, 38.8, 28.2, 26.8, 22.3, 16.7, 12.0; HRMS (ESI) for C16H27NO3Na: calculated (MNa+): 304.1883, found (MNa+): 304.1869.

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(3R,4R)–tert–Butyl–4–(4–(benzyloxy)but–2–yn–1–yl)–3–ethylpiperi dine–1–carboxylate: Alcohol (290 mg, 1.03 mmol) was dissolved in 4 mL DMF and cooled to 0 °C. Sodium hydride (62 mg, 1.54 mmol, 60% in mineral oil) was added in portions. The resulting mixture was allowed to come to room temperature and stirred for 2 h. Next benzyl chloride (0.13 mL, 1.43 mmol) was added and the stirring was continued overnight. The mixture was quenched with NH4Cl and the transferred to a separating funnel. The resulting mixture was 3 times extracted with EtOAc. The organic layers were combined and were

washed 4 times with brine. The organic layer was dried with MgSO4 and the crude mixture was concentrated under reduced pressure. The product was purified by flash column chromatography (PE/EtOAc 10:1) to give the benzylether (337 mg, 0.91 mmol, 88%) as a colorless oil. [α]D = +18.9 (c = 1.71, CH2Cl2); IR (neat, cm–1) ν 2969, 2930, 2861, 2225, 1688, 1426, 1364, 1280, 1166, 1091, 1072; 1H NMR (400 MHz, CDCl3) δ 7.39–7.29 (m, 5H), 4.06 (s, 2H), 4.18 (t, 2H, J = 2.0 Hz), 4.00 (br, 1H), 3.73 (br, 1H), 3.05 (br, 1H), 2.90–2.83 (m, 1H), 2.23 (d, 2H, J = 7.6 Hz), 1.89 (m, 1H), 1.62 (m, 3H), 1.47 (s, 9H), 1.31–1.16 (m, 2H), 0.99 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 154.9, 137.5, 128.3, 127.9, 127.7, 85.2, 79.1, 77.0, 71.3, 57.6, 46.2, 42.8, 39.3, 38.9, 28.3, 27.0, 21.9, 16.6, 12.2; HRMS (ESI) for C23H33NO3Na: calculated (MNa+): 394.2353, found (MNa+): 394.2333. (3R,4R)–4–(4–(Benzyloxy)but–2–yn–1–yl)–3–ethylpiperidine 28: According to the

general procedure for the Boc–deprotection, Boc–protected piperidine (330 mg, 0.89 mmol) was dissolved in 9 mL of CH2Cl2 and 0.9 mL of TFA was added. After work up the free amine 28 (240 mg, 0.88 mmol, 99%) was obtained as an colorless oil. [α]D = +10.6 (c = 0.6, CH2Cl2); IR (neat, cm–1) ν 3263, 2923, 2856, 2222, 1689, 1454, 1354, 1087, 1070, 737, 698; 1H NMR (400 MHz, CDCl3) δ 7.38–7.28 (m, 5H), 4.61 (s, 2H), 4.18 (t, 2H, J = 2.1 Hz), 2.97 (dt, 1H, J = 12.4, 5.3 Hz), 2.89 (dd, 1H, J = 12.6, 5.5 Hz), 2.74–2.67 (m, 2H), 2.24 (m,

2H), 1.93 (m, 2H), 1.63–1.55 (m, 3H), 1.40–1.35 (m, 1H), 1.33–1.27 (m, 1H), 0.94 (t, 3H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 137.4, 128.1, 127.8, 127.5, 85.6, 76.7, 71.1, 57.5, 47.7, 44.6, 39.4, 37.6, 28.6, 20.4, 18.7, 11.8. HRMS (ESI) for C18H26NO: calculated (MH+): 272.2009, found (MH+): 272.2002. General procedure for the silver catalyzed hydroami nation of alkynes Free amine (0.3M) was dissolved in toluene under an argon atmosphere. Next, silver triflate (5 mol%) was added and the resulting mixture was stirred at 100 °C until all the starting material had reacted according to thin layer chromatography. The solution was allowed to cool down to room temperature and was directly purified by flash column chromatography to obtain the bicyclic quinuclidine. (1S,4S,5R,E)–5–Ethyl–2–((6–methoxyquinolin–4–yl)methylene)quin uclidine 29:

According to the general procedure for the silver catalyzed hydroamination of alkynes, free amine 13 (92 mg, 0.3 mmol) was dissolved in 1 mL of toluene, followed by the addition of silver triflate (4 mg, 0.015 mmol). The mixture was stirred for 2 h at 100 °C. Purification by flash column chromatography (EtOAc) yielded the bicyclic quinuclidine 29 (87 mg, 0.29 mmol, 95%) as an orange oil. [α]D = +8.3 (c = 0.57, CH2Cl2); IR (neat, cm–1) ν 2939, 2870, 1620,


161

1590, 1560, 1508, 1265, 1229, 1036, 859, 819 ; 1H NMR (400 MHz, CDCl3) δ 8.72 (d, 1H, J = 4.4 Hz), 8.00 (d, 1H, J = 9.2 Hz), 7.36 (dd, 1H, J = 9.2, 2.4 Hz), 7.30–7.25 (m, 2H), 6.88 (s, 1H), 3.91 (s, 3H), 3.40 (dd, 1H, J = 13.6, 10.0 Hz), 3.13 (t, 2H, J = 7.2 Hz), 2.66–2.56 (m, 2H), 2.28 (d, 1H, J = 18 Hz), 1.90 (d, 1H, J = 2.4 Hz), 1.66–1.56 (m, 3H), 1.34 (quintet, 2H, J = 7.6 Hz), 0.87 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 157.6, 155.0, 147.3, 144.5, 140.5, 131.4, 127.8, 121.7, 120.4, 115.7, 101.9, 56.9, 55.4, 49.4, 37.4, 28.5, 27.9, 27.6, 26.6, 11.9; HRMS (ESI) for C20H25N2O: calculated (MH+): 309.1961, found (MH+): 309.1969. (1S,4S,5R,Z)–5–Ethyl–2–(pyridin–4–ylmethylene)quinuclidine 30: According to the

general procedure for the silver catalyzed hydroamination of alkynes, free amine 15 (68 mg, 0.3 mmol) was dissolved in 1 mL of toluene, followed by the addition of silver triflate (4 mg, 0.015 mmol). The mixture was stirred for 1.5 h at 100 °C. Purification by flash column chromatography (EtOAc) yielded the bicyclic quinuclidine 30 (63 mg, 0.28 mmol, 93%) as an colorless oil. [α]D = +12.2 (c = 0.69, CH2Cl2); IR (neat, cm–1) ν 3049, 2928, 2864, 1653, 1592, 1460, 1450, 1414, 873, 668, 637; 1H NMR (400 MHz, CDCl3) δ 8.47 (d, 2H, J = 6.0 Hz), 7.65 (d, 2H, J = 6.0 Hz), 5.79 (s, 1H),

3.27 (dd, 1H, J = 13.6, 9.5 Hz), 3.06–2.94 (m, 1H), 2.94–2.88 (m, 1H), 2.57 (dd, 1H, J = 17.6, 2.2 Hz), 2.43 (ddd, 1H, J = 13.6, 6.3, 2.2 Hz), 2.24 (d, 1H, J = 17.6 Hz), 1.92 (m, 1H), 1.66–1.56 (m, 3H), 1.38–1.22 (m, 2H), 0.88 (t, 3H, J = 7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 156.6, 149.7, 144.0, 123.2, 117.4, 55.0, 47.3, 37.2, 30.3,27.8,27.5, 26.4, 11.9. HRMS (ESI) for C15H21N2: calculated (MH+): 229.1699, found (MH+): 229.1710. (1S,4S,5R,Z)–2–Benzylidene–5–ethylquinuclidine 31: According to the general

procedure for the silver catalyzed hydroamination of alkynes, free amine 17 (68 mg, 0.3 mmol) was dissolved in 1 mL of toluene, followed by the addition of silver triflate (4 mg, 0.015 mmol). The mixture was stirred for 1.5 h at 100 °C. Purification by flash column chromatography (PE/EtOAc 20:1) yielded the bicyclic quinuclidine 31 (62 mg, 0.27 mmol, 91%) as an orange oil. [α]D = +40.4 (c = 0.24, CH2Cl2); IR (neat, cm–1) ν 3062, 2954, 2929, 2862, 1693, 1598, 1573, 892, 755, 694; 1H NMR (400 MHz, CDCl3)

δ 7.75 (d, 2H, J = 7.2 Hz), 7.30–7.27 (m, 2H), 7.15 (t, 1H, J = 7.4 Hz), 5.83 (t, 1H, J = 1.8 Hz), 3.26 (dd, 1H, J = 13.5, 9.4 Hz), 3.02–2.95 (m, 2H), 2.57 (dd, 1H, J = 17.1, 2.4 Hz), 2.48 (ddd, 1H, J = 13.5, 8.3, 6.2 Hz), 2.23 (d, 1H, J = 16.8 Hz), 1.88 (q, 1H, J = 2.9 Hz), 1.66 (m, 1H), 1.55 (m, 2H), 1.42–1.36 (m, 2H), 0.89 (t, 3H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 149.5, 136.8, 128.7, 127.9, 125.8, 119.0, 55.2, 47.3, 37.4, 30.0, 28.0, 27.7, 26.4, 11.9; HRMS (ESI) for C16H22N: calculated (MH+): 228.1752, found (MH+): 228.1748. (1S,4S,5R,Z)–5–Ethyl–2–(naphthalen–1–ylmethylene)quinuclidine 32: According to

the general procedure for the silver catalyzed hydroamination of alkynes, free amine 19 (83 mg, 0.3 mmol) was dissolved in 1 mL of toluene, followed by the addition of silver triflate (4 mg, 0.015 mmol). The mixture was stirred for 4 h at 100 °C. Purification by flash column chromatography (PE/EtOAc 15:1) yielded the bicyclic quinuclidine 32 (69 mg, 0.25 mmol, 83%) as an orange oil. [α]D = +29.4 (c = 0.32, CH2Cl2); IR (neat, cm–1) ν 3055, 2925, 2680, 1692, 1650, 1460, 1449,

893, 793, 773; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, 1H, J = 7.4 Hz), 7.86 (d, 1H, J = 7.3), 7.83 (d. 1H, J = 7.3 Hz), 7.43 (d, 1H, J = 8.2 Hz), 7.53–7.45 (m, 3H), 6.52 (s, 1H),

N

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3.27 (dd, 1H, J = 13.4, 9.3 Hz), 3.02–2.97 (m, 2H), 2.74 (dd, 1H, J = 17.1, 2.4 Hz), 2.52 (ddd, 1H, J = 13.4, 7.4, 1.4 Hz), 2.41 (d, 1H, J = 17.1 Hz), 1.96 (q, 1H, J = 2.9 Hz), 1.79–1.71 (m, 1H), 1.64–1.51 (m, 2H), 1.50–1.32 (m, 2H), 0.94 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 150.3, 133.6, 133.2, 131.7,128.4, 127.0, 126.5, 125.7, 125.3, 125.1, 124.3, 116.4, 55.9, 48.0, 37.5, 29.9, 28.1, 27.7, 26.6, 12.0; HRMS (ESI) for C20H24N: calculated (MH+): 278.1903, found (MH+): 278.1916. (1S,4S,5R)–5–Ethyl–2–methylenequinuclidine 33: According to the general

procedure for the silver catalyzed hydroamination of alkynes, free amine 26 (46 mg, 0.3 mmol) was dissolved in 1 mL of toluene, followed by the addition of silver triflate (4 mg, 0.015 mmol). The mixture was stirred for 5 h at 100 °C. Purification by flash column chromatography (EtOAc/MeOH 100:4)

yielded the bicyclic quinuclidine 33 (36 mg, 0.23 mmol, 78%) as an orange oil. [α]D = +22.2 (c = 0.65, CH2Cl2); IR (neat, cm–1) ν 2955, 2928, 2870, 1656, 1461, 1433, 1260, 1031, 877; 1H NMR (400 MHz, CDCl3) δ 4.91 (t, 1H, J = 2.1 Hz), 4.57 (t, 1H, J = 2.1 Hz), 3.27 (dd, 1H, J = 13.4, 9.6 Hz), 3.01–2.94 (m, 2H), 2.50–2.44 (ddd, 2H, J = 13.7, 8.4, 2.2 Hz), 2.16 (dd, 1H, J = 17.1 1.2 Hz), 1.84 (q, 1H, J = 2.8 Hz), 1.65–1.58 (m, 1H), 1.55–1.49 (m, 2H), 1.39–1.35 (m, 2H), 0.89 (t, 3H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 155.1, 104.4, 56.4, 49.0, 37.1, 28.1, 27.8 27.7, 26.5, 11.9; HRMS (ESI) for C10H18N: calculated (MH+): 152.1434, found (MH+): 152.1441. (1S,4S,5R,Z)–5–Ethyl–2–ethylidenequinuclidine 34: According to the general

procedure for the silver catalyzed hydroamination of alkynes, free amine 27 (50 mg, 0.3 mmol) was dissolved in 1 mL of toluene, followed by the addition of silver triflate (4 mg, 0.015 mmol). The mixture was stirred for 16 h at 100 °C. Purification by flash column chromatography (EtOAc) yielded the bicyclic quinuclidine 34 (35 mg, 0.21 mmol, 70%) as an orange oil. [α]D = +33.0 (c = 0.33, CH2Cl2); IR (neat, cm–1) ν 2962, 1283, 1238, 1244, 1158, 1029, 638;

1H NMR (400 MHz, CDCl3) δ 5.34 (q, 1H, J = 7.2 Hz), 3.77 (dd, 1H, J = 12.6, 10.4 Hz), 3.50 (m, 1H), 3.24 (m, 1H), 2.74 (ddd, 1H, J = 12.9, 9.0, 2.2 Hz), 2.62 (dt, 1H, J = 19.0, 2.0 Hz), 2.35 (d, 1H, J = 16.4 Hz), 2.07 (q, 1H, J = 2.7 Hz), 1.89–1.82 (m, 6H), 1.45 (quintet, 2H, J = 7.4 Hz), 0.93 (t, 3H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 141.2, 115.8, 55.7, 48.6, 36.5, 28.0, 27.1, 26.7, 26.2, 11.7, 11.5; HRMS (ESI) for C11H20N: calculated (MH+): 166.1590, found (MH+): 166.1598. (1S,4S,5R,Z)–2–(2–(Benzyloxy)ethylidene)–5–ethylquinuclidine 3 5: According to

the general procedure for the silver catalyzed hydroamination of alkynes, free amine 28 (81 mg, 0.3 mmol) was dissolved in 1 mL of toluene, followed by the addition of silver triflate (4 mg, 0.015 mmol). The mixture was stirred for 4 h at 100 °C. Purification by flash column chromatography (PE/EtOAc 4:1) yielded the bicyclic quinuclidine 35 (65 mg, 0.24 mmol, 80%) as an orange oil. [α]D = +53.9 (c = 0.36, CH2Cl2);

IR (neat, cm–1) ν 2928, 2861, 1678, 1496, 1096, 1065, 734, 697; 1H NMR (400 MHz, CDCl3) δ 7.36–7.30 (m, 5H), 5.18 (t, 1H, J = 6.6 Hz), 4.51 (s, 2H), 4.23 (d, 2H, J = 6.6 Hz), 3.20 (dd, 1H, J = 13.6, 9.6 Hz), 2.93 (m, 1H), 2.84 (m, 1H), 2.44 (d, 1H J = 16.9 Hz), 2.36 (ddd, 1H, J = 13.4, 8.4, 2.1 Hz), 2.12 (d, 1H, J = 16.9 Hz), 1.82 (q, 1H, J = 2.5 Hz), 1.62 (m, 1H), 1.54–1.48 (m, 2H), 1.38–1.33 (m, 2H), 0.88 (t, 3H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 150.4, 138.7, 128.2, 127.7, 127.3, 116.5, 72.0, 65.3, 55.8, 48.3, 37.4, 28.5, 27.9, 27.5, 26.4, 11.9; HRMS (ESI) for C18H26NO: calculated (MH+): 272.2009, found (MH+): 272.2020.


163

(1S,4S,5R,Z)–2–Benzylidene–5–vinylquinuclidine 36: According to the general procedure for the silver catalyzed hydroamination of alkynes, free amine 21 (67 mg, 0.3 mmol) was dissolved in 1 mL of toluene, followed by the addition of silver triflate (38 mg, 0.15 mmol). The mixture was stirred for 16 h at 100 °C. Purification by flash column chromatography (PE/EtOAc 20:1) yielded the bicyclic quinuclidine 36 (42 mg, 0.19 mmol, 63%) as 5:1 mixture of Z and E isomers as an orange oil. IR (neat, cm–1) ν 2927, 2863, 1657, 1492, 912, 893, 693; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, 2H, J = 7.6 Hz), 7.33 (m, 2H), 7.18 (t, 1H, J = 7.4 Hz), 5.92–5.85 (m, 2H), 5.10–

5.04 (m, 2H), 3.31 (m, 1H), 3.07 (m, 2H), 2.77 (dd, 0.8H, J = 13.7, 6.4 Hz), 2.65 (dd, 0.8H, J = 18.6, 1.5 Hz), 2.59 (dd, 0.2H, J = 17.2 2.3 Hz), 2.52 (ddd, 0.2H, J = 13.5, 6.2, 1.9 Hz), 2.41 (q, 0.8H, J = 7.8 Hz), 2.30–2.23 (m, 1H), 1.96 (m, 0.8H), 1.90 (m, 0.2H), 1.71–1.64 (m, 2H), 1.57 (m, 0.2H); 13C NMR (100 MHz, CDCl3) δ 149.1, 141.2, 136.7, 128.8, 28.0, 126.0, 125.9, 125.3, 119.5, 119.1, 114.4, 55.2, 53.5, 47.4, 47.4, 39.9, 37.5, 30.3, 30.1, 29.8, 28.1, 27.7, 27.3, 26.5. HRMS (ESI) for C16H20N: calculated (MH+): 226.1590, found (MH+): 226.1602. (E)–2–((6–Methoxyquinolin–4–yl)methylene)quinuclidine 37: According to the

general procedure for the silver catalyzed hydroamination of alkynes, free amine 23 (67 mg, 0.24 mmol) was dissolved in 0.8 mL of toluene, followed by the addition of silver triflate (3.1 mg, 0.012 mmol). The mixture was stirred for 40 h at 100 °C. (After 24 h 5 mol% of silver triflate was added extra, to obtain full conversion). Purification by flash column chromatography (EtOAc/MeOH 97:3) yielded the bicyclic quinuclidine 37 (49 mg, 0.18 mmol, 73%) as an orange oil. IR (neat, cm–1) ν 2937, 2868, 1619, 1583, 1563, 1506,

1260, 1227, 1029, 851, 825; 1H NMR (400 MHz, CDCl3) δ 8.73 (d, 1H, J = 4.6 Hz), 8.01 (d, 1H, J = 9.2 Hz), 7.87 (dd, 1H, J = 9.2, 2.8 Hz), 7.31 (d, 1H, J = 5.2 Hz), 7.28 (m, 1H), 6.95 (s, 1H), 3.93 (s, 3H), 3.27–3.15 (m, 4H), 2.51 (s, 2H), 2.06 (m, 1H), 1.64 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 157.6, 145.5, 147.3, 145.0, 140.3, 131.4, 127.8, 121.8, 120.4, 116.3, 101.9, 55.5, 49.6, 33.7, 26.0, 23.8; HRMS (ESI) for C18H21N2O: calculated (MH+): 281.1654, found (MH+): 281.1649. (Z)–2–Benzylidenequinuclidine 38: According to the general procedure for the silver

catalyzed hydroamination of alkynes, free amine 25 (60 mg, 0.3 mmol) was dissolved in 1 mL of toluene, followed by the addition of silver triflate (16 mg, 0.06 mmol). The mixture was stirred for 64 h at 100 °C. Purification by flash column chromatography (PE/EtOAc 30:1) yielded the bicyclic quinuclidine 38 (24 mg, 0.13 mmol, 42%) as 9:1 mixture of Z–and E–isomers as an colorless oil. IR (neat, cm–1) ν 2934, 2831, 1658, 1468, 694; 1H NMR (400 MHz, CDCl3) δ 7.75 (d, 1.8H, J = 7.2 Hz), 7.62 (d, 0.2H, J = 7.2 Hz), 7.33–7.28 (m, 2.1H), 7.16 (t, 0.9H, J = 7.4 Hz), 6.13 (t, 0.1H, J =

4.4 Hz), 5.88 (s, 0.9H), 3.30 (m, 0.2H), 3.22 (m, 0.2H), 3.11 (m, 1.8H), 3.02 (m, 1.8H), 2.56 (t, 0.2H, J = 4.0 Hz), 2.44 (s, 1.8H), 2.00 (m, 1H), 1.60 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 149.5, 136.8, 128.8, 128.1, 128.0, 126.9, 125.9, 125.4, 122.9, 119.7, 49.7, 47.9, 38.3, 35.2, 27.6, 27.6, 26.2, 23.9. HRMS (ESI) for C14H18N: calculated (MH+): 200.1434, found (MH+): 200.1452.

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(1S,2R,4S,5R)–5–Ethyl–2–((6–methoxyquinolin–4–yl)methyl)quinucl idine and (1S,2S,4S,5R)–5–ethyl–2–((6–methoxy–

quinolin–4–yl)–methyl)quinuclidine 39: Bicyclic quinuclidine 29 (100 mg, 0.32 mmol) was dissolved in 4 mL of methanol. Pd/C (17 mg, 0.016 mmol) was added and the mixture was stirred under a H2 atmosphere for 1 h. The resulting mixture was filtered over celite and the

solvent was evaporated under reduced pressure giving a 4:1 mixture of 39a and 39b. The diastereoisomers were purified by flash column chromatography (CH2Cl2/MeOH/NH4OH 100:3:1) yielding 39a and 39b (92 mg, 0.29 mmol, 92%) as an inseparable mixture and as a colorless sticky oil. IR (neat, cm–1) ν 2928, 2867, 1620, 1508, 1240, 1227; 1H NMR (400 MHz, CDCl3) δ 8.68 (d, 1H, J = 4.4 Hz), 8.02 (d, 1H, J = 9.2 Hz), 7.38 (dd, 1H, J = 9.2, 2.7 Hz), 7.31 (d, 1H, J = 2.7 Hz), 7.25 (d, 1H, J = 4.4 Hz), 3.97 (s, 3H), 3.42–3.36 (m, 1H), 3.25–1.16 (m, 1.6H), 3.06–2.99 (m, 1.8H), 2.96–2.88 (m, 1.4H), 2.85 (m, 0.2H), 2.68 (dd, 0.8H, J = 13.5, 4.8 Hz), 2.52–2.43 (m, 0.2H, 1.74–1.67 (m, 1.6H), 1.58–1.40 (m, 5.4H), 0.95 (t, 2.4H, J = 7.3Hz), 0.85 (t, 0.6H, J = 7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 157.6, 157.6, 147.5, 144.3, 143.9, 143.7, 131.6, 128.6, 121.7, 121.3, 57.8, 55.6, 55.5, 55.5, 55.4, 49.3, 49.3, 41.1, 38.4, 37.6, 37.4, 37.0, 28.5, 28.5, 28.0, 27.4, 27.1, 26.0, 25.7, 25.5, 12.0; HRMS (ESI) for C20H28N2O: calculated (MH+): 311.2218, found (MH+): 311.2127. Dihydroquinidine (40) and dihydroquinine (41): Sodium hydride (15 mg, 0.35 mmol,

60% in mineral oil) was dissolved in 1.4 mL of DMSO. The mixture was heated to 70 °C and stirred for 1 h. Next 39a and 39b (50 mg, 0.16 mmol) in 0.7 mL DMSO were added and after 1 min stirring the solution became red. Oxygen was bubbled through the mixture for 45 min. 5 mL of saturated NaHCO3 was slowly added followed by 20 mL of EtOAc and 5 mL of water.

The layers were separated and the organic layer was washed with water and brine. After drying over Na2SO4, the product was concentrated providing a mixture of dihydroquinidine (40), dihydroquinine (41), epi–dihydroquinidine, epi–dihydroquinine in a ratio of 10:2.5:3:0.5. Dihydroquinidine (40) and dihydroquinine (41) were separated from their epi–analogues by flash column chromatography (CH2Cl2/MeOH/NH4OH 100:5:1) yielding a 3:1 mixture of products 40 and 41 (27 mg, 0.085 mmol, 53%) as a white powder. 1H NMR (400 MHz, CDCl3) δ 8.73 (d, 0.25H, J = 4.5 Hz), 8.69 (d, 0.75H, J = 4.5 Hz), 8.02 (d, 0.25H, J = 9.2 Hz), 7.99 (d, 0.75H, J 9.2 Hz), 7.62 (d, 0.25H, J = 4.5 Hz), 7.58 (d, 0.75H, J = 4.5 Hz), 7.39 (d, 0.25H, J = 2.6 Hz), 7.36–7.32 (m, 1H), 7.23 (d, 0.75H, J = 2.6 Hz), 5.84 (br, 0.25H), 5.73 (d, 0.75H, J = 3.0 Hz), 3.97 (s, 0.75H), 3.88 (s, 2.25H), 3.70 (m, 0.25H), 3.16–3.04 (m, 1.75H), 2.92 (m, 1H), 2.86 (m, 0.75H), 2.79 (m, 0.75H), 2.39 (m, 0.5H), 2.00 (t, 0.75H, J = 11.5 Hz), 1.84–1.78 (m, 0.75H), 1.70 (s, 0.75H), 1.55–1.33 (m, 4.5H), 1.24 (m, 0.5H), 1.10 (m, 0.75H), 0.83 (t, 2.25H, J = 7.2 Hz), 0.78 (t, 0.75H, J = 7.3 Hz). All the analytical data was in accordance to those reported in literature.33


165

5.9 References

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2) a) Morgan, Jr., T. K.; Lis, R.; Marisca, A. J.; Argentieri, T. M.; Sullivan, M. E.; Wong, S. S. J. Med. Chem. 1987, 30, 2259–2269 b) Sakamuri, S.; Enyedy, I. J.; Zaman, W. A.; Tella, S. R.; Kozikowski, A. P.; Flippen–Anderson, J. L.; Farkas, T.; Johnson, K. M; Wang, S. Bioorg. Med. Chem. 2003, 11, 1123–1136.

3) Mazurov, A.; Klucik, J.; Miao, L.; Phillips, T. Y.; Seamans, A.; Schmitt, J. D.; Hauser, T. A.; Johnson Jr., R. T.; Miller, C. Bioorg. Med. Chem. Lett. 2005, 15, 2073–2077.

4) a) Forsyth, D. A.; Prapansiri, V. J. Am. Chem. Soc. 1989, 111, 4548–4552 b) Breining, S. R.; Bencherif, M.; Grady, S. R.; Whiteaker, P.; Marks, M. J.; Wageman, C. R.; Lester, H. A.; Yohannes, D. Bioorg. Med. Chem. Lett. 2009, 19, 4359–4363.

5) a) Nugent, T. C.; Seemayer, R. Org. Process Res. Dev. 2006, 10, 142–148 b) Mazurov, A. A.; Kombo, D. C.; Hauser, T. A.; Miao, L.; Dull, G.; Genus, J. F.; Fedorov, N. B.; Benson, L.; Sidach, S.; Xiao, Y.; Hammond, P. S.; James, J. W.; Miller, C. H.; Yohannes, D. J. Med. Chem. 2012, 55, 9793–9809.

6) Chandramouli, S. V.; Ayers, T. A.; Wu, X.–D.; Tran, L. T.; Peers, J. H.; Disanto, R.; Roberts, F.; Kumar, N.; Jiang, Y.; Choy, N.; Pemberton, C.;. Powers, M. R.; Gardetto, A. J.; D’Netto, G. A.; Chen, X.; Gamboa, J.; Ngo, D.; Copeland, W.; Rudisill, D. E.; Bridge, A. W.; Vanasse, B. J; Lythgoe D. J. Org. Process Res. Dev. 2012, 16, 484–494.

7) a) Gates, M.; Sugavanan, B.; Schreiber, W. L. J. Am. Chem. Soc. 1970, 92, 205 b) Tønder, J. E.; Begtrup, M.; Hansen, J. B.; Olesen, P. H. Tetrahedron 2000, 56, 1139–1146 c) Sakamuri, S.; Enyedy, I. J.; Kozikowski, A. P.; Wang, S. M. Tetrahedron Lett. 2000, 41, 9949–9952.

8) Wong, J. W.; Burns, M. P. Tetrahedron: Asymmetry 1999, 10, 4295–4305. 9) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467–4470. 10) Nativa, C.; Taddei, M. J. Org. Chem. 1988, 53, 820–826. 11) a) Pohlki, F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104–114 b) Severin, R.; Doye, S. Chem. Soc.

Rev. 2007, 36, 1407–1420 c) Müller, T, E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795–3892.

12) a) Bates, R. W.; Satcharoen, V. Chem. Soc. Rev. 2002, 31, 12–21 b) Breman, A. C.; Dijkink, J.; van Maarseveen, J. H.; Kinderman, S. S.; Hiemstra, H. J. Org. Chem. 2009, 74, 6327–6330 c) Nishina, N.; Yamamoto, Y. Tetrahedron 2009, 65, 1799–1808 d) Alcaide, B.; Almendros, P. Adv. Synth. Catal. 2011, 353, 2561–2576 d) Krause, N.; Winter, C. Chem. Rev. 2011, 111, 1994–2009.

13) a) Hultzsch, K. C. Adv. Synth. Catal. 2005, 347, 367–391 b) Hesp, K. D.; Stradiotto, M ChemCatChem 2010, 2, 1192–1207 c) Yadav, J. S.; Antony, A.; Rao, T. S.; Reddy, B. V. S. J. Organomet. Chem. 2011, 696, 16–36 d) Hannedouche, J.; Schulz, E. Chem. Eur. J. 2013, 19, 4972–4985.

14) For examples of hydroamination reactions in natural product synthesis see: a) Wang, C.; Sperry, J. Org. Lett. 2011, 13, 6444–6447 b) Chiba, H.; Shinya Oishi, S.; Fujii, N.; Ohno, H. Angew. Chem. Int. Ed. 2012, 51, 9169–9172 c) Hienzsch, A.; DeimL, C.; Reiter, V.; Carell, T. Chem. Eur. J. 2013, 19, 4244–4248.

15) a) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395–3442 b) Patil, N. T.; Kavthe, R. D.; Shinde, V. S. Tetrahedron 2012, 68, 8079–8146.

16) a) Li, Z.; Zhang, J.; Brouwer, C.; Yang, C.–G.; Reich, N. W.; He, C. Org. Lett. 2006, 8, 4175–4178. b) Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.; Utsunomiya, M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179–4182.

17) a) Seayad, J.; Tillack, A.; Hartung, C. G.; Beller, M. Adv. Synth. Catal. 2002, 344, 795–813 b) Zhang, W.; Werness, J. B.; Tang, W. Org. Lett. 2008, 10, 2023–2026 c) Quinet, C.; Sampoux, L.; Markó, I. E. Eur. J. Org. Chem. 2009, 1806–1811.

18) a) Yamamoto, Y.; Radhakrishnan, U. Chem. Soc. Rev. 1999, 28, 199–207 b) Patil, N. T.; Lutete, L. P.; Wu, H.; Pahadi, N. K.; Gridnev, I. D.; Yamamoto, Y. J. Org. Chem. 2006, 71, 4270–4279 c) Minatti, A.; Muñiz, K. Chem. Soc. Rev. 2007, 36, 1142–1152 d) Narsireddy, M.; Yamamoto, Y. J. Org. Chem. 2008, 73, 9698–9709.

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19) a) Fürstner, A.; Davies P. W. Angew. Chem. Int. Ed. 2007, 46, 3410–3449 b) Brunet, J.–J.; Chu, N.–C.; Rodriguez–Zubiri, M. Eur. J. Inorg. Chem. 2007, 4711–4722 c) Chianese, A. R.; Lee, S. J. Gagné, M. R. Angew. Chem. Int. Ed. 2007, 46, 4042–4059.

20) a) Weibel, J.–M.; Blanc, A.; Pale, P. Chem. Rev. 2008, 108, 3149–3173 b) Alvarez–Corral, M.; Munoz–Dorado, M.; Rodriguez–Garcia, I. Chem. Rev. 2008, 108, 3174–3198.

21) a) Widenhoefer, R, A; Han, X. Eur. J. Org. Chem. 2006, 4555–4563 b) Hashmi, A. S. K.; Stephen, K. Chem. Rev. 2007, 107, 3180–3211 c) Shen, H. C. Tetrahedron 2008, 64 3885–3903 d) Corma, A.; Leyva–Pérez, A.; Sabater, M. J. Chem. Rev. 2011, 111, 1657–1712.

22) Sperger, C. A.; Fiksdahl, A. J. Org. Chem. 2010, 75, 4542–4553. 23) Crawley, S. L.; Funk, R. L. Org. Lett. 2006, 8, 3995–3998. 24) Hutchison D. R.; Khau V. V; Martinelli M. J.; Nayyar N. K.; Peterson B. C.; Sullivan, K. A. Org.

Synth. 1998, 75, 223–228. 25) a) Colvin, E. W.; Hamill, B. J.; J. Chem. Soc. Perkin Trans. 1 1977, 869–874; b) Van de Sande,

M.; Gais, H.–J. Chem. Eur. J. 2007, 13, 1784–1795. 26) This was also reported in: Gupta, K. A.; Saxena, A. K.; Jain, P. C.; Anand, N. Ind. J. Chem. 1987,

26B, 344–347. 27) Frackenpohl, J.; Braje, W. M.; Hofmann, H. M. R. J. Chem. Soc., Perkin Trans. 1 2001, 47–65. 28) Müller, T. E.; Grosche, M.; Herdtweck, E.; Pleier, A.–K.; Walter, E.; Yan, Y.–K. Organometallics

2000, 19, 170–183. 29) Wang, W.; Hammond, G. B.; Xu, B. J. Am. Chem. Soc. 2012, 134, 5697–5705. 30) Nolan, S. P. Acc. Chem. Res. 2011, 44, 91–100. 31) a) Seth, M.; Dolg, M.; Fulde, P.; Schwerdtfeger, P J. Am. Chem. Soc. 1995, 117, 6597–6598 b)

Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395–403. 32) a) Uskoković, M.; Gützwiller, J. J. Am. Chem. Soc. 1970, 92, 204–205 b) Uskoković, M.;

Gützwiller, J. J. Am. Chem. Soc. 1978, 100, 576–581 c) Stork, G.; Niu, D.; Fujimoto, A.; Koft, E. R.; Balkovec, J. M.; Tata, J. R.; Dake, G. R. J. Am. Chem. Soc. 2001, 123, 3239–3242.

33) For experimental data of dihydroquinidine 41 see: Berkessel, A.; Seelig, B.; Schwengberg, S; Hescheler, J.; Sachinidis, A. ChemBioChem. 2010, 11, 208–217 and for experimental data of dihydroquinine 42 see: Palacio, C.; Connon, S. J. Org. Lett. 2011, 13, 1298–1301.

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Summary

Enzymes are the catalysts in living systems and responsible for the production of new compounds, usually with very high stereoselectivity. Each enzyme has an active site where the stereoselective reaction takes place. The mimicking of the active site of enzymes with an active metal center has received extensive attention for several decades. However, the mimicking of the active site without a metal center has only been studied intensively since the end of the last century. This way of synthesizing chiral molecules is now referred to as asymmetric organocatalysis and has become a well–established field for the synthesis of enantiomerically enriched compounds. A well–studied class of catalysts are Cinchona alkaloids (scheme 1). These alkaloids play a dominant role in the field of asymmetric organocatalysis because they are inexpensive, are available in two pseudoenantiomeric forms and feature useful functional groups in a highly chiral environment. The nitrogen atom in the quinuclidine ring is able to deprotonate a variety of nucleophiles, while the C9 OH–group can activate electrophiles through hydrogen bonding. This allows the Cinchona alkaloids to act as so–called bifunctional catalysts. Also these alkaloids can be easily modified by introducing functional groups with the purpose of improving the catalyst activity.

Scheme 1. The four major compounds of Cinchona alkaloids.

In chapter 1, a short introduction is given about covalent and non–covalent activation in asymmetric organocatalysis. Furthermore, the historical background of Cinchona alkaloids is described, including their discovery, isolation, characterization and total synthesis. Finally the application in chemistry of Cinchona alkaloids is discussed. Cinchona alkaloids and derivatives are able to catalyze many reactions with high levels of enantiomeric excess. However, the mechanisms of non–covalent activation by Cinchona alkaloids are far from being understood.

Chapter 2 describes the organocatalytic functionalization of α–amino acids derivatives through the introduction of a thiol at the β–carbon atom (scheme 2). In order to achieve this a new class of Michael acceptors based on α,β–dehydro–α–amino acids were developed. Protecting the amine with a TFA–group was crucial in order to suppress the enamine character of the double bond. The α,β–dehydro–α–amino acids derivatives were successfully applied as acceptors in the thiol addition to these derivatives. Cinchona alkaloids functionalized at the C6’–position proved to be good catalysts giving high yields, poor to moderate diastereoselectivity and ee’s up to 95% for the major

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diastereoisomer. By changing the thiol nucleophile (PhSH to BnSH) inversion of the stereochemistry at the β–carbon atom for the major diastereoisomer was observed. The addition products were converted successfully into suitable building blocks for peptide chemistry.

Scheme 2. Thiol functionalization of α–amino acids derivatives.

Optimization studies for the thiol addition to α,β–dehydro–α–amino acids are described in chapter 3. In order to increase the applicability of this method two major issues had to be addressed: i) improvement of the diastereoselectivity and ii) the use of catalysts that can be easily obtained. In order to improve the diastereoselectivity, the type of hydrogen bond donor was changed, leading to a change in the catalyst activity. Protection of the C9 OH–group of quinidine with the more stable benzyl group, resulted in easier syntheses of the catalysts. The introduction of different types of hydrogen bond donors at the C6’–position like urea, benzimidazole, amide and sulfonamide is described first. Thiol additions to both α,β–dehydro–α–amino acid derivatives and to α,β–unsaturated N–acetylated oxazolidinones were investigated (scheme 3).

Scheme 3. Optimization studies.

In the latter reaction it was found that by changing the hydrogen bond donor motif from thiourea to sulfonamide inversion in the stereochemistry of the product was observed. The introduction of electron donating substituents on the sulfonamide improved the enantioselectivity. Moreover, the sulfonamide catalysts proved to be the best catalysts in the thiol addition to α,β–dehydro–α–amino acid derivatives in terms of

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diastereoselectivity and enantioselectivity. Inversion of the stereochemistry as compared to the thiourea catalyst was not observed. Both reactions tolerated benzylic and allylic thiols giving in all examples high levels of enantiomeric excesses. To demonstrate the applicability of this chemistry, the β–functionalized amino acids were applied successfully in native chemical ligation.

Chapter 4 concerns an experimental study performed in order to gain more insight in to the mechanisms of Cinchona alkaloid catalyzed reactions. Novel synthetic analogues of quinidine were prepared, all having modifications in the quinuclidine ring system (scheme 4). These modifications influence the direction of the lone pair on the nitrogen atom and its basicity. The preferred synthetic route to construct the bicyclic system dealt with a cyclization reaction of secondary amines to epoxides. This cyclization strategy was not successful for the synthesis for the [3.2.2]–analogue. Therefore a racemic synthesis was performed followed by separation of the enantiomers. The novel analogues were examined in four different types of conjugate additions and compared with three known catalysts. The results show that the modifications in the quinuclidine ring have a significant influence on the enantioselectivity. The activities of the catalysts were obtained by kinetic measurements and the pKAH’s were determined with fluorescence spectroscopy. The results indicate that the activity of the catalysts is not directly correlated with the basicity of the tertiary amine.

Scheme 4. Novel synthetic analogues of quinidine applied in conjugate additions.

To further improve the use of Cinchona alkaloids (analogues) for studies on the mechanism of organocatalytic reactions, a new synthetic strategy to Cinchona alkaloids (analogues) is described in chapter 5. The key step in this approach is an intramolecular hydroamination of alkynes yielding 2–alkylidenequinuclidines (scheme 5).

Scheme 5. Intramolecular hydroamination of alkynes.

It was found that AgOTf was a superior catalyst for the cyclization. The products of this process were obtained in high yields and in most examples the Z–isomer was obtained. Only when the alkyne was substituted with a quinoline moiety after cyclization the Z–isomer isomerized completely to the more stable E–isomer. The difference between the reactivity of cis–di–substituted and mono–substituted piperidines was also investigated. The cis–di–substituted piperidines reacted faster than the mono–substituted ones

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because of the conformational preference of the propynyl group for the axial position. After cyclization the Cinchona alkaloids dihydroquinidine and dihydroquinine were obtained in a two–step procedure.

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Samenvatting

Enzymen zijn verantwoordelijk voor de synthese van enantiomeer zuivere stoffen uit prochirale verbindingen in levende organismes. Elk enzym heeft een actief centrum waar de stereoselectieve synthese plaats vindt. Het nabootsen van het actieve centrum van enzymen dat een actief metaal bevat, is al een aantal decennia intensief onderzocht. Maar het imiteren van een enzym dat geen metaal bevat in het actieve centrum is pas sinds het eind van de vorige eeuw intensief onderzocht. Deze manier van het synthetiseren van chirale moleculen is nu bekend als ‘asymmetrische organokatalyse’ en is nu een gerenommeerd veld om verbindingen te synthetiseren met een hoge enantiomere overmaat. Een belangrijke groep katalysatoren binnen dit veld zijn de Cinchona alkaloïden (schema 1). Dit type verbindingen is belangrijk in asymmetrische organokatalyse, omdat deze natuurstoffen goedkoop zijn, verkrijgbaar zijn in beide pseudo–enantiomere vormen en bruikbare functionele groepen bevatten in een geschikte chirale omgeving. Het basische stikstofatoom in het bicyclische chinuclidine ringsysteem kan door deprotonering nucleofielen genereren. De C9 OH–groep kan elektrofielen activeren door middel van waterstofbrug vorming. Zo is het mogelijk om Cinchona alkaloïden te gebruiken als bifunctionele organokatalysatoren. Verder kunnen deze alkaloïden gemakkelijk chemisch worden aangepast waardoor functionele groepen kunnen worden geïntroduceerd die de activiteit van de katalysator verhogen.

NN

N

N

OH

OH

R

R

kinidine R = OMecinchonine R = H

kinine R = OMecinchonidine R = H

1

3

4

1011

89

1'

4'

6'

1

3

1011

4

8

94'

1'

6'

Schema 1. De vier meest voorkomende Cinchona alkaloïden.

In hoofdstuk 1 wordt een korte inleiding gegeven over covalente en non–covalente activering in asymmetrische organokatalyse. Vervolgens wordt de geschiedenis van Cinchona alkaloïden beschreven, bestaande uit de ontdekking, isolering, karakterisering en totaalsynthese. Als laatste worden de chemische toepassingen van Cinchona alkaloïden besproken. (Gemodificeerde) Cinchona alkaloïden katalyseren vele reacties met hoge enantioselectiviteit, maar de mechanismes van deze reacties zijn nog vaak onduidelijk.

In hoofdstuk 2 wordt het asymmetrisch introduceren van thiolen op het β–koolstofatoom van aminozuren door middel van een organokatalytisch proces beschreven (schema 2). Hiervoor is een nieuw type Michael–acceptor ontwikkeld, gebaseerd op α,β–dehydro–α–aminozuren. Het beschermen van het stikstofatoom met een TFA–groep is cruciaal gebleken om het enamine karakter van de dubbele binding te onderdrukken. Deze derivaten van α,β–dehydro–α–aminozuren zijn vervolgens toegepast in een thioladditie.

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Cinchona alkaloïden gemodificeerd op de C6’–positie met een thioureum zijn goede katalysatoren gebleken. Hiermee zijn goede opbrengsten, lage tot redelijke diastereoselectiviteit en een enantiomere overmaat tot 95% verkregen. Door het veranderen van het zwavelnucleofiel (PhSH naar BnSH) is inversie van de stereochemie op het β–koolstofatoom voor het hoofd–diastereoisomeer waargenomen. Verder is aangetoond dat de additieproducten kunnen worden omgezet naar bruikbare bouwstenen voor peptide–chemie.

Schema 2. Thiol–additie aan derivaten van α,β–dehydro–α–aminozuren.

In hoofdstuk 3 wordt het optimaliseren van de reactiecondities voor de additie van thiolen aan derivaten van α,β–dehydro–α–aminozuren beschreven. Om deze methode meer toepasbaar te maken, zijn twee facetten belangrijk: i) het verbeteren van de diastereoselectiviteit en ii) het gebruik van katalysatoren die gemakkelijk verkregen kunnen worden. Door het veranderen van het type waterstofbrugdonor wordt de activiteit van de katalysator aangepast en door het introduceren van een benzylether op de C9–positie van kinidine, wordt het mogelijk grote hoeveelheden katalysator te verkrijgen. De synthese van de verschillende types waterstofbrugdonoren op de C6’–positie wordt eerst beschreven. Vervolgens zijn de thiol addities aan derivaten van α,β–dehydro–α–aminozuren en aan α,β–onverzadigde N–geacetyleerde oxazolidinonen onderzocht met deze katalysatoren (schema 3).

Schema 3. Optimalisatie studies.

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In de thioladditie aan α,β–onverzadigde N–geacetyleerde oxazolidinonen is inversie van de stereochemie van het product waargenomen, wanneer het type waterstofbrugdonor van thioureum naar sulfonamiden is veranderd. Het introduceren van elektrondonerende groepen op het sulfonamide heeft geresulteerd in verdere verbetering van de enantioselectiviteit. De sulfonamiden bleken ook de beste katalysatoren te zijn voor de additie van thiolen aan derivaten van α,β–dehydro–α–aminozuren wat betreft diastereoselectiviteit en enantioselectiviteit. In deze reactie is geen inversie van de stereochemie waargenomen ten opzichte van de thioureum katalysator. Om de toepasbaarheid van de ontwikkelde chemie aan te tonen zijn de β–gefunctionaliseerde aminozuren toegepast in “native chemical ligation”.

Een experimentele studie om meer inzicht te krijgen in het mechanisme van door Cinchona alkaloïden gekatalyseerde reacties is beschreven in hoofdstuk 4. Hiervoor zijn analogen van kinidine gesynthetiseerd met aanpassingen in het chinuclidine ringsysteem (schema 4). De aanpassingen hebben erin geresulteerd dat de richting en de basiciteit van het elektronenpaar van het stikstofatoom is veranderd. De bicyclische systemen zijn bij voorkeur gesynthetiseerd door reacties van secundaire amines met chirale epoxides. Het was niet mogelijk gebleken om het [3.2.2]–analoog via deze route te verkrijgen. Daarom is een racemische synthese verricht, gevolgd door het scheiden van de enantiomeren. Vervolgens zijn de analogen in vier verschillende conjugaat–addities onderzocht en vergeleken met drie bekende katalysatoren. Uit de resultaten is naar voren gekomen dat de aanpassingen in het chinuclidine ringsysteem een grote invloed kunnen hebben op de enantioselectiviteit. De activiteiten van de katalysatoren zijn gemeten met kinetische methoden en de pKAH’s zijn bepaald met fluorescentie spectroscopie. Hieruit is gebleken dat de activiteit van de katalysator niet direct gecorreleerd kan worden aan de basiciteit van het tertiaire stikstofatoom.

Schema 4. Synthetische analogen van kinidine toegepast in conjugaat–addities.

In hoofdstuk 5 is een nieuwe strategie om Cinchona alkaloïden en analogen te synthetiseren beschreven. De belangrijkste stap is een intramoleculaire hydroaminering van alkynen, waardoor 2–alkylideenchinuclidines worden verkregen (schema 5).

Schema 5. Door zilver gekatalyseerde intramoleculaire hydroaminering van alkynen.

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AgOTf bleek de meest geschikte katalysator voor de cyclizatie te zijn. De gevormde producten zijn verkregen in hoge opbrengsten en in de meeste voorbeelden als Z–isomeer. Alleen wanneer het alkyn met een chinoline is gesubstitueerd, isomeriseert het gevormde Z–isomeer volledig naar het meer stabiele E–isomeer. Het verschil in reactiviteit tussen cis–3,4–digesubstitueerde piperidines en 4–mono–gesubstitueerde piperidines is ook onderzocht. De cis–3,4–digesubstitueerde piperidines reageren sneller dan de mono–gesubstitueerde omdat de conformationele voorkeur van de propynyl–groep voor de axiale positie groter is. De Cinchona alkaloïden dihydrokinidine en dihydrokinine zijn verkregen in twee stappen na de cyclisatiereactie.

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Dankwoord

Na vier mooie jaren, vele experimenten, cursussen, reisjes naar mooie congressen en het schrijven van dit proefschrift zit het er dan echt op. Het geeft een goed gevoel dat het nu echt klaar is. Het is echter ook jammer, want deze mooie tijd komt helaas niet meer terug. Gelukkig heb ik deze tijd beleefd met vele mensen die mij geholpen hebben om dit mooie proefschrift mogelijk te maken (ook al hebben sommige mensen het niet door gehad). Mocht ik iemand in mijn dankwoord niet noemen, dan bied ik hiervoor mijn excuses aan.

Als eerste wil ik graag mijn promotor bedanken. Henk , bedankt dat ik de mogelijkheid heb gekregen om binnen jouw werkgroep een promotieonderzoek te doen. Ook voor het vertrouwen in mij ondanks mijn aparte “afkomst”. Tijdens deze vier jaar ben ik niet alleen gegroeid als chemicus, maar ook als mens. De mogelijkheden die ik heb gehad waren echt geweldig. Als er weer eens een goed congres in een mooie plaats in Europa of zelfs Amerika was, hoefde ik het, bij wijze van spreken, niet eens te vragen of ik er heen kon. Verder de vrijheid die ik tijdens mijn onderzoek kreeg gaf mij veel ruimte om dingen te onderzoeken. Ook al kostte dat af en toe een beetje veel aan oplosmiddelen, hiervoor mij excuses. Naast het labwerk waren er natuurlijk andere leuke activiteiten. Zeker de probleemavonden vond ik altijd heel leuk en interessant om daaraan mee te doen. Ik hoop dat dit bij jou ook zo is overgekomen. Ik weet dat het soms zwaar was om een hoofdstuk van mij te corrigeren, maar ik hoop dat jij tevreden bent met het eindresultaat. Ik in ieder geval wel!

Ook mijn co–promotor, Steen , hartelijk bedankt. Voor jou was het misschien nog zwaarder om de eerste versies van mijn proefschrift door te lezen, maar ik heb aan jouw feedback veel gehad. Ook buiten het schrijven om was jij altijd bereid om mij te helpen; door de vele discussies over het onderzoek hebben wij toch een redelijk beeld van alles gekregen, ook al is er nog wel wat uit te zoeken. Wij gaan ongemerkt samen toch een tijdje terug, doordat ik samen met Asbjørn op het St. Michaël College heb gezeten. Het is fijn om te horen dat het goed met hem gaat.

En dan is er natuurlijk Jan v M . Ik ben nog nooit zo’n enthousiast persoon tegen gekomen als jij. Toen ik als HLO–analytisch chemicus op de UvA kwam met de vraag of ik een stage kon lopen binnen de werkgroep was dat geen probleem. Jij zag niet mijn gebreken, maar jij zag de mogelijkheid om mij om te scholen. Ik denk dat jij dit uiteindelijk goed hebt gezien. Ik kon jou altijd lastig vallen met een vraag, ook al had jij het altijd veel te druk. Verder hebben wij mooie reisjes beleefd via de ORCA–meetingen. Het was nooit vervelend om met jou naar deze congressen te gaan. Ik zal ook niet snel mijn eerste zweefvlucht vergeten: dubbele loopings en bochten met veel g–krachten waren echt niet normaal. Ik vond het echt super. Als laatste wil ik jou bedanken dat jij in mijn commissie wilt deelnemen.

Graag wil ik ook de andere commissieleden bedanken: prof. dr. J. N. H. Reek , prof. dr. A. M. Brouwer , prof. dr. P. Timmerman (ook voor de stageplaats tijdens mijn HLO–afstudeerproject), prof. dr. ir. R. V. A. Orru en prof. dr. F. P. J. T. Rutjes . I especially like to thank prof. dr. S. Connon from Dublin for taking part in my committee.

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Voor mijn promotieonderzoek is er een aantal mensen geweest waarvan ik veel heb geleerd. Jasper , jij had de zware taak om mij organische chemie te leren. Toen ik aan mijn HLO–afstudeerproject begon, had ik eigenlijk nog nooit synthetisch werk gedaan. Dus ik moest alles leren. Bedankt dat jij het geduld had om dit aan mij te leren. Ook mijn begeleider tijdens mijn master–onderzoek, Sape, wil ik heel erg graag bedanken. Door jouw hulp en kennis heb ik me verder weten te ontwikkelen. Ook na mijn master–stage hadden wij nog vaak contact. Even een sigaretje roken en even bijpraten was altijd gezellig. Ook voor het doorlezen van een aantal hoofdstukken van dit proefschrift wil ik je graag bedanken. Door jouw feedback is het een beter verhaal geworden. Ook Jan D was betrokken bij mijn master–onderzoek. Ook jij was altijd beschikbaar en ik kon jou altijd om hulp vragen. Uit dit onderzoek is toch een mooie publicatie gekomen. Ook de andere twee “lab–oudjes” wil ik graag bedanken. Martin W , jij bent toch een soort ‘lopende organische encyclopedie’. Bedankt voor alle hulp en dat jij altijd kritisch naar mijn resultaten keek. Mijn excuses voor de zwavellucht die af en toe op het lab hing. Squashen tijdens de lunch was ook een leuke bezigheid. Dan is er natuurlijk het stralende zonnetje, Hans B . Ook jij bedankt voor de toch altijd gezellige sfeer en positieve kijk op het leven.

Dan zijn er natuurlijk mijn paranimfen: Stanimir en Roel . First I want to thank you both for being my paranimfs. Stanimir , we started around the same time more or less. It was nice to have you as my fellow PhD–student. The course we had to take at Schiermonnikoog in snowy November and the exam we had to take was kind of tricky. Thanks for the help with peptide related chemistry and I am curious how your thesis will look like. Roel , bedankt voor de leuke tijd die ik met jou op het lab heb gehad. Als ik er even niet was (wat nog wel eens gebeurde!) was jij er om mijn studenten te helpen. Verder de vele sportsessies die wij tijdens de lunch hadden waren een mooie manier om te ontspannen. Dan hebben wij natuurlijk ook nog een te gek congres bezocht in Amerika (misschien was de roadtrip er naar toe een stuk leuker…). Dan waren er verder nog de ‘leuke’ ideeën van jou en Ginger om te gaan vissen. Ik kan mij er nog een keer herinneren ergens in het noorden van Nederland; dat was volgens mij niet de beste keer om te gaan vissen, maar toch ook wel weer een ervaring. Gelukkig waren andere keren een stuk beter. Ginger , jij niet alleen bedankt voor het vissen, maar ook voor de tips aan het begin van mijn promotieonderzoek. Het was mooi om te horen dat Alma en jij nu toch samen een kindje hebben gekregen. Jochem , het congres in Namen was nog niet zo slecht. Het was altijd gezellig even een bakkie te doen en slap te ouwe hoeren. Verder even naar de sportschool was altijd goed en ontspannend. Ik heb gehoord dat jij ook goed op weg bent met je proefschrift. Succes met afronden!! Linde , squashen, fitnessen en voetballen: daar was jij altijd wel voor in. Dat waren toch wel relaxte momentjes tijdens de afgelopen vier jaar. Bedankt voor de tips met betrekking tot de lay–out van mijn proefschrift en natuurlijk voor het organiseren van het kleiduivenschieten, dat was wel echt top!! Gaston , jij nog veel succes met je promotieonderzoek. Het was toch nog bijna gelukt op het WK. Elize , we worked only for a small time together at the Roeterseiland, but I would also thank you for the fun we had during that time.

Dit proefschrift zou niet tot stand zijn gekomen zonder de hulp van een groot aantal getalenteerde studenten. Het begon allemaal met twee echte Zaankanters: Luuk en Gydo . Ik was blij dat ik jullie als eerste studenten had gekregen. Jullie konden allebei al goed zelfstandig werken. Luuk , ook al staan de resultaten van jou niet in dit proefschrift, jouw studies naar de 2–aminobenzimidazool katalysator hebben toch wel geholpen.

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Toen al had jij vele creatieve ideeën en volgens mij komt dat goed van pas bij jouw promotieonderzoek. Gydo , jij begon met het project om de analogen van kinidine te maken. Door jouw onderzoek bleek het voor mij niet meer zo moeilijk om het [1.2.2]–analoog te maken. Ook als master–student kwam jij weer bij mij terecht en ging jij weer verder met het analogen project, nu alleen de [3.2.2]–analogen. De eerste twee analogen had jij al snel gemaakt, maar de derde bleek toch vrij lastig te maken (daar weet ik alles van). Ook de katalyse met de analogen had jij gedaan en ik moet zeggen dat alles goed reproduceerbaar was. Gelukkig kon jij ons cadeau voor je master–diploma goed waarderen. Merande , jij was net als mij een HLO–student en de opvolger van Luuk voor het project van de 2–aminobenzimidazool katalysator. Het lukte jou om de katalysator te maken, alleen daarvoor was een extra CH2–groep voor nodig. En toen kwam Suze. Eerst had jij al een heel mooi overzicht gemaakt van alle synthetische routes naar kinine en kinidine. Voor mijn proefschrift heb ik hieraan veel gehad. Maar ook jouw harde werken naar het ontwikkelen van de 2–aminobenzimidazool katalysator zonder de CH2–groep en de ureum katalysator is zeer nuttig geweest voor mijn onderzoek. Ook alle rookpauzes die wij hebben gehad waren toch wel gezellig. And then Jan came with the great idea, that I had to supervise a chica from Spanje. Andrea , your preliminary studies towards the synthesis of substituted 2–alkylidenequinuclidines has finally resulted in a nice chapter in this thesis (but I am not done with you yet). Max en Michiel , jullie werk staat niet beschreven in dit proefschrift, maar het heeft wel geholpen om iets meer inzicht in de katalyse te krijgen. Vervolgens kwamen er drie bachelor studenten die een goede impuls gaven om hoofdstuk 3 af te ronden. Roy , door jouw harde werken voor katalysator syntheses en screening (wel genoeg stof in het monster doen) zijn wij toch mooi op de sulfonamiden katalysatoren terecht gekomen. Ook al rinkelde het wel eens in je zuurkast (ken er nog één). Rosa , jouw eerste katalyse experiment gaf gelijk 99% ee; ik was best wel jaloers maar toch ook heel blij. Suzanne door jou zijn wij uitgekomen op diphenylmethaanthiol als het beste nucleofiel voor de additie reacties. Als laatste kreeg ik nog een studente die als zij te veel koffie drinkt af en toe rare dingen zegt. Dieuwertje , ik vond dat helemaal niet zo erg. Dat jij verder ging met het meer toepasbaar maken van de chemie in hoofdstuk 3 vind ik zeer interessant. Veel succes met je promotieonderzoek. Jamie , although you were not directly my student, thanks for doing the catalysis with some of the analogues. This has provided a nice table in chapter 4. Naast verschillende mensen waarmee ik direct heb samengewerkt, is er ook een groot aantal mensen binnen de werkgroep waarmee ik een leuke tijd en goede discussies heb gehad: Martin B , Sandrine , Maxime , Tomasso , Merel , Channan , Bart , Rowan , Danijela , Isabel , Nabil , Elma , Jordy en Martien .

Dan is er natuurlijk een groot aantal mensen buiten de werkgroep die ik graag wilt bedanken. Als eerste Jan G ; jij hoorde eigenlijk bij onze werkgroep. Als ik een structuur van een molecuul moest toekennen, was jij nooit te beroerd om dit te doen. En ook al was de structuur helemaal toegekend, dan ging jij toch nog naar verder bewijs zoeken. Ook bedankt voor de leuke sfeer tijdens het Roeterseiland voetbaltoernooi. Dat ik de laatste doelpunten van het Organische team had gemaakt, vind ik toch wel speciaal. Ook Els en Jan M bedankt voor de hulp met de ophelderingen van de structuur. Voor de exacte massa’s wil ik eerst graag Han bedanken. Ook toen jij al met pensioen ging en het massa–apparaat stuk was, wilde jij mij nog steeds helpen. Gelukkig kon ik terecht op de VU voor de laatste berg massa’s. Elwin bedankt dat jij tijd voor mij hebt vrij gemaakt. Ook andere mensen binnen het E–gebouw wil ik graag bedanken voor de leuke sfeer en samenwerking: Sandra , Rene, Rosalba , Mona Lisa , Fred , Zohar , Lidie ,

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Ruben , Bart , Evelien , Annnemarie , Taasje (onze bodybuilder), Erik (als er weer een formuliertje moest worden ingevuld) en Danny (voor het verbinden van mijn oorlogswond). Ik moet zeker even stil staan bij twee mensen die ik vaak heb lastig gevallen (sorry hiervoor): Remko en Sander . Bedankt voor jullie hulp met de chirale HPLC en het testen van chirale hydrogeneringen (ook al staan de resultaten niet beschreven in dit proefschrift). Also Tatu thanks for the help with the pKAH determinations and Tomislav thanks for the nice time in Maastricht. Ron W en Louis ook bedankt voor de vragen met betrekking tot biokatalyse. Ron en Johan zonder jullie was de practicumbegeleiding toch een stuk zwaarder geweest. Ook mijn favoriete glasboer, Eduard , wil ik graag bedanken. Door jouw slappe grappen en weghalen van bergen glaswerk was het voor mij een stuk makkelijker om te werken. Verdere ondersteuning van het magazijn heeft hieraan ook bijgedragen. Ook de mannen van het Roeterseiland voetbaltoernooi: Richard , Peter , Sander , Robin en Jelle bedankt dat ik als niet–voetballer toch met jullie heb mogen spelen. De sfeer was altijd top!!

Buiten de universiteit zijn er ook genoeg mensen die ik graag wil bedanken. Als eerste ma en pa. Ook al heb ik jullie tijdens de middelbare school wel eens een slapeloze nacht bezorgd, ik denk dat jullie wel trots op mij zijn. Ik heb altijd het gevoel gehad dat jullie in mij geloofden en door de mogelijkheden die jullie mij gaven heb ik mijzelf toch goed weten te ontwikkelen. Ook al begrepen jullie niets van mijn onderzoek, jullie waren toch altijd zeer geïnteresseerd in wat ik aan het doen was. Als jullie mij ergens mee konden helpen, stonden jullie altijd voor mij klaar. Niels , ook jij bedankt voor alles. Toen ik terug kwam uit Barcelona wilde ik echt niet meer thuis wonen. Gelukkig was jouw huis net klaar en het was groot genoeg voor ons tweeën. Dat ik twee jaar bij jou kon wonen en een eigen plekkie had was echt top. Als ik weer eens geen zin had om voor mezelf te koken, kon ik altijd een bordje mee–eten bij de Molenaartjes. Mark en Amy , bedankt hiervoor. Tijdens alle bordspelletjes (scrabble, risk en rummikub) die wij samen hebben gespeeld, bleek toch wel dat ik de beste was. Nu Marley in jullie leven is gekomen, wordt jullie gezin steeds meer compleet. Romano en Michelle , ook jullie bedankt voor jullie interesse. Verder Romano , super bedankt dat jij mijn kaft hebt willen maken. Het is echt onwijs mooi geworden. Ook al onze chille sportzondagen waren altijd goede ontspanmomentjes. Michael , fijn om te zien dat alles weer goed met je gaat! Dat doet mij echt goed. Verder moet jij eens stoppen met het kijken van films zonder mij. Anders hebben wij niks meer te kijken. Ik woon nu ruim twee jaar in mijn eigen huis en het was niet zo mooi geworden dankzij jou, Koen . Super bedankt dat jij dit voor mij hebt willen doen. Ik heb echt een plekkie waar ik me thuis voel. We moeten snel maar weer eens afspreken. Verder zijn er nog: Menno , Javier , Craig , Geoffry , Gino , Jim en Mike . Jongens bedankt voor de vele pokeravondjes, paintball sessies of gewoon even chillen aan het Zwaansmeer. Bob en Irma , ook jullie wil ik bedanken. Doordat ik ben gaan kickboksen, heb ik veel discipline gekregen. Zonder jullie was ik niet zover gekomen. De prettige sfeer en de pittige trainingen gaven mij altijd energie en motivatie om weer verder te gaan. Er was niks beter dan dat ik na een training amper mijn t–shirt uit kon doen omdat al mijn spieren pijn deden. Osu!!!!!!

Also to my friends (Marta , Peter , Laura , Gonzalo , Pablo , Luca , Sean, Kader , Eva and Lorena ) from Barcelona I like to say thanks. First for the amazing time I had when I lived there (the Cool–off will never be the way it was, right Laura?) and also for the time afterwards. It is a shame that everybody is leaving Barna, but hopefully we still see each other in other parts of Europe.

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Andrea (chicatje), the last three years have been amazing and special. Although we live more than 1000 km apart, it doesn’t feel like that. It is cool that we still can see each other once a month and the best thing is that you live with me now for a while. We have been to amazing places in this time and for sure a lot more places will come. Thanks for all the support you gave me (especially those sometimes weird WhatsApp–messages) and for going picky through my thesis. Soon you will have to do the same and for you to know I will do that for you too. Te quiero, guapa!!! Also to my family (Javier , Isabel and Marta ) from Spain I like say: muchos gracias para todo. You made me feel at home right away.

Arjen

new asymmetric transformations and catalysis brem

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