Complexes in Asymmetric Synthesis The Use of N,P-Iridium ...1169503/FULLTEXT01.pdf · This thesis...

The Use of N,P-Iridium and N,P-PalladiumComplexes in Asymmetric SynthesisWangchuk Rabten

Academic dissertation for the Degree of Doctor of Philosophy in Organic Chemistry atStockholm University to be publicly defended on Wednesday 31 January 2018 at 10.00 inMagnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B.

AbstractThe work presented in this thesis concerns asymmetric catalysis using chiral N,P-ligands and iridium or palladiumtransition metals. The first part (Chapters 2 and 3) highlights the N,P-iridium catalyzed asymmetric hydrogenation of 1,4-cyclohexadienes having functionalized or unfunctionalized substituents, including allylsilane side chains. A series of N,P-iridium catalysts were synthesized and screened on a number of cyclohexadienes. The developed N,P-iridium catalystshave provided excellent chemo-, regio- and enantioselectivity for most of the products obtained. For substrates havingan allylsilane sidechain, the chiral cyclic allylsilane products were used to induce stereocontrol in a subsequent Hosomi-Sakurai reaction using TiCl4 as Lewis acid and aldehydes as electrophiles. The corresponding homoallylic alcohols wereobtained in good to excellent diastereoselectivity.

The second part (Chapter 4) describes the N,P-iridium catalyzed asymmetric hydrogenation of various vinyl fluorides.A number of tri- and tetrasubstituted vinyl fluorides were synthesized and evaluated for the asymmetric hydrogenation.The corresponding saturated chiral fluoro compounds were obtained in very high enantioselectivity (up to 99% ee). Thedefluorination, usually known to occur under the catalytic hydrogenation conditions, were not observed for the majorityof the substrates.

Finally, Chapter 5 describes the application of N,P-ligands in the asymmetric cycloisomerization of 1,6-enynes using apalladium precatalyst. The enantioselectivities for the products were found to depend both on the substrate as well as thehydrogen source. These developed catalytic reactions provide attractive methods to create multiple stereogenic centers ina molecule in relatively few steps from readily available starting materials.

Keywords: Iridium, Asymmetric Hydrogenation, Palladium, Asymmetric Cycloisomerization and Hosomi-SakuraiAllylation.

Stockholm 2018http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-150602

ISBN 978-91-7797-061-3ISBN 978-91-7797-062-0

Department of Organic Chemistry

Stockholm University, 106 91 Stockholm

TheUseofN,P-IridiumandN,P-PalladiumComplexesinAsymmetricSynthesis

WangchukRabten

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© Wangchuk Rabten, Stockholm 2018 Cover picture: By Umaporn Sratongyung ISBN: 978-91-7797-061-3 Printed in Sweden by Eprint, Stockholm 2018 Distributor: Department of Organic Chemistry, Stockholm University

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DedicatedtomylatefatherRinzinandtomymotherPemaDema

v

Abstract

Thework presented in this thesis concerns asymmetric catalysis using chiralN,P-ligandsandiridiumorpalladiumtransitionmetals.Thefirstpart(Chapters2and3)highlightstheN,P-iridiumcatalyzedasymmetrichydrogenationof1,4-cyclohexadienes having functionalized or unfunctionalized substituents,including allylsilane side chains. A series of N,P-iridium catalysts weresynthesized and screened on a number of cyclohexadienes. The developedN,P-iridium catalysts have provided excellent chemo-, regio- andenantioselectivityformostoftheproductsobtained.Forsubstrateshavinganallylsilanesidechain, thechiralcyclicallylsilaneproductswereusedto inducestereocontrol in a subsequent Hosomi-Sakurai reaction using TiCl4as Lewisacid and aldehydes as electrophiles. The corresponding homoallylic alcoholswereobtainedingoodtoexcellentdiastereoselectivity.The second part (Chapter 4) describes the N,P-iridium catalyzed asymmetrichydrogenationofvariousvinylfluorides.Anumberoftri-andtetrasubstitutedvinyl fluorides were synthesized and evaluated for the asymmetrichydrogenation. The corresponding saturated chiral fluoro compounds wereobtained in very high enantioselectivity (up to 99% ee). The defluorination,usuallyknowntooccurunderthecatalytichydrogenationconditions,werenotobservedforthemajorityofthesubstrates.Finally, Chapter 5 describes the application ofN,P-ligands in the asymmetriccycloisomerization of 1,6-enynes using a palladium precatalyst. Theenantioselectivities for the products were found to depend both on thesubstrateaswellasthehydrogensource.Thesedevelopedcatalyticreactionsprovide attractive methods to create multiple stereogenic centers in amoleculeinrelativelyfewstepsfromreadilyavailablestartingmaterials.

vi

Listofpublications

This thesis is based entirely on the following papers, which will bereferredtoby theirRomannumerals I-IV.Reprintsof thearticlesweremade with the kind permission of the publishers. The author hasclarifiedcontributionforeachpublicationinAppendixA.

I. Enantio-andRegioselectiveIr-CatalyzedHydrogenationofDi-andTrisubstitutedCycloalkenesByronK.Peters,†JianguoLiu,†CristianaMargarita,†WangchukRabten,†SutthichatKerdphon,†AlexanderOrebom,ThomasMorsch,andPherG.Andersson*J.Am.Chem.Soc.,2016,138,11930-11935.

II. Ir-Catalyzed Asymmetric and Regioselective Hydrogenation ofCyclicAllylsilanesandGenerationofQuaternaryStereocentersviatheHosomi-SakuraiAllylationWangchuk Rabten, CristianaMargarita, Lars Eriksson and Pher G.Andersson*Chemistry–AEuropeanJournal,DOI:10.1002/chem.201704684. InpressHOTPAPER

III. N,P-Iridium Catalyzed Asymmetric Hydrogenation of VinylFluoridesWangchukRabten†,SudiptaPonra†,SutthichatKerdphon,HaiboWuandPherG.Andersson*Manuscriptinpreparation

IV. Thiazole, Imidazole and Oxazoline Based N,P-Ligands forPalladium-CatalyzedCycloisomerizationof1,6EnynesXuQuan,JianguoLiu,WangchukRabten,SimoneDiomedi,ThishanaSingh,andPherG.Andersson*Eur.J.Org.Chem.,2016,3427-3433

†Authorscontributedequallytothiswork.

Publicationnotincludedinthisthesis:

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I. Catalytic Water Oxidation by a Molecular Ruthenium Complex:

UnexpectedGenerationofaSingle-SiteWaterOxidationCatalystWangchuk Rabten, Markus D. Kärkäs,* Torbjörn Åkermark, HongChen, Rong-Zhen Liao, Fredrik Tinnis, Junliang Sun, Per E. M.Siegbahn,PherG.Andersson,*andBjörnÅkermark*Inorg.Chem.,2015,54,4611-4620

II. ARutheniumWaterOxidationCatalystBasedonCarboxamideLigandWangchukRabten,TorbjörnÅkermark,MarkusD.Kärkäs*,HongChen,JunliangSun,PherG.Andersson*,andBjörnÅkermark*DaltonTrans.,2016,45,3272-3276

III. Catalyst–Solvent Interactions in a Dinuclear Ru-based WaterOxidationCatalystAndreyShatskiy,ReinerLomoth,AhmedF.Abdel-Magied,WangchukRabten,TanjaM.Laine,HongChen,JunliangSun,PherG.Andersson,MarkusD.Kärkäs,*EricV.Johnston*andBjörnÅkermark*DaltonTrans.,2016,45,19024-19033

IV. An Enantioselective Approach to the Preparation of ChiralSulfonesbyIr-CatalyzedAsymmetricHydrogenationByron K. Peters, Taigang Zhou, Janjira Rujirawanich, Alban Cadu,ThishanaSingh,WangchukRabten, SutthichatKerdphon,andPherG.Andersson*J.Am.Chem.Soc.,2014,136,16557-16562

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Contents

Abstract v

Listofpublications vi

Contents viii

Abbreviations x

1 Introduction 11.1 Chirality...............................................................................................................11.2 Chiralresolutionofracemicmixtures....................................................21.3 Asymmetricsynthesis....................................................................................3

1.3.1 Chiralpoolmethod........................................................................................31.3.2 Chiralauxiliarymethod..............................................................................41.3.3 Asymmetriccatalysis...................................................................................5

1.4 Aimsofthisthesis..........................................................................................11

2 Enantio- and Regioselective Hydrogenation of Di- andTrisubstituted1,4-Cyclohexadienes(PaperI) 122.1 Introduction.....................................................................................................122.2 Resultsanddiscussion................................................................................13

2.2.1 Substratessynthesis..................................................................................132.2.2 Catalystscreening.......................................................................................142.2.3 Regioselectivity............................................................................................20

2.3 Conclusion........................................................................................................21

3 Ir-Catalyzed Asymmetric and Regioselective Hydrogenation ofCyclic Allylsilanes. Generation of Quaternary Stereocenters via theHosomi-SakuraiAllylation(PaperII) 223.1 Introduction.....................................................................................................223.2 Hosomi-Sakuraireactionusingcyclicallylsilane.............................22

3.2.1 MechanismoftheHosomi-Sakuraiallylation.................................243.3 Resultsanddiscussion................................................................................25

3.3.1 Synthesisofchiralcyclicallylsilane....................................................253.3.2 Optimizationoftheasymmetricmono-hydrogenation.............26

ix

3.3.3 DiastereoselectiveHosomi-Sakuraiallylation...............................293.4 Conclusion........................................................................................................35

4 N,P-Iridium Catalyzed Asymmetric Hydrogenation ofVinylfluorides 364.1 Introduction.....................................................................................................364.2 Substratesynthesis.......................................................................................384.3 Resultsanddiscussion................................................................................394.4 Determinationofabsoluteconfiguration............................................444.5 Conclusion........................................................................................................46

5 Palladium-CatalyzedCycloisomerizationof1,6-Enynes(PaperIII) 475.1 Introduction.....................................................................................................47

5.1.1 Palladiumcatalyzedcycloisomerization..........................................475.1.2 Mechanismofpalladiumcatalyzedcycloisomerization............49

5.2 Resultsanddiscussion................................................................................515.2.1 Substratescope............................................................................................525.2.2 Investigationofthehydrogensource................................................54

5.3 Enantioselectivityandabsoluteconfiguration.................................555.4 Conclusion........................................................................................................56

6 PopulärvetenskapligSammanfattningpåSvenska 57

AppendixA:Contributionlist 58

Acknowledgements 59

References 61

x

Abbreviations

* StereogeniccentreAc AcetylAr AromaticAx ChiralauxiliaryBArF- Tetrakis[3,5-bis(trifluoromethyl)phenyl]borateCat. CatalystCOD 1,5-CyclooctadieneConv. ConversionCy Cyclohexyldba DibenzylideneacetoneDIBAL DiisobutylaluminiumhydrideDMF DimethylformamideDMSO DimethylsulfoxideDNA DeoxyribonucleicacidDTBB 4,4’-Di-tert-butylbiphenylDCA Dichloroaceticaciddr Diastereomericratio ee EnantiomericexcessE Electrophileequiv EquivalentEt EthylEWG ElectronwithdrawinggroupEDG ElectrondonatinggroupGC GasChromatographyh Hour(s)Het HeterocycleHPLC HighPerformanceLiquidChromatographyinv InvertIPA Isopropylalcoholi-Pr Isopropyli-Bu Isobutyl

xi

K RateconstantL LigandLA LewisacidM MolarMe MethylMS Molecularsievem MetaNFSI N-FluorobenzenesulfonimideNMR NuclearMagneticResonancen-Bu NormalButyln-BuLi n-Butyllithiumn-Hex n-Hexylo Orthoo.n. OvernightOct Octylo-Tol ortho-Tolylp ParaPh PhenylPNB p-NitrobenzylPVP Poly(4-vinylpyridine)PHOX Phosphine-OxazolinePy PyridinePF6- Hexafluorophosphater.t. Roomtemperaturerac RacemicSFC SupercriticalFluidChromatographyt-BDMS tert-Butyldimethylsilylt-Bu tert-Butylt-BuOH tert-ButanolTFA TrifluoroaceticacidTHF TetrahydrofuranTMS TrimethylsilylTs TosylTS TransitionstateTBAF Tetra-n-butylammoniumfluoride

1

1 Introduction

1.1 Chirality

The term “chirality”was derived from theGreekword “χειρ” (kheir)[1],whichmeanshand, and it therefore indicates thehandednessof anobject.Our leftandrighthandsareindeedasimpleexampleofchirality,beingmirrorimagestooneanother,butnotsuperimposable.Likewise,moleculesaresaidtobechiralifthecompoundpossessesstereogenicelements,likestereogeniccentersthatarisewhendifferent substituents on an atomwith the same connectivity butarearrangeddifferently in three-dimensionalspace (Figure1.1).Thepresenceof stereogenic centers gives rise to different types of stereoisomers, namelyenantiomersanddiastereoisomers.

Figure1.1Simplerepresentationofchiralmolecule.

Enantiomers are a pair of stereoisomeric compounds, which are non-superimposablemirrorimagesofoneanother.Enantiomersarealsoreferredtoasopticalisomers,duetotheirabilitytorotatetheplaneofpolarizedlightandthey essentially display identical physicochemical properties, for examplemelting points, solubility and it is fairly difficult to separate them byconventionalmethods.[2]Ontheotherhand,diastereoisomericcompoundsarenot mirror images of one another and have significantly different physicalproperties,thustheycanbeseparatephysically.At the molecular level, biological systems are made of macromolecules likeproteins,polynucleotides (DNA),andglycolipids,which in turnaremade from

!

⍺

"##

"

⍺

!

Mirror

#"

⍺

! !

⍺

"#

Cannot besuperimposed

2

chiralbuildingblocks(L-aminoacidsandD-carbohydrates).Inthedevelopmentof drugs, in the pharmaceutical industry, the importance and need forevaluation of individual enantiomers have become evenmore crucial. This isbecause their interaction with chiral receptors such as enzyme and proteinsexhibitdifferentpharmacologicalactivitiesandpharmacokineticsproperties.[3]Oneoftheinfamousexamplesthatlaterleadtodevelopmentofsingleisomerdrugs is the thalidomide tragedy (Figure 1.2a).[4] The (R)-thalidomide hassedative properties, while the (S)-thalidomide causes severe birth defects.However, the tragedy in the early 1960swould not have been avoided if thedrughadbeenusedasasingleisomersincethedrugracemizesduringuptakein the body.[5] In the same way, the two enantiomers of ethambutol actdifferently (Figure 1.2b). (S,S)-(+)-ethambutol is used for the treatment oftuberculosis, but on other hand (R,R)-(-)-ethambutol causes blindness.[6] As aresultofthedifferentpharmacologicalactivityshownbyoppositeenantiomers,theuseofsingleenantiomericdrugshasincreaseddrastically.Thus,developingstereoselectivemethodsthatprepareexclusivelyonesingleenantiomerwouldbe themethodof choice. Thereare twowell-knownmethodologies toobtainsingleenantiomers;chiralresolutionandasymmetricsynthesis.

Figure1.2Examplesofdrugswithdifferentpharmacologicalactivities.

1.2 Chiralresolutionofracemicmixtures

Chiral resolution is the process for producing optically pure chiral moleculesfromracemicmixturesbycreatingandiastereomericenvironment.[7]Basedonthe separation method, chiral resolution can be divided into numerouscategories.Resolutionbydiastereomerformationconsistsof thetreatmentofthe racemic mixture with an optically active reagent to form diastereomericsalts. Due to their significant difference in physical properties, those cansometimesbeseparatedbyrecrystallizationorbycolumnchromatography.Kinetic resolution relies on the different rate of the reaction of twoenantiomers with a chiral reagent; the enantiomer that reacts faster will be

NNH

O

OO

O

NNH

O

OO

O

(R)-thalidomide (S)-thalidomide

HN

NH

OH

HO

(S,S)-(+)-ethambutol

HN

NH

OH

HO

(R,R)-(-)-ethambutol

a b

3

convertedtotheproductwhiletheunreactive(slower)enantiomerwillbeleftin the solution. To achieve kinetic resolution, the difference in reaction ratebetween the two enantiomersmust be significantly large. A racemicmixturecan also be separated by chiral chromatography. However these methodsmentioned above cannever be able to achieve amaximumyield higher than50%.Analternative tokinetic resolutionwouldbedynamickinetic resolution;the process that combines racemization and resolution (Figure 1.3). Theunreactive or mismatched enantiomer in the racemic mixture is rapidlyconverted to the faster reacting enantiomer by a catalyst and sequentiallyconsumed in the conversion to product. The process continues until bothenantiomersarecompletelyconsumed,thusintheoryitcanbeabletodeliver100%yield.

Figure1.3Principlesofdynamickineticresolution.

1.3 Asymmetricsynthesis

Asymmetricsynthesis is thepreparationofopticallyactivemoleculesbychiralinductiononanachiralsubstratethroughchiraltransferfrompre-existingchiralmolecules.Itcanbedividedintoseveralcategories:

• Chiralpoolmethod• Chiralauxiliarymethod• Asymmetriccatalysis

1.3.1 Chiralpoolmethod

Thechiralpoolmethodusesnaturallyoccurringchiralmaterialssuchasaminoacids, carbohydrates and terpenes to make an enantiomerically purecompounds.Forexample,thedrugPrimaxinwhichisusedforthetreatmentofbacterial infections was synthesized using aspartic acid as a chiral startingmaterial(Figure1.4).[8]Thenaturallyoccurringchiralmoleculescanprovideanoptical purity up to 100%, however their scarcity, availability in only one

SS

PR

PSSlow

kB

Fast

kA

Racemizationkinv

kinv-1 SR, SS : Substrate enantiomersPR, PS : Product enantiomers

SR

X

4

enantiomeric form and tedious extraction from nature makes them moredifficulttoaccess.

Figure1.4SyntheticrouteforthedrugPrimaxinstartingfromasparticacid.

1.3.2 Chiralauxiliarymethod

Chiralauxiliariesareopticallypurecompoundsthatcanbetemporarilyinstalledon the substrate to direct the stereochemical outcome of a reaction (Figure1.5).[9]Thechiralauxiliarycancomeeitherfromnaturalsource(chiralpool)orsynthetic.Normallythesubstratesrequirescertainfunctionalgroupsinordertoselectively attach to the auxiliary.[10] This unit is installed on the substratesbefore the stereoselective reaction and then removed later in the synthesis.The use of stoichiometric chiral auxiliary adds two additional steps, additionandremoval,whichmakethismethodlessefficientforthechemicalsynthesisofenantiomericallypurematerials.

Figure1.5Diastereoselectivesynthesiswithchiralauxiliaries.

HO2CNH2

CO2H

NO

CO2H

H NO

CO2H

H

OH

NO

OAc

H

OH

NO

OAc

H

Ot-BDMS OSiMe3

N2

CO2PNB1. Lewis acid2. H+

TolueneN

O H

OH

O

N2

CO2PNB+

Rh(Oct)2MeOAc

NO

OH

O

CO2PNB

NO

OH

S

CO2H

H H HNNH

L-aspartic acid

Imipenem (Primaxin®)

O

OHR Introduction

of the auxiliary

O

AxR Diastereo-

selective reaction

*O

AxR

E

*O

OHR

EHydrolysis

Ax = Chiral auxiliary Auxiliary recycle

Ax H

5

1.3.3 Asymmetriccatalysis

In asymmetric catalysis chiral compounds are generated through asymmetricinductionusingachiralcatalyst.Acatalystisaspeciesthatenhancestherateofchemical reaction by lowering the activation energy.[11] In the process thecatalyst is neither consumed nor destroyed, therefore sub-stoichiometricamounts(frequentlylessthan1mol%)issufficienttocatalyzethebulkreaction.Theuseofacatalystoftenfacilitatestheisolationofaproduct,sincetherearenotmanyunwantedbyproducts tobe removedat theendof a reaction; it isthus an atom economical, environmental friendly and cost effective strategy.Oneofthemostfrequentlyusedreactionsinasymmetriccatalysisinvolvestheasymmetricreductionofprochiralcarbon(C=O,C=C,C=N).(Figure1.6).[12]

Figure1.6Genericexamplesofcatalyticasymmetricsynthesis.

1.3.3.1 Asymmetrichydrogenationofolefins

The asymmetric hydrogenation of an alkene to an alkane by usinghomogeneous transitionmetal catalysts has been one of themost successfulandwell-studiedmethodologies inacademiaaswellas industries,[13]owing toits straightforward strategy to access enantiomerically pure moleculesemploying a relatively inexpensive and environmentally benign reductant(hydrogen). More importantly, the successes in academic research onasymmetric hydrogenation was often complemented with industrialapplications,whichinturndrawsmoreinterestinthisfield.[14]Thehomogeneouscatalytichydrogenationofsimpleolefinswasfirstdisclosedin1965byWilkinsonandco-workersusingtherhodium(Rh(PPh3)3Cl)catalystinorganic solvent.[15] This laid the foundation for the development of chiralanalogs for an asymmetric induction. In 1968 the groups of Knowles[16] andHorner[17] reported independently on the asymmetric hydrogenation of an

R′O

R

R′

R

R′

R

R′

R

R′N

R

R′

R

H2

Catalyst

H

OH

R′′′

R′′

R′′′

R′′H2

Catalyst

R′′NH

HR′′

H2

Catalyst

HH reduction of alkenes

reduction of prochiral ketones

reduction of prochiral imine

6

olefin using chiral phosphine ligands in presence of the Rh metal precursor(Figure1.7).

Figure 1.7 Earlier work by the group of Knowles (a) and Horner (b) on asymmetrichydrogenationofolefins.

However,thelevelofasymmetric inductionwas low,affordingonly15%eeofthe hydrogenated product. Thereafter, a series of chiral monodentatephosphineligands[18](PAMP,CAMP)weredevelopedwhichleadtoanincreasedlevelofenantioselectivity,resultingin88%eeintheasymmetrichydrogenationofα-acetamidocinnamicacid.Despitethesuccesswithmonodentatephosphineligands, the focuswas slowly diverted towards the development of bidentatephosphine ligands. The chiral bidentate phosphine ligands DIOP[19] DIPAMP[20]BINAP[21]weresuccessfullydevelopedandappliedinasymmetrichydrogenationofα-acetamidocinnamicacidusingaRhpre-catalyst(Figure1.8).Highcatalyticreactivityandhighenantioselectivitywereobserved.TheRu-BINAPcatalystwasalso found useful for asymmetric hydrogenation of unsaturated carboxylicacid.[3a, 21] Almost all the reported asymmetric hydrogenations were mainlybased on Rh and Ru catalyst and also limited to substrates containingfunctionalitiesthatcouldformachelatewiththemetalcatalyst.

HOOCCOOH

RhCl3L3*

HOOCCOOHH2

OMePh

[Rh-(1,5 hexadiene)Cl]2, L

H2*OMePh

(a) Knowles and Sabacky

(b) Horner and co-workers

P*i-PrL =

P*n-Pr

L =

up to 8% ee

up to 15% ee

7

Figure 1.8 The chiralmonoandbidentatephosphine ligands and their comparison inasymmetrichydrogenationofα-acetamidocinnamicacid.

Thehydrogenationofunfunctionalizedolefinswasnotamainfocusyet,duetotheirpoorreactivityandenantioselectivity.In1977Crabtreeandco-workers[22]reported the iridium [Ir(COD)(PCy3)(Py)]+PF6- (Figure 1.9b) catalyzedhydrogenation of unfunctionalized olefins. They noticed that a smallmodification of theOsborn iridium complex (Figure 1.9a),[23] by replacing thetriphenylphosphine groups with pyridine and a tricyclohexylphosphine group,andconductingthereaction inpoorlyorweaklycoordinatingsolvents(CH2Cl2,CHCl3orchlorobenzene)increasedthecatalyticefficacy.Itwasbyfarthemostactivehomogeneoushydrogenationcatalystatthattime.In1997Pfaltzandco-workersintroducedtheasymmetricversionoftheiridiumcatalystbyreplacingCrabtree’spyridineandphosphine ligandswith thechiralbidentate N,P-ligand (PHOX) (Figure 1.9c). This ligand was then used forasymmetrichydrogenationoftheiminesandunfunctionalizedolefins.[24]Later,theyalsoobserved that thebulkyandweakly coordinatingBArF-counteranionincreased the reactivity and stability of the catalyst. Since then, many chiralN,P-ligands has been reported and successfully applied in the asymmetrichydrogenationofolefins.[25]

OH

O

NHAc

* OH

O

NHAc

Rh-phosphine catalyst,H2

OMeP

Ph

OMeP

Cy

PAMP CAMP

PPh2

PPh2O

O

DIOP

PMeO P OMePPh2PPh2

DIPAMP BINAP

50-60% ee 80-88% ee 72% ee 95% ee 84% ee

8

Figure1.9Developmentofnon-functionalizedolefinshydrogenationcatalysts.

The mechanistic understanding of the N,P-iridium catalyzed asymmetrichydrogenationofolefinshasbeen fully investigatedby various groups. Itwasproposedtooccureithervia IrI/IrIII[26]or IrIII/IrV[27]catalyticcycles(Figure1.10).Whilebothcatalyticcyclesproceedthroughintermediate3,whichisgeneratedupon the addition of hydrogen to the iridium metal precursor 1, the onlydifferenceliesinthenumberofhydridesboundtothemetalinthekeyreactiveintermediates 4 and 7. From the recent low temperature NMR experimentalstudiesby thePfaltz group,[28] itwaspossible to identify and characterize theiridium dihydride alkene complexe 10. They described the dihydride as acatalyticallycompetent intermediate,and it representtherestingstageof thecatalytic cycle. Addition of onemolecule of hydrogen is required in order toproceed in the catalytic cycle. This experiment demonstrates that the IrIII/IrVcatalyticcyclesproposedbytheAnderssonandBurgessgroupsismostlikelytooperate. The olefin undergoes migratory insertion of hydride trans to thedihydrogen together with oxidative addition of the dihydrogen to giveintermediate 5, which upon reductive elimination gives 6 and finallydisplacementofthealkaneproductwithtwomoleculesofsolventregeneratesthecatalyst.

IrIPPh3Ph3P

Cl

IrIPCy3Py PF6

O

N

P IrPh

Ph BArF

(a) Osborn’s catalyst (b) Crabtree’s catalyst

(c) Pfaltz’s catalyst

B

CF3F3C

CF3

CF3

CF3F3C

F3C

F3CNa

NaBArF

9

Figure 1.10 Proposed Ir(I)/Ir(III) and Ir(III)/Ir(V) catalytic pathways for the iridiumcatalyzedhydrogenation.

Based on the mechanistic studies carried out by the Andersson group,[29] aselectivitymodel for theN,P-iridium catalyzed asymmetric hydrogenation hasbeen developed that can predict the absolute configuration of thehydrogenated products. The model basically describes the steric hindranceimposedby theN,P ligandwhere theolefincoordinate iridium.Dependingonthe level of steric bulk of the iridium catalyst, this area is divided into fourquadrants (i, ii, iii and iv) (Figure 1.11). Thequadrant that is occupiedby thephenylringfromtheligandisassignedasthemosthinderedquadrant(IforR-cat.and iii forS-cat.).Oneofthephenylgroupsonthephosphorousoccupiespartially the other quadrant,which is assigned as semi-hindered quadrant (ivforR-cat. and ii for S-cat.). The other two quadrants are left relatively open.Placing the olefin vertically (energetically favored) and trans to thephosphorousatominawaythatthesmallestsubstituent(H)occupiesthemosthinderedquadrant (I forR-cat. and iii forS-cat.) toavoid steric repulsionand

IrI

PNIrIII

H

PNHH2

2H2 + 2S

IrIII

HS

PNH

S

1 2 3

IrV

HH

PNH

H

IrIII

HS

PNH

S

IrIII

H

PNH

IrIII

HH

PNH

H

IrIII

H

PNH

S

IrIII

H

PNH

S

IrI

SS

PN 2S

HHH2

HH

SH2

2SS

H H

IrIII/IrVIrI/IrIII

S

3

4

5

6

7

8

9

IrIII

H

PNH

10

10

results in a favored configuration. Thus the addition of the hydride from thefaceofiridiummetaldeterminestheabsoluteconfiguration.

Figure 1.11Use of the selectivitymodel to predict the absolute configuration of thehydrogenatedproduct.

PN

i ii

iii iv

IrN

N P

i ii

iii iv

Ir

N

N

N

PIr

PN

N

i ii

iii iv

i ii

iii iv

Sterically favored

Sterically unfavored

Ir

(R)

(S)

N P

i ii

iii iv

Ir

N

Sterically favored

N

N

P

N

N

P

H

H

H

H

H(R)

H

(S)

11

1.4 Aimsofthisthesis

Theaimsoftheworkpresentedinthisthesisfocusesonthedevelopmentandfine-tuning of the N,P-ligands structure to enhance catalytic reactivity andenantioselectivity. The application of the N,P-iridium catalyzed asymmetrichydrogenationof variousolefins including substrates containing acid-sensitivefunctionalgroups,aswellasregioselectivemono-hydrogenationsarediscussed.The Ir-catalyzed asymmetric hydrogenation of cyclic molecules such ascyclohexanes to introduce multiple stereocenters is a difficult task and alsointriguingas it is found inmanynaturalcompounds. Theregioselectivemonohydrogenationofadieneisanotherchallengingreaction,asitrequiresasystemthat selectively can hydrogenate one olefin over another. Thus objectives ofthis thesis includemultiple aspects of (chemo-, regio- and enantio-) selectivehydrogenation as well using this stereocontrol for further chemicaltransformations. Finally, the application of the N,P-ligands in the palladiumcatalyzedcycloisomerizationofenynesarealsoinvestigated.

12

2 Enantio-andRegioselectiveHydrogenationofDi-andTrisubstituted1,4Cyclohexadienes(PaperI)

2.1 Introduction

Cyclohexane rings are frequently found in nature[30] and are often used asbuildingblocksforthetotalsynthesisofmanynaturalproducts.[31]Themajorityofthesenaturalproductscontainsstereogeniccentersonthecyclohexanering,forexampleβ-Santonin,[31c]Occidentalol[31b]and(+)-Lycorine (Figure2.1).[32]Thedevelopmentofstereoselectivesynthesesofenantioenrichedcyclohexaneshasthereforebeenanimportantandlongstandinggoalinorganicsynthesis.

Figure2.1Chiralcyclohexanesinnature.

Althoughtherearemanysuccessfulmethodsreportedintheliteratureforthepreparation of cyclohexanes bearing chiral centers,[33] the majority of thesereactions uses chiral reagents or chiral auxiliary in stoichiometric. Thecombination of the Birch reduction and N,P-iridium catalyzed asymmetrichydrogenation provides a new and complementary approach to access chiralcyclohexanesundermild reaction conditions and lowcatalyst loading (0.5-1.0mol%). In 2011, the Andersson group first reported the asymmetrichydrogenationof substituted1,4-cyclohexadienes.[34] In theworkdescribed inthischapter,thefocushasbeenorientedtowardsthedevelopmentofnewandrobustcatalystsforthehydrogenationofsubstratescontainingawiderangeoffunctionalitiesincludingheterocycles(Figure2.2).

OO

OH

⍺-Santonin

OO

OH

!-Santonin

HOH

H

Occidentalol

O

O N

OHHO

H

H

(+)-Lycorine

13

Figure2.2Classesofsubstratesinvestigatedforasymmetrichydrogenation.

2.2 Resultsanddiscussion

2.2.1 Substratesynthesis

The carbocyclic substrates for asymmetric hydrogenation can easily besynthesized from the well known Birch reduction (Scheme 2.1a)[35] of thecorresponding aromatic startingmaterials, using alkalimetals such as sodiumand lithium in presence of liquid ammonia and a proton source (for exampleEtOH, MeOH, and t-BuOH). Co-solvents like THF and diethyl ether are oftenusedtofacilitatethesolubilityofthestartingmaterials.Ingeneral,thereactionissimpleandusuallytheendpointofthesereductionscanbemonitoredbythediscolorationofthedeepbluecolorthatisgeneratedupontheadditionofthealkalimetaltoliquidammonia.IncertaincaseswherethesubstrateisnotsuitableforBirchreduction,duetothe presence of functional groups that can be reduced (such as phenyl,thiophene)thecyclohexadienesubstratescanbepreparedusingtheDiels-Alderreaction(Scheme2.1b).[36]

Scheme2.1Synthesisofsubstrates.

R R

RR

EWG

HetR

Class 1 Class 2 Class 3

Minimally functionalized Functionalized Heterocycle fused

EDG

R1 R2 R1 R2Li/Na

NH3, EtOH R1 R2 R1 R2

+

Birch Diels-Alder

(a) (b)

14

2.2.2 Catalystscreening

Figure2.3Catalystsusedinthisstudy.

Aprofoundeffort has beendedicated to thedevelopmentof awide arrayofN,P-iridium complexes. Tuning the properties of the iridiummetal centers byalteringtheligandstructureandtheelectronicproperties isawell-establishedmethodology to reach themaximum reactivity andattainhigh chemo-, regio-andstereoselectivity.Frompreviousstudiesitwasknownthattheacidityofthehydrogenationcatalystsoftencauseproblemsandmightleadtotheformationofbyproducts.AseriesofN,P-ligandscontainingthebasicimidazolemotifhavebeen successfully synthesized. The reactivity and enantioselectivity of thesecomplexeshavebeenstudiedonthreeselectedmodelssubstrates:monocyclicdihydrobenzene 11a and bicyclic tetrahydronaphthalenes 12a and 13a. TheresultsforthecatalystscreeningareshowninTable2.1.Fullconversiontothedesiredhydrogenatedproductwereobtainedinalmostallcasesusing0.5mol%catalystat50barH2in17h.Althoughthereactivityofthecatalystswerenotaffectedbythesubstitutiononthe imidazole ligands, a strong influence on the enantioselectivity wereobserved.Themethyl substituenton4position (cat. III,entry3)gavea slightimprovement in selectivity compared to cat. II. Changing the position of themethylgroupfrom4to2(cat.IV,entry4),resultedindecreasedselectivityfor

S

N

P Ir

PhPh

N

N

P Ir

PhPh

N

N

P Ir

PhPh

N

N

P Ir

PhPh

N

N

P Ir

PhPh

MeO

OMeN

N

P Ir

PhPh

N

N

P Ir

PhPh

N

N

P Ir

PhPh

IVI II III

V VII VIIIVI

OMe F

O

O

N

P Ir

PhPh

N

S

N

P Ir

PhPh

IX X

B

F3C

F3C

F3C CF3

CF3

CF3

CF3F3C

NaBArF =

BArF BArF

BArF BArF BArF

BArF

BArF

BArFBArFBArF

15

11a, however higher enantioselectivity were observed for the bicyclicsubstrates12a and13a compared to cat. II and cat. III. Replacing themethylsubstituent on position 4 to methoxy (cat. V) or fluoride (cat. VI) groupsresultedin lowerenantioselectivity.Excellentenantioselectivitywereobtainedwithcatalystsbearingtwomethyl (cat.VII,entry7)ortwomethoxy(cat.VIII,entry8)substituentsonpositions2and4.

Table 2.1 Evaluation of catalyst in the asymmetric hydrogenation of unsaturatedcarbocycles.a-c

aReactionconditions:0.25mmolofsubstrate,0.5mol%catalyst,2mLofCH2Cl2,50barof H2, 17 h, r.t. bAll examples are hydrogenated to full conversion whereenantioselectivityisreported,whichwasdeterminedby1HNMRspectroscopy.Nosideproducts were detected. cDetermined by chiral HPLC or GC analyses.dOnly startingmaterialwasdetectedbesidetheproduct.

A series ofminimally functionalized cyclohexadienes (class 1)were evaluatedfor the asymmetric hydrogenation (Table 2.2). The substrates bearing alkylgroupswerehydrogenatedwithcatalystVIIaffordinggoodtoexcellentee'supto99%(entries1-4and14-15).

R3

R2R1

R3

R2R10.5 mol% catalyst

50 bar H2, CH2Cl217 h, r.t.

Ph

Me

Me * Me * i-Bu *

Entry

11a-13a 11b-13b

11b 12b 13b

Conv. ee (%) Conv. ee (%) Conv. ee (%)Catalyst

1

2

3

4

5

6

7

8

I

II

III

IV

V

VI

VII

VIII

99 92 99 87 99 92

99 79 99 65 99 65

99 81 99 62 99 78

99 67 99 81 99 88

99 65 99 43 99 59

99 35 99 17 99 26

99 93 99 86 99 84

59d 94 99 94 99 92

16

Table2.2Asymmetrichydrogenationofminimallyfunctionalizedcyclohexadienes.a

aReactionconditions:0.125mmolofsubstrate,0.5mol%catalyst,1mLofCH2Cl2,50barofH2,17h,r.t.

bPredictedabsolutestereochemistryforthemajorproduct(>90%transselectivity observedwhere applicable, unless otherwise stated). cIsolated yield unless

99e 99

Entry Substrate Productb Catalyst Yield (%)c ee (%)d

R3

R2R1

R3

R2R10.5 mol% catalyst


14a-34a 14b-34b

R1 R2 R1 R2

14a: R1= Me, R2 = Me 14b1

15a: R1= Et, R2 = Et 99e,f 9415b2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

16a: R1= i-Pr, R2 = Et

17a: R1= i-Pr, R2 = i-Pr

18a: R1= Me, R2 = Ph

19a: R1= Me, R2 = Ph-4-Me

20a: R1= Me, R2 = Ph-4-CF3

21a: R1= OMe, R2 = Me

22a: R1= OMe, R2 = i-Pr

23a: R1= i-PrO, R2 = Me

24a: R1= OMe, R2 = i-Bu

16b

17b

18b

19b

20b

21b

22b

23b

24b

99e,f

76e

91

81

99e

99e,f

99e

71e

96

99

99

99

99

99

99

98

9968

PentylMeO PentylMeO81 98I26a 26b

25a: R1= OMe, R2 = OMe 25b VII 99e 99

OMeMe

Me

R1 R2

R3

OMeMe

Me

R1 R2

R3

99e 99

99e 94

99e 98

99e 92

99e 98

31b31a

27a: R1, R2 , R3 = Me 27b

28a: R1= Me, R2, R3 = Et

29a: R1= Me, R2 = OMe R3 = i-Pr

30a: R1= i-Pr, R2 = OMe R3 = Me

28b

29b

30b VII

VII

VII

VII

MeO OMe

OMe

MeO

MeO OMe

OMe

MeO82 98

98 99

72 99

32a 32b

33b33a

34a 34b

I

VII

VII

I

VII

VII

VII

VII

VII

VII

VII

VII

VII

VII

VII

17

otherwise specified. dDetermined by HPLC or GC analyses using a chiral stationaryphase.eConversiondeterminedby1HNMRspectroscopy.fSelectivitytotrans<90%.

Employing substrates containingphenyl,p-tol andp-CF3-tol didnot affect thereaction and catalyst VII was still the best catalyst resulting in excellentenantioselectivity (99% ee, entries 5-7). The acid labile methyl ether groupswere also well tolerated by this catalytic system, once again catalyst VIIperformedwellandprovidedee’sup to99%(entries,8-12and16-17). In fewinstances,thecatalystcontainingathiazole(cat.I)motifprovedtobeeffective(entries13,18and20).Forbicyclicsubstrates32aand34aonceagaincatalystVIIperformedwell, furnishinghighenantioselectivityupto99%ee (entries19and21).

Table2.3Asymmetrichydrogenationofremotelyfunctionalizedcyclohexadienes.a

aReactionconditions:0.125mmolofsubstrate,0.5mol%catalyst,1mLofCH2Cl2,50barof H2, 17 h, r.t.

bPredicted absolute stereochemistry for the major product (>90%selectivity trans observed where applicable, unless otherwise stated). cIsolated yieldunless otherwise specified. dDetermined by HPLC or GC analyses using a chiralstationaryphase.eSelectivitytotrans<90%.

MeOH

MeOTBDMS

Me

O

OMe

Entry Substrate

1

2

3

Productb Catalyst Yield (%)c ee (%)d

86e 99

84 99

87e 99

MeOH

MeOTBDMS

Me OTBDMS Me OTBDMS

4 97e 92

Me

O

OMe

MeO

OMe

O Me MeO

OMe

O Me

79e 975

35a 35b

36a 36b

37a 37b

38a 38b

39a 39b

R2R1 * R2*R10.5 mol% catalyst


VII

VII

VII

VII

IX

35a-39a (trans) 35b-39b

18

Cyclohexadienes having functional tethers groups such as OH, OTBDMS, andCOOMeconnectedbyone,twoorthreecarbonsawayfromtheringwerealsoevaluated (Table2.3).Substrateswith the functionalgroup (OH,OTBDMSandphenyl ether) two or three carbons away from the ring were effectivelyhydrogenated with catalyst VII affording enantioselectivity up to 99% ee(entries1-3and5).Whenthefunctionalgroup(COOMe)wasonecarbonawayfromthering,catalystIXperformedwell(92%ee,entry4).

Table2.4Asymmetrichydrogenationofcyclicolefinswithring-bondedfunctionality.a


bPredictedabsolutestereochemistryforthemajorproduct(>90%transobservedwhere applicable, unless otherwise stated). cIsolated yield unless otherwisespecified. dDeterminedbyHPLCorGCanalysesusinga chiral stationaryphase. e>95%trans-dimethyl product. fFor both cis-fused diastereomers (1:1). gConversiondeterminedby1HNMRspectroscopy.

Substrates bearing functional groups attached directly to the cyclohexadienering (class 2) were also evaluated (Table 2.4). Having acid moieties directly

Entry Substrate

1

4

3


99g 97

91e 99

98f 99

2 98e 99

COOMe

COOMe

Me

COOHMeMe

O

Me

COOH

MeMe

COOH

MeMe

COOMe

COOMe

Me

O

Me

COOHMeMe

O

Me

O

Me

40a 40b

41a 41b

rac-42a

42b

42c

+ +

43a 43b

I

X

VII

VII

R3

R2

R3

R20.5 mol% catalyst


40a-43a 40b-43b

R1 R1

EWG EWG

19

bondedtotheringresultedinhydrogenationswithexcellentenantioselectivityand high yields, 91% and 98% respectively (entries 1 and 2), but in this casecatalystsIandXturnedouttobethebest.Hexahydronaphthalenone42awasalso hydrogenated to the desired product in high selectivity (99% ee) withcatalystVII.Thepresenceoftwoestergroupsontheringdidnotinfluencethereactivity and selectivity and provided the desired product in 97% ee withcatalystVII(entry4).

Table 2.5 Asymmetric hydrogenation of unsaturated cyclohexadienes connected toheterocycles.a


bPredictedabsolutestereochemistryforthemajorproduct(>90%trans

NH

MeO

NH

NHMeO

N

OMe

NTs

Me

S

Me

Ts

Entry Substrate

1

2

3


85 90

98 99

83 92

4 99e 99

99e 995

n-Bu

n-Bu

NH

n-Bu

NH

n-Hex

6

7

8

NH

MeO

NH

NHMeO

N

OMe

NTs

Me

S

Me

Ts

n-Bu

n-Bu

NH

n-Bu

NH

n-Hex

98 90

99e 99

99e 99

44a 44b

45a 45b

46a 46b

47a 47b

48a 48b

49a 49b

50a 50b

51a 51b

VII

VII

VII

VII

I

I

I

II

0.5 mol% catalyst


44a-51a 44b-51b

R1 R1

NH

NH

20

selectivity observed where applicable). cIsolated yield unless otherwise specified.dDetermined by HPLC or GC analyses using a chiral stationary phase. eConversiondeterminedby1HNMRspectroscopy.

Lastly,carbocyclescontainingheterocyclicmotifs (class3)wereevaluatedandscreenedwiththeN,P-iridiumcatalyticsystem(Table2.5).CatalystVIIworkedwell for the substrates bearing Me and OMe groups, both on indole andcarbazole derivatives (entries 1,4-5 and 7). However, substrates bearing longalkyl chains (n-Hex and n-Bu) were handled better by catalyst I (Table 2.5,entries2and3)giving90%and92%ee respectively,except for thecarbazolewith then-Bugroup (49a), inwhich case catalyst II gavehigh selectivity (90%ee,Table2.5,entry6).Forthethiophenesubstrate(51a)catalyst I resulted inhighenantioselectivity(99%ee,Table2.5,entry8).The asymmetric hydrogenation of the majority of substrates smoothlyconverted them to the desired saturated carbocycles in a clean reaction andhighconversion.

2.2.3 Regioselectivemonohydrogenations

Typically the N,P-iridium catalyzed asymmetric hydrogenation of di- andtrisubstitutedolefinsproceedswithfullconversiontothesaturatedproductinvery high enantioselectivities at 20-50 bar of hydrogen, while the morechallenging tetrasubstituted olefins are left untouched. However, with thenewly developed imidazole catalyst VII, it was possible to discriminate alsobetween two trisubstituted olefins based on their steric and electronicproperties. For instance, cyclic dienes having amethyl group and a aromaticgroup,wheretheolefinπ-electronispartiallydelocalizedintheringgaverisetoconsiderable regioselectivity. Most likely, less steric bulk and higher electrondensity on the olefin facilitate its coordination to the metal, makinghydrogenation faster. The regioselectivity of the monohydrogenation wasoptimized on the two selected substrates 20a and 51a and the results arepresented in Table 2.6. At 50 bar of hydrogen pressure, the olefins werehydrogenatedto the fullysaturatedproducts in17h (Table2.6,entries1and3). However, a decrease in hydrogen pressure or reaction time leads to theselective formation of mono-hydrogenated compounds (Table 2.6, entries 2and 4). The productwas obtained in 83% and 94% conversionwith excellentenantioselectivity(99%ee).

21

Table2.6Regioselectivemonohydrogenations.a

aReaction conditions: 0.125mmolof substrate, 0.5mol% catalystVII, 1mLofCH2Cl2.EnantioselectivitydeterminedbyHPLCorGCanalysesusinga chiral stationaryphase.Conversiondeterminedby1HNMRspectroscopy.

2.3 Conclusion

Anarrayofimidazolephosphineligands,comprisingbothelectrondonatingandelectron withdrawing substituents on the imidazole were synthesized andappliedsuccessfullyintheasymmetrichydrogenationofcyclicprochiralolefins.The dimethyl imidazole catalyst VII was found to give very highenantioselectivitiesinthereactionandresultedinee’supto99%inhighyield.SubstrateswithacidsensitiveenolethermoietieswereleftintactbycatalystVIIanditalsotolerateacid,alcohol,andheterocyclefunctionalities,thusallowingaconsiderable expansion of the substrate scope. For carbocycles giving rise totwostereogeniccenters,thethermodynamicallyunfavorabletrans isomerwaspreferentiallyobtained.Regioselectivemonohydrogenationswerealsopossibletoachievebytuningthehydrogenpressureandreactiontime.

Me Ph-4-CF3

Me R Me RH2 (bar) Time (h)

5 0.5 94 (99% ee) 6

50 5 83 (99% ee) 17

1

2

Me

S

51a

20a

Entry

4

3

50 17 0 99 (99% ee)

50 17 0 99 (99% ee)

Conv.

R2R1 R2R10.5 mol% catalyst VII

H2, CH2Cl2r.t.

R2R1

+

Ratio

> 99

> 99

> 99

> 99

22

3 Ir-CatalyzedAsymmetricandRegioselectiveHydrogenationofCyclicAllylsilanes.GenerationofQuaternaryStereocentersviatheHosomi-SakuraiAllylation(PaperII)

3.1 Introduction

The regioselective asymmetricmono-hydrogenation of a di-olefin provides anopticallyactivemoleculewhile leavingoneolefingroupuntouched,andcouldlater be used for other chemical transformations. To further enhance theeffectiveness of the procedure, it would be interesting to introduce allylicfunctionalities (such as silanes, stannanes and borane) rather than simpleolefins. These allylic moieties provide possibilities to transform and increasemolecular complexity by applying well-known methods, for example theHosomi-Sakurai allylation. The degree of enantioselectivity otained byasymmetric hydrogenation would then enable the use of optically activeintermediates to direct the stereochemical outcome of succeeding steps. Forexample, in this project, the goal was to retain an allylsilane moiety after aselectivemonohydrogenation and then investigate its use in further chemicaltransformation.

3.2 Hosomi-Sakuraireactionusingcyclicallylsilane

Theadditionofanallylsilanetoanelectrophile inpresenceofLewisacidswasfirstreportedbyHosomiandSakuraiin1976.[37]Thereactionprovidescarbon-carbonbond formationwithexcellentdiastereocontrolundermildconditions.Duetoitsabilitytoconferahighdegreeofstereoselectivity,[38]thismethodhasbeen applied as a key step in the total synthesis of many complex naturalproducts,[39]suchas(+)-Tetronomycin[40]andLycopodiumalkaloids.[41]

23

This well-developed methodology provides a versatile approach to obtainstereochemically defined molecules, which in turn are useful in thepharmaceutical and agrochemical-industry. This has attracted enormousinterest in development of chiral molecules by using chiral Lewis[42] andBrønstedacids[43]aswellopticallyactiveallylsilanereagents.[38b,44]

Figure3.1PreviousworkbyOrgan(a)andShea(b)group.

The major focus for Hosomi-Sakurai allylation has been devoted to acyclicallylsilanes,[38b] and only few examples have been reported on cyclicallylsilanes.[45] The Hosomi-Sakurai allylation on cyclic silanes containing astereogenic center was reported by Organ and co-workers in 1997 (Figure3.1a).[45a] The reaction took place smoothly with electrophiles in presence ofTiCl4resultinginhighdiastereoselectivity.Thestereoselectivitywashighandinsomecases,onlyasinglediastereoisomerwasobtained.Likewise,Sheaandco-workersalsoreportedtheformationofasinglediastereoisomerwhenacyclicallylsilanewasusedundersimilarreactionconditions(Figure3.1b).[45b]Howeverinbothcasesthestartingmaterialswereinracemicform,thusonlytherelativestereochemistry of the products could be controlled. We anticipated thatsimilar transformations could be carried out with a stereochemically definedchiralcenter inproximitytotheallylsilanemoiety, inordertoalsocontroltheabsolutestereochemistry,asoutlinedinScheme3.1.

Scheme3.1Hosomi-Sakuraiallylationwithchiralcyclicallylsilanes.

H Ph

Si OO

O

R HR

Ph

CO2H

OHH

R’R’R

OHR’R

OH

+(a)

(b)

Si(CH3)2Ph

HHR

O

*Si

R2* * *

OH

R3R2

Hosomi-Sakuraiallylation

R1 R1

24

3.2.1 MechanismoftheHosomi-Sakuraiallylation

An open transition state (extended)mechanismwas proposed[46] forHosomi-Sakurai allylationwhen allylsilane is employed (Scheme 3.2). The reaction isinitiatedbytheactivationofacarbonylelectrophilebyaLewisacid,followedbythe addition of the nucleophilic allylsilane.[46-47] A unique and characteristicfeature of allylsilanes is their ability to stabilize the carbocation formeduponthe electrophilic attack. This effect is due to the interaction between the σcarbon-siliconbondwiththeunhybridizedp-orbitalofthecarbocationthroughhyperconjugation,[48]anditisknownasbeta-siliconeffectorbetaeffect(Figure3.2). The mode of addition of the allylsilane nucleophiles determines thestereochemistry of the product. Usually, the antiperiplanar orientation ispreferredinordertoavoidstericrepulsionbetweenthetwobulkysubstituentsof the reagents.[46, 47b] Thus, exclusively syn homo-allylic alcohol is producedupon elimination of the silyl group,which is independent of the geometry ofthestartingallylsilane.

Figure3.2AnexampleofLewisacidcatalyzedallylationofaldehydes.

Scheme3.2TheproposedmechanismforallylationcatalyzedbyLewisacid.

SiMe3 PhCHOTiCl4CH2Cl2 Ph

OH+

Si

Ph

O

TiCl4Hyperconjugation

Ph H

OLA

Me

SiMe3

Ph H

OLA

Me

SiMe3

Ph H

OH

MeH Ph

OH

Me

25


Figure3.3Catalystsusedinthisstudy.

3.3.1 Synthesisofchiralcyclicallylsilane

Itisknownthatallylsilanespossesshighthermalstabilityandarenotsensitiveto oxygen and moisture. In addition, they are relatively inert to a range ofsynthetic methodologies including hydrogenation and oxidation.[46] Thus itmakesthemsuitablesubstratesforthisproject.The unsymmetrical prochiral dienes for the regioselective asymmetric mono-hydrogenation were synthesized as shown in the Scheme 3.3. The benzylsilaneswereeasilyobtainedfromthecommerciallyavailablesubstitutedbenzylalcohol. Benzyl alcohols were converted to benzyl chlorides and subsequentsilylation[49] affords the benzyl silanes (54). The benzyl silanes were furthersubjectedtoBirchreductiontogivethefunctionalizedprochiral1,4.dienes.Theolefinswerethenscreenedforasymmetricregioselectivemono-hydrogenationusingiridiumN,P-catalysts.

S

N

P Ir

PhPh

N

N

P Ir

PhPh

N

N

P Ir

PhPh

N

N

P Ir

PhPh

MeO

OMeN

N

P Ir

PhPh

I II

VII VIIIVI

F

BArF BArF BArF

BArFBArF

26

Scheme 3.3 Synthesisof chiral cyclic substratesviaasymmetric regioselectivemono-hydrogenation.

3.3.2 Optimizationoftheasymmetricmono-hydrogenation

Theregio-andenantioselectivemono-hydrogenationswereinitiallyattemptedon differently trisubstituted olefins 55a (Scheme 3.4). From our previousstudies, it was already known that iridium N,P-catalysts containing thiazole Iand imidazole II ligands were themost successful classes of catalyst when itcomestohydrogenationofcyclohexadienes.[50]Theeffectofhydrogenpressureon the regioselective hydrogenationwas also observed, thus catalyst I, and IIwere evaluated for selective mono-hydrogenation at low hydrogen pressure.Bothcatalystsresultedinfullyhydrogenatedproduct(57).Theintroductionofabulkysilyl (55b)groupand theadditionofbasicadditivessuchasPVP,KHPO4andKH2PO4failedtoimprovetheregioselectivity.

Scheme3.4Regio-andenantioselectiveasymmetricmono-hydrogenation.

Tetrasubstitutedolefinsareusuallylesssusceptibletohydrogenationcomparedto trisubstituted olefins. By taking advantage of this substitution effect, 2,4-dimethyl substituted allylsilane (58) was synthesized and evaluated for theiridium N,P-catalyzed asymmetric mono-hydrogenation. The catalysts I and IIwerescreenedagainandresultedinthedesiredproduct59.Ligandsareknownto have great influence on the acidity of iridium catalysts.[51] The catalystcontainingathiazoleringhadbeenreportedtobemoreacidiccomparedtotheimidazole,[51b]andleadtoloweryieldofthedesiredproduct(Table3.1,entries

OH

R2

Cl

R2

SOCl2DMF

CH2Cl2

Li, DTBBTMSCl

THFSi

R2

Si

R2

Si

R2

Li, NH3t-BuOH

THF

Ir cat. H2

R1R1 R1

R1 R1

52 53 54

55 56

SiR3 SiR3

Cat. I/II,5 bar H2,additives

55a R = Me, 55b R = Et

56a 56b

SiR3

57a57b

+

0 100CH2Cl2,16 h, r.t.

27

1 and 2). The effect of basic additives (PVP and KHCO3); were studied andresultedinanimprovementinreactionoutcome,togetherwithasmallincreaseintheenantioselectivity(from65to71%ee,entries2,3and4).Next,theelectronicpropertiesonthephenylringofimidazolecatalystIIwerestudied. Introducing an electron withdrawing fluoride resulted in poorconversionandenantioselectivity(34%ee,Table3.1,entry5).Substitutingthefluoride with two electron donating methyls at 2,4-positions of the phenyl(catalyst VII) resulted in enhanced reactivity and selectivity, providing 92%conversion with 88% ee (Table 3.1, entry 6). Introducing two even moreelectrondonatingmethoxygroups(catalystVIII),grantedimprovementinbothconversion(95%)andenantioselectivity(98%ee,entry7).

Table 3.1 Optimization of the reaction conditions for the asymmetricmonohydrogenationof58.a

aReactionconditions:0.05mmolsubstrate,0.5mol%catalyst,0.5mLofsolvent,10barof H2, 18 h, r.t.

bYield determined by 1H NMR spectroscopy. cEnantiomeric excessdeterminedbyGCanalysisusingchiralHydrodexβ-6TBDMandHydrodexβ-3P.

7 95 98CH2Cl2

Ir cat. (0.5 mol%)H2 (10 bar)

18 h, r.t. *

Entry Cat. solvent Additive Yield (%)b ee (%)c

1 70 80

2 90 65

5 75 34

6 92 88

CH2Cl2

CH2Cl2

CH2Cl2

CH2Cl2

3 99 70CH2Cl2 PVP

4 99 71CH2Cl2 KHCO3

10 99 99α,α,α-trifluorotoluene

58 59

8 Benzene 93 97

9 Toluene 97 97

Si Si

I

II

II

II

VI

VII

VIII

VIII

VIII

VIII

28

Scheme3.5Possibleprotodesilylationpathwaygeneratingundesiredbyproducts.

Most of the catalysts afforded themonohydrogenated product togetherwithvolatile byproduct 61, probably resulting from protodesilylation of the allylsilaneandfurtherhydrogenation(Scheme3.5).Protodesilylationwasfoundtodecrease drastically with the dimethoxy catalyst VIII, most likely due to itsdecreased acidity and it was thus chosen to screen solvent effects. Solventssuchasbenzene,CH2Cl2,andtoluenegavesimilarresults(Table3.1,entries7-9), however, the use of α,α,α-trifluorotoluene resulted in a much cleanerreactionwithfullconversionand99%ee(Table3.1,entry10).Anumberofcyclicallylsilanesbearingdifferentalkylchainsonthe2,4-and2,5-positions of the ring were synthesized and screened under the optimizedreaction conditions. The results from the asymmetricmono-hydrogenation ofthesesubstratesarepresentedinTable3.2.Thesubstratesbearingethylandn-butyl groups at the 4 and 5 positions of allylsilanes resulted in slightly lowerenantioselectivity (92-94% ee, entries 1,2,5 and 6) compared to the methylgroup.However, the efficiencyof the catalystwas stillmaintained, furnishing84-89%of isolatedyield.Havingan isobutylgrouponposition4didnotaffectthe enantioselectivity (99% ee, entry 3). Similarly, substituting themethyl onposition 2 of the allylsilane to ethyl and n-butyl did not alter theenantioselectivity either (entries 7 and 8). The corresponding chiral cyclicallylsilaneswere obtained in 98-99%ee. Overall, catalystVIII resulted in highreactivityandstereoselectivity.

Si Si

Mono-hydrogenation Protodesilylation

Hydrogenation

58 59 60

61

29

Table3.2Substratescopeoftheasymmetricmonohydrogenationofcyclicallylsilanes.a

aReactionconditions:0.05mmolsubstrate,0.5mol%catalyst,0.5mLofsolvent,10barofH2,18h,r.t.

bPredictedabsoluteconfigurationforthemajorproduct.cIsolatedyield.dEnantiomeric excess determined byGC analysis using chiral Hydrodex β-6TBDM andHydrodexβ-3P.

3.3.3 DiastereoselectiveHosomi-Sakuraiallylation

WetheninvestigatedthereactivityandstereoselectivityofthepreparedchiralallylsilanesintheHosomi-Sakuraiallylation.The2,4-dimethylallylsilane59waschosenasthemodelsubstratewhileemployingbenzaldehydeasthestandard

Ir cat. VIII (0.5 mol%)H2 (10 bar)

α,α,α-trifluorotoluene18 h, r.t.

Si

R2

Si

R2

Entry Yield (%)c ee (%)d

1 84 92

2 84 93

3

70 994

Substrate Productb

Si

Et

Si

Et

Si

n-Bu

Si

n-Bu

62 63

64 65

Si Si

68 69

96 99Si

i-Bu

Si

i-Bu66 67

R1 R1

87 935

89 946

7

8

76 77

Si SiEt Et

Si Sin-Bu n-Bu

70 71

70 99

95 98

Si

Et

Si

Et

Si

n-Bu

Si

n-Bu

72 73

74 75

30

electrophile in presence of a Lewis acid. Different types of Lewis acids wereexaminedand itwas found thatTiCl4was thebestcatalyst,offeringacleanerreactionandhigherstereoselectivity.TheresultsofthescreeningoftheLewisacidsaregiveninTable3.3.A similar level of stereoselectivity was found using SnCl4, but the reactionresulted in complexmixturesbeside thedesiredproduct. Interestingly, in thiscaseacompletereversalofstereoselectivitywasobserved.Inpreviousstudies,SnCl4was foundtoundergotransmetallationwiththeallylsilane.[52]Thiscouldresult in a closed six-membered transition state thus generating thedifferentselectivity. Lewis acids such as BF3�Et2O and SiCl4 did not provide the desiredproduct, and gave instead either a complex reaction mixture or theprotodesilylated byproduct respectively. It is also known that fluoride anionsare capable of activating certain allylsilanes towards electrophile addition bycoordinating to silicon.[53] Nevertheless, we did not observe such reactivitywhenTBAFwastestedwithourallylsilanesubstratesandonlystartingmaterialwere recovered. An increased yield of isolated product was observed whenmolecularsieveswereadded(entry6,from34to68%).TiCl4wasthenchosentooptimizethediastereoselectivityinCH2Cl2at-78°C.

Table3.3ScreeningofLewisacidsfortheHosomi-Sakuraiallylation.a

aReactionconditions:0.15mmolsubstrate,1.1eq.Lewisacid,1.1eq.PhCHO,1.5mLofCH2Cl2,1h,-78°C.

bDiastereomericratiodeterminedby1HNMRspectroscopy.cIsolatedyield.

The reaction between the allylsilanes and aldehydes introduces two newstereogeniccentersintheproduct.Ifthereactionwouldnotbestereoselective,

Si

OH

Ph

CH2Cl21 h, - 78 °C

Lewis acid,PhCHO

59 78a

Entry Lewis acid Yield (%)cAdditive

1

2

3

4

5

TiCl4

SnCl4

SiCl4

BF3.Et2O

TBAF

6 3Å MS 68

TiCl4 -

-

-

34

20

-

-

-

dr b

5:1

5:1

1:6

-

-

-

OH

Ph

78b

+

(relative stereochemistry)

31

the reaction could potentially generate up to eight different stereoisomers.Amongtheseeight,fourstereoisomerscanbeeasilyexcludedbymeansoftheenantioselective asymmetric mono-hydrogenation, leaving only the fourstereoisomersasdepictedinFigure3.4.Thiscanbefurthernarroweddowntotwodiastereoisomersdependingontheallylsilanepreferredmodeofattack,inwhich the incoming electrophile is positioned in such way that its largestsubstituent (the phenyl ring) is oriented away from the cyclohexyl ring toreduce steric repulsion. Finally, there are two possible facial attacks, eitherfromthetoporbottomof thering.Theattack fromthetopface leadstothemore stable chair-like and thermodynamically favored transition state TS 1aandTS1b.Thebottomattackgeneratestwistboatlikeandthermodynamicallyunfavored transition stateTS 2a and TS 2b. Thereby, trans adductswouldbeexpectedforsubstratescontainingamethylat4position, (inaccordancewithOrgan's work), on the other hand, cis adducts will be obtained when thesubstituent occupies the 5 position. These results were further confirmed bythex-raycrystalstructureobtainedforcompound78aand85a(Figure3.5).

32

Figure3.4Proposedtransitionstatesfortheformationof78aand85a.

Figure3.5Crystalstructureofcompound78aand85a

HPh

OTiCl4

Si

SiHPh

OTiCl4

SiSi

Above

Below

H Ph

OCl4Ti

SiH Ph

OCl4Ti

SiHPh

OTiCl4

Si SiHPh

OTiCl4

Unfavored

Favored

Si

Si

OH

Ph

TiCl4

OH

Ph

TiCl4

OH

Ph

TiCl4

OH

Ph

TiCl4

Ph

OH

Ph

OH

transMajor

cisMinor

TS 1a

TS 2a

SiHPh

OTiCl4

Above

Ph

OH

cisMajor

TS 1b

12

345

6

123

45

6

123

45

6

4-Substituted

4-Substituted

5-Substituted

Si

OH

Ph

TiCl4

Si

OH

Ph

TiCl4

78a

78b

85a

HPh

OTiCl4

SiSi

Below

Si

OH

Ph

TiCl4

OH

Ph

TiCl4

Ph

OH

transMinor

TS 2b

123

45

6

5-Substituted

85b

654

321

OH

Ph

654

321

OH

Ph

654

321

OH

Ph

654

321

OH

Ph

78a 85a

33

It was found that the ratio of the two observed diastereoisomers could befurther optimized. After numerous experiments, an improvement indiastereoselectivity was observed by increasing the concentration of thereaction (Table 3.4). This lead us to study the concentration effects of theindividual reagents and the allylsilane.When the reactionwas run at 0.3M adecrease in diastereoselectivity was observed with higher concentration ofbenzaldehyde (entry5), on the contrary, increasing the concentrationof TiCl4gave rise to very high diastereoselectivities (entry 6). The reason for thisconcentration effects are still unknown to us and have no literatureprecedence.

Table3.4ConcentrationdependenceintheHosomi-Sakuraiallylation.

aDiastereomericratiodeterminedby1HNMRspectroscopy

A range of carbon electrophiles was evaluated under the optimized reactionconditions.Thereactionbetweenthedimethylallylsilaneandvariousaliphaticaldehydes gave overall excellent diastereoselectivity with moderate to goodisolated yields. The results are shown in Table 3.5. Employingcyclohexanecarboxaldehyderesultedinasinglediastereoisomerin65%isolatedyield (entry1).Goodtoexcellentdiastereoselectivitywasalsoobservedwhenisovaleraldehydeandpropionaldehydewereemployedand thecorrespondingproductswereobtained inhighratiosof24:1and46:1,respectively(entries2and 3). Changing to isobutyraldehyde (entry 4) resulted in a decreasediastereoselectivity affording a 9:1 ratio of the desired homoallylic alcohol. A

Si

OH

PhCH2Cl2

1 h, - 78 °C

TiCl4PhCHO

59 78a

Entry Allylsilane (M) dr a

1

2

3

4

0.10

0.26

0.73

3:1

5:1

12:1

30:1

0.03

OH

Ph

78b

+

(relative stereochemistry)

Benzaldehyde (M) TiCl4 (M)

0.10

0.22

0.60

0.03

0.10

0.26

0.73

0.03

5 0.60 2:10.30 0.30

6 0.30 45:10.30 0.60

34

highdrof49:1wasalsoobservedwhencyclopentanecarboxaldehydewasused(entry5).

Table3.5SubstratescopefortheHosomi-Sakuraiallylation.a

aReaction conditions: 0.30mmol substrate, 1.1 eq. TiCl4, 1.1 eq. aldehyde, 0.5mL ofCH2Cl2, 1 h, -78 °C.

bIsolated yield. The lower yields are most likely due toprotodesilylation and loss of volatile byproducts. cDiastereomeric ratio and relativestereochemistrydeterminedby1HNMRspectroscopy.

*

OH

R3R2

CH2Cl2, 3Å MS1 h, - 78 °C

TiCl4R3CHOSi

R2

Entry Yield (%)b dr c

7

69 single stereoisomerobserved8

37 34:19

6

Product

OH

Ph

Et

OH

Ph

n-Bu

42 31:1

OH

Ph

OH

Phi-Bu 30 24:1

*

OH

R2+

1 65 single stereoisomerobserved

2 32 24:1

3

4

OH

Cy

OH

i-Bu

40 46:1

OH

Et

56 9:1

OH

i-Pr

5 42 49:1

OH

R1R1 R1

R3

79

80

81

82

83

84

85

86

87

a b

35

The scope of the reactionwas further studied by varying the allylsilanes andemploying benzaldehyde as the standard electrophile. Interchanging methylgrouponcarbon4ofthecyclicallylsilanetoanisobutylgroupdidnotaffectthediastereoselectivity(24:1,entry6).Movingthemethylgroupfromcarbon4tothe 5 position did not influence the level of diastereoselectivity either andfurnished thecis alcoholwitha31:1dr (entry7). The reactionon the5-ethylsubstitutedallylsilaneaffordedasinglediastereoisomer(entry8)andswitchingtoan-butylgroupresultedinadrof34:1(entry9).

3.4 Conclusion

In conclusion, a number of differently substituted dienes containing anallylsilane were synthesized and screened for the asymmetric iridium N,P-catalyzed regioselective mono-hydrogenation. The effect of the electronicpropertiesoftheN,P-ligandwasfoundtobesignificantforbothreactivityandstereoselectivity. Thus, excellent ee’s (92-99%) could be obtained employingimidazole-basediridiumcatalystVIIIreachingisolatedyieldsof70–96%forthechiralallylsilanes.High diastereoselectivity was obtained in the subsequent Hosomi-Sakuraireactionforthechiralallylsilanesgivingrisetotwonewstereogeniccentersinarelatively short synthetic route, starting fromachiral reagents.Thisdevelopedmethodologygeneratesstericallycrowdedquaternarystereogeniccentersnextto a homoallylic alcohol; these can in turn could serve as interesting chiralbuildingblockforfurtherchemicaltransformations.

36

4 N,P-IridiumCatalyzedAsymmetricHydrogenationofVinylfluorides

4.1 Introduction

Organofluorine compounds are almost entirely absent in nature;[54] however,theirgrowingapplicationinthelifescienceshasinspiredasubstantialresearchinterest, in particular in development of drug and agrochemicals.[55] Thefluorine atom possesses strong electron withdrawing properties with anelectronegativity value of 4, and as a consequence the C-F bond is highlypolarized.[56]This increasesthestrengthoftheC-Fbondtoapproximately116kcal/mol, representingoneof thestrongestknown inorganicchemistry.[55b,57]The incorporation of fluorine atoms in molecules generally enhances theirthermalandoxidativestability,whichconfersanadvantageouseffectontheirbiological properties.[55b,57b] In thepast fewdecades, thenumberofbioactivemoleculescontainingfluorineatomshaveincreasedtremendously:from2%in1970 to more than 18% in pharmaceuticals and even higher (28%) inagrochemicalsin2006.[55c]Thesefiguresareexpectedtorisegloballytoaround20-25%ofdrugcandidatesdevelopedinthepharmaceuticalindustry.

Figure4.1Fluorinecontainingbioactivemolecules.

N

O

OO

Ezetimibe

N

ON

N

FFOH

(a) (c)

N

O

OH

OH

F

F(b)

Azetidinone

N

ON

N

F

FFOH

(d)

KSP inhibitors

37

Inpharmaceuticals, fluorine isusuallyappliedasachemically inertbioisostereofhydrogentomodulatethephysiochemicalandpharmacokineticpropertiesofdrug molecules (bond strength, lipophilicity, conformation, pKa, tissuedistribution route and rate of metabolism).[55a, 57b, 58] For example, theintroduction of a fluorine atom in azetidinone (a cholesterol absorptioninhibitor, Figure4.1aand4.1b) increases themetabolic stability.[58-59]Anotherexample is the kinesin spindleprotein (KSP) inhibitor (Figure4.1c),where thefluorinated analogue (Figure 4.1d) has shown to reduce the basicity of theamine.[60]There are various asymmetric methodologies developed to generate fluorinecontaining stereogenic centers for example electrophilic fluorination ofaldehydes using organocatalysts,[61] fluorination using chiral metalcomplexes,[62] and NHC-catalyzed fluorination of aliphatic aldehydes (Figure4.2).[63]However,thecatalyticasymmetrichydrogenationoffluorinecontainingolefins has been reported only a few times. In 2002 Saburi and co-workersreported the asymmetric hydrogenation of (E)- and (Z)-2-fluoroalkenoic acidsusing a Ru-BINAP catalyst.[64] High enantioselectivity (up to 91% ee) wasobtainedwith1mol%ofcatalyst,at5barH2 in24h.Thepreferredchoiceofsolventismethanolandthereactionwascarriedoutat50°C(Figure4.3a).

Figure4.2Examplesofasymmetricfluorination.

R

CHOOH

R

N N

NOR

OR

F

NFSINHC

NFSI

RH

O ROH

F

N

NH

O

Ph

·DCA

(20 mol%)

2. NaBH4, CH2Cl2/EtOH, r.t.

1

RO

ClR

O

Nu

F1. BQd,

trans-(PPh3)2PdCl2NFSI, Base

2. NuH

N

OMe

NOCOPh

BQd

(a) Fluorination via organocatalysis

(b) NHC catalyzed fluorination

(c) Transition metal catalyzed fluorination

NFSI, THF/IPA - 20 ºC

38

Figure4.3Examplesofasymmetrichydrogenationofvinylfluorides.

Using a similar reaction condition Nelson and co-worker also reported theasymmetric hydrogenation of vinyl fluorides employing Walphos ligand and[Rh(COD)Cl]2/[(norbornadiene)2Rh]BF4asthecatalystprecursor(Figure4.3b).[65]An excellent enantioselectivity (up to 98% ee) was obtained with 99%conversion.In this chapter, the generation of enantiomerically enriched C-F compoundsthroughN,P-iridiumcatalyzedasymmetrichydrogenationofvinylfluorideswillbediscussed.VariousN,P-iridiumcomplexeswerepreviouslydevelopedintheAnderssongroupfortheasymmetrichydrogenationofvinylfluorides,butwerestudied only on α-fluorocinnamyl derivatives. Therefore, wewanted to studyandwidenthescopeofthereaction.

4.2 Substratesynthesis

Tri- and tetrasubstituted vinyl fluoride substrates can be easily prepared asshown in Scheme 4.1. A range of α, β-unsaturated esters containing an α-fluorineatomwasreadilysynthesizedbyapplyingthewellestablishedHorner-Wadsworth-Emmons method A. The reaction of triethyl 2-fluoro-2-phosphonoacetate 88 with aldehydes 89 (A1),[66] ketone 92 (A2),[67] andglyoxylate95 (A3)[68]gavemixturesofEandZα-fluoro-α,β-unsaturatedesters(90,93and96).TheestersweresubsequentlysubjectedtoDIBALreductiontogivethecorrespondingalcoholproducts91and 94.TheEandZ isomersweresimplyseparatedbyflashchromatographyeitherattheesteroralcoholstage,dependingontheirpolarityandhowwelltheycouldbeseparatedoncolumn.In few cases, where it was too difficult to separate them, the stereospecificMizoroki-Heckreaction[69](Scheme4.2)wasemployed.

RF

COOHR

F

COOH

PPh2PPh2

5-50 bar H2Ru-(R)-BINAP

MeOH, 50 ºC,24 h

NBn

up to 91% ee

(a)

F

OH

H

Cl(b) N

Bn F

OH

6 bar H20.1 mol% [(COD)RhCl]2

(R)-(R)-WalphosMeOH, 50 ºC,

15-16 h98% ee

(R)-BINAP

Fe

P(c-C6H11)2

PPh2

(R)-(R)-Walphos

39

Scheme4.1SynthesisofE/Zvinylfluorides.

Scheme4.2Stereospecificsynthesisofvinylfluorides.


Figure4.4Catalystsusedforthisstudy.

Afterathoroughcatalystscreeningwith0.5mol%catalystat10barH2inCH2Cl2itwasfoundoutthatthebicyclicN,P-iridiumcatalystswithathiazole(XI)andan oxazoline (XII) motifs were the best for vinyl fluorides. With these twocatalysts,anarrayofsubstrateswasscreened.CatalystXIgavethebestresultin the asymmetric hydrogenation of trisubstituted vinyl fluorides (Table 4.1).ThesubstrateZ-100wasfullyhydrogenatedtothesaturatedproduct(101a)inexcellent enantioselectivity (97% ee, Table 4.1, entry 1). A decrease in

PO

O

O

F

EtOEtO

MgBr, Et3N

THF,50 ºC, 1 h

R1 O

O

F

n-BuLiR1 R2

O

- 78 ºC - r.t.R1 O

O

F

R2

88

92

95

R1 H

O 89

E/Z-90

E/Z-93

R1

OO

O

NaHTHF,

0 ºC-r.t., o.n.R1

O O

O

O

F

E/Z-96

A2

A3

R1 OHF

DIBALTHF

- 78 ºC - r.t.

E/Z-94

A1

E/Z-91

DIBALTHF

- 78 ºC - r.t.R1 OH

F

R2

FO

O I Pd(TFA)2, Ag2CO3

Dioxane90 ºC, 4 h

O

O

F+

98 Z-9997

N

S

N

P Iro-Tol

o-Tol BArF

N

O

N

P Iro-Tol

o-Tol BArF

S-XI R-XII

40

enantioselectivityaswellasreactivitywasobservedfortheestersubstrateZ-99(31% conv., 65% ee, entry 2). A similar result was reported previously forcatalystXIIwhentheethylesterversionofZ-99wasemployed(99%conv.,29%ee).[70] Both catalysts gave lower enantioselectivity for olefin E-100with ee’s65%and28%respectively;however,thehighcatalystactivitywasstillretained,giving 99% conversion (Table 4.1, entry 3). For the aliphatic olefin Z-103,catalystXIprevailedonceagainwith84%eecomparedtocatalystXII(76%ee)(entry4).Surprisingly,whenE-aliphaticolefinsE-103andE-105wereemployed,the enantioselectivity was not affected, affording respectively ee’s 86% and92%withcatalystXI(Table4.1,entries5and6).However,withcatalystXIIthehydrogenatedproductwasobtainedinracemicform.

Table4.1Asymmetrichydrogenationoftrisubstitutesvinylfluorides.a

Entry Substrate Conv. (%) (a:b)b ee (%)c

R1

R2R1

F

R2

Catalyst XI, 10 bar H2

CH2Cl2, 24 h, r.t.

1

2

3

4

5

FOMe

O

FOH

F

OH

OHF

F

OH

FOH

6

F R1

R2+

65(-)

97(-)

65(+)

84(-)

86(+)

92(+)

101>99 (99:1)

101>99 (99:1)

104>99(100:0)

104>99 (100:0)

106>99 (100:0)

10231 (99:1)

Z-100

Z-99

E-100

Z-103

E-103

E-105

Catalyst XI Catalyst XII

Conv. (%) (a:b)b ee (%)c

-

80d

28d

76

rac

rac

10199 (94:6)

10199 (97:3)

10483 (100:0)

104>99(100:0)

106>99(100:0)

-

a b

41

aReactionconditions:0.13mmolofsubstrate,0.5mol%catalyst,0.5mlofCH2Cl2,10barofH2,24h,r.t.

bConversionandratiodeterminedby1HNMR.cDeterminedbyHPLCorGCanalysesusingachiralstationaryphase.dDatausedfrompreviousstudy.[70]

Themajorityoftheasymmetrichydrogenationsoftrisubstitutedvinylfluoridesproceeded incleanconversion to thesaturateddesiredproductsat10barH2pressurewith0.5mol%catalystloading.Infewinstances,hydrogenolysisoftheC-F bondwas detected as a side reaction (Figure 4.5).Despite the strongC-Fbond, this hydrogenolytic cleavage of the C-F bond is a common problem inhydrogenationandhaveearlierbeenreportedbothbyus[70]andHudlický.[71] Itwas suggested that the C-F bond breakage occurs either through theenergetically favored five-membered transition state (Figure 4.5a)[72] or via afree radical mechanism (Figure 4.5b), generating carbene or carbene-likespecies in the process. During the transition from sp2 to sp3 carbon, the C-Fbond length is increased approximately by 3% and as a result this leads to adecrease in bond dissociation energy, thus making the C-F bond moresusceptibleforcleavage.

Figure4.5HydrogenolysisofC-Fbondincatalytichydrogenation.

Whencompared todi- and trisubstitutedalkenes, tetrasubstitutedolefinsareusually considered the least reactive class of olefins,mainly due to the stericbulkthathindersthe insertion intothemetalhydrideofthecatalystandthusmakes itmoredifficult to hydrogenate. Additional difficulties also involve thedifferentiation of the prochiral faces of the fully substituted olefin by thecatalyst.Thisdifferentiationbecomesevenmoredifficultwhenthesubstituentsare unfunctionalized.[73] As a result, there are only few reports on theasymmetric hydrogenation of tetrasubstituted olefins having either

HF

OORRO

O

H H

Cat.

HF

OORRO

O

H

Cat.

H H

OORRO

O

H H

Cat.

H- HF H

OORRO

O

H

Cat.

HH

HF

OORRO

O

H H

Cat.

(a)

(b)

42

functionalized(Figure4.6a)[74]orunfunctionalizedsubstituents (Figure4.6b)[75]The challenging and compelling aspect of asymmetric hydrogenation oftetrasubstituted olefins is the ability to generate two contiguous stereogeniccenters in one step. Thus, we wanted to evaluate the N,P-iridium catalystdeveloped in thegroup for theasymmetrichydrogenationof tetrasubstitutedolefins.

Figure4.6Twoexamplesofasymmetrichydrogenationoftetrasubstitutedolefins.

Next,anumberoftetrasubstitutedvinylfluorideswerescreenedusingcatalystsXI and XII. The initial screening using catalyst XI resulted in either lowconversion(3%-8%at100barH2)ornoreactionatall.Increasingthecatalystloading (2 mol%) did not improve the conversion. However, catalyst XII wasfound to hydrogenate tetrasubstituted vinyl fluorides in good conversion andexcellentenantioselectivity.Inthiscaseaswell,aslightlyhighercatalystloading(1.5 mol%) and high H2 pressure (100 bar) was required to obtain highconversion.TheresultsforthesubstratescreeningusingcatalystXIIisshowninTable 4.2. The olefin E-107 was hydrogenated in excellent enantioselectivity(97% ee) with 79% conversion (Table 4.2, entry 1). Introducing a methylsubstituentontheparapositionofthephenylring(E-109)resultedinincreasedconversion(91%)withsamelevelofenantioselectivity(97%ee,Table4.2,entry2).InhydrogenationofthecorrespondingalcoholsE-111andE-113,thedesiredsaturatedalcoholswereobtained in full conversionand theenantioselectivitywasnotaffected,resultingin97%ee(Table4.2,entries3and4).Gratifyinglyinall cases, defluorinated byproducts that are normally amajor concern in thistypeofhydrogenationswerenotobserved.

R1

R2

R1

R2

[Ir(L)COD]BArF

H2

R1 = n-Bu, Ph, EtR2 = Ph

Pfaltz and co-workers (2007)

N

O

Ph

Cy2P

L =

OAc

NHAcO

O OAc

NHAcO

O[Rh(COD)2]BF4, L

H2R1 R1

R1 = Cl, F, OMe, i-Bu

Zhang and co-workers (2017)

(a)

(b)

L = P P

H

H

up to 99% ee

up to 96% eeH

H

43

Table4.2Asymmetrichydrogenationoftetrasubstitutedvinylfluorides.a

aReactionconditions:0.13mmolof substrate,1.5mol%catalyst,0.5mlofCH2Cl2,100barofH2,24h,r.t.

bConversionandratiodeterminedby1HNMR.cDeterminedbyHPLCorGCanalysesusingachiralstationaryphase.dBenzenewasusedinsteadofCH2Cl2.

Replacing either the phenyl or methyl substituent at the β carbon with anadditional ethyl ester resulted in maleic esters E-115 and E-117. Thehydrogenation of E-115 resulted in decreased conversion (47%), but theenantioselectivitywasstillretained,obtainingin99%ee(Table4.2,entry5).Afurther decrease in conversion (32%) was observed with E-117. Neverthelessthe high enantioselectivity was not perturbed, affording 86% ee (Table 4.2,entry 6). However, for both substrates 8-15% defluorinated byproduct wasobserved.

F

OEtO

F

OH

F

OH

F

OEtO

F

O

OEt

OEtO

F

O

OEt

OEtO

Entry Substrate Product Conv. (%) (a:b)b ee (%)c

R1

R3R1

* * F

R3

Catalyst XII, 100 bar H2

CH2Cl2, 24 h, r.t.

1

2

3

4

5

6

FR1

*

R3

+

97(+)

97(+)

97(+)

97(+)

99d(-)

86d(+)

91 (100:0)

Full (100:0)

Full (100:0)

47 (92:8)

32 (85:15)

79 (100:0)

R2 R2 R2

* * F

OEtO

* * F

OH

* * F

OH

* * F

OEtO

* *

F

O

OEt

OEtO

* *

F

O

OEt

OEtO

E-107

E-109

E-111

E-113

E-115

E-117

a b

108

110

112

114

116

118

44

4.4 Determinationofabsoluteconfiguration

Figure4.7DeterminationofabsoluteconfigurationofolefinsZ-100,andE-100.

The enantioselectivity of the reaction depends on the steric interactionsbetween the substrate olefin and coordination sphere around the catalystXIandisbasedonthecomputationalmodelproposedbytheAnderssongroup.[29]Theolefincoordinateverticallytranstophosphorous,andfromtheperspectiveof the olefin the area around the iridium metal can be divided into fourquadrants as shown in Figure 4.7b and 4.7c. The phenyl ring on the thiazoleoccupiesthequadrantiii,whichbecomesstericallyhindered.Theo-tolylgroupson the phosphine partially occupy quadrant ii, which therefore is semi-hindered.Theothertwoquadrants(iandiv)arerelativelyopen.Placingolefintranstophosphorousinsuchwaythatthesmallestsubstituent(H)occupiesthehindered quadrant iii, give the most sterically favored arrangement. As thesubstrate contain two groups (H and F) that are relatively similar in size, onecould imaging that both of these could be accommodated in the stericallyhinderedquadrantandthus leadto lower levelofenantioselectivity incertaincases.For theolefinsZ-100bothorientationsof thedoublebond (positioningeitherHorFinthehinderedquadrantiii(Figure4.7dand4.7e),wouldleadto

Sterically favoredSterically favored?(d) (e)

(S)

FOH

(S)

OHF

i ii

iii iv

i ii

iii iv

OHF

HOH

F

H

Ir

P

N H

H

F

PhH

OH

i ii

iii iv

Semi-Hindered

Hindered Open

Open

i ii

iii iv

(a)

NS

NP

S-XI

(b) (c)

Schematic 3Dquadrant model

Z-100

S-101 S-101

i ii

iii iv

i ii

iii iv

(f) (g)

F

H

OH

F

H

OH

(R)F

OH

(S)

FOH

S-101 R-101

Sterically favored? Sterically favored

E-100

45

thesameenantiomer.However,thestereoisomericolefinE-100wouldleadtooppositeenantiomerdependingonwhetherHor F isoccupying thehinderedquadrantiii(Figure4.7fand4.7g).ThismightbethereasonforthelowerlevelofenantioselectivityobservedforE-100(65%ee)ascomparedtoZ-100 (97%ee).The absolute configuration of the hydrogenated product of Z-100 could beassignedasS-101,andtheonescomingfromZ-105andE-105wereassignedasS-106 and R-106 respectively, based on comparison of the measured opticalrotation with the data reported in the literature (Table 4.3).[70, 76] Theseabsoluteconfigurationsareconsistentwith theprediction fromtheselectivitymodel.Fromtheseresults itcanbeconcludedthatH ismore likely tooccupythemosthinderedquadrantiiiandnotF.

Table4.3Assignedabsoluteconfiguration.a

aAbsoluteconfigurationbasedonselectivitymodelwithcatalystXI.

Entry SubstratePredictedproduct

Absconf. [⍺]

Reported Abs. conf. [⍺]

OHF

OHF

F

OH

(S)

OHF

(S)OH

F

(R)OH

F

Z-100

Z-105

E-105

1

2

3

(S) [ -12.75] (R) [ +12.00]

(S) [ -20.33] (R) [ +28.20]

(R) [ +21.00] -

101

106

106

46

4.5 Conclusion

Tri-and tetrasubstituted olefins containing vinylic fluorine atoms have beensynthesizedandevaluatedforasymmetrichydrogenation.Thebicyclicthiazolecatalyst XI was found to be the best for trisubstituted vinyl fluorides givingenantioselectivities up to 97% ee and >99% conversion. For tetrasubstitutedvinyl fluorides, the bicyclic oxazoline catalyst XII gave excellentenantioselectivity (up to 99% ee) with good to high conversion. It was alsoobservedthathighH2pressure(100bar)wasrequiredforthetetrasubstitutedvinyl fluorides,while trisubstitute vinyl fluorideswere easily hydrogenated atlowH2pressure (10bar).Forboth tri-and tetrasubstitutedvinyl fluorides thereactionproceed smoothly and resulted in desiredproduct in high yields andselectivities. In a few cases a small amount of defluorinated byproduct wasobserved.

47

5 Palladium-CatalyzedCycloisomerizationof1,6-Enynes(PaperIII)

5.1 Introduction

Cycloisomerization is a reaction inwhich a polyunsaturated organicmoleculegetstransformedintoacyclicorpolycycliccompound.Intheprocess,newC-Cbondsare formedwithout lossorgainofanyatomswhileconsumingat leastone degree of unsaturation.[77] Such transformation enables the synthesis ofhighlyfunctionalizedfiveorsix-memberedcarbo-andheterocycliccompoundsfromreadilyavailablestartingmaterials.Considerablyfocushasbeendivertedto the transition metal catalyzed cycloisomerization of polyunsaturatedcompounds to form C-C bonds rather than to its counterpart, the Alder-enereaction, which usually requires harsh conditions.[78] The use of transitionmetals in catalyticamountallows the reaction tobecarriedoutundermilderconditions and also tolerate a range of functional groups, thus extending thepossibilityforfurtherchemicaltransformations.Furthermore,interesthasbeenfocused to theuseof transitionmetal complexes inwhich the ligands canbefine-tuned to achieve optimal reactivity as well as enantio-, regio- and/orstereoselectivity.

5.1.1 Palladiumcatalyzedcycloisomerization

PioneeringworkoncatalyticcycloisomerizationswasreportedbyTrostin1985whileworkingonpalladiummetalcatalyzedalkylations.[79]Itwasreportedthat(Ph3P)2Pd(OAc)2 efficiently catalyze the cyclization of 1,6 enynes via anisomerization under mild reaction conditions. This method was successivelyapplied further by the same group for asymmetric induction using (S)-binaphthoicacid(Figure5.1a)asthechiralligandinpresenceofPd2(dba)3CHCl3and triphenylphosphine (Scheme 5.1).[80] The rearrangement of a 1,6-enyneinto the corresponding Alder-ene type product took place in moderateenantiomericexcess(33%ee).Severalyearslatertheyalsoreportedtheuseof

48

bidentate phosphine ligands (Figure 5.1b),[81] in asymmetric cyclizations,providing50%ee.

Scheme5.1Firstexamplesofcycloisomerizationcatalyzedbypalladium.

Figure5.1Examplesofchiralligandsusedinpalladium-catalyzedasymmetriccyclizationofenynes.

Due to the modest success in asymmetric induction, the enantioselectivecycloisomerizations have been further investigated by fine-tuning the ligandstructureandthechoiceofmetalinordertoachievehigherenantioselectivity.In1996,Itoandco-workersreportedthefirsthighlyenantioselectiveene-typecarbocyclization reaction using a diarylphosphino ferrocene ligand in thepresence of Pd2(dba)3.[82] Similarly, the groupofMikami employed a rangeofBINAP derivatives, providing high enantioselectivity (up to 99% ee).[83] Thiscatalytic system was later applied successfully to the total synthesis ofPhomactinA(Scheme5.2).[84]TheyhavealsoexaminedaN,P-ligandbearinganoxazoline unit (Figure 5.1d),[85] which was equally efficient as its predecessorBINAP ligands: the cycloisomerized product was obtained in highenantioselectivity (up to 99% ee) and good to excellent yield. The chiral

MeO2C

MeO2CPd2(dba)3·CHCl3

PPh3, (S)-binaphthoic acid

MeO2C

MeO2C

61% yield 33% ee

OH

O

OHOH

HNNH

OO

PPh2

Ph2P

a b

P

P

Ar

Ar

Ar

Ar

Fe Fe

c

PAr2PAr2

O

O

O

O

N

O

R2R1

PPh2

R1 = t-Bu, R2 = HR1,R2 = HR1,R2 = Me

Ar = (3,5-Me2-C6H3)

Ar = p-F3C-C6H5

O N N OR

RR

R

R = HR = i-Pr

d e f

49

bidentatephosphineligand(Figure5.1e)hasalsobeenemployedsuccessfullyinene-typecyclizationof1,7-enynes.[85b,85c]

Scheme5.2Theapplicationofasymmetriccycloisomerisationintotalsynthesis.

Recently, several N,P-ligands comprising cyclic and bicyclic frameworks havebeen developed in the Andersson group. The N,P-ligands were successfullyapplied in the iridium-catalyzed asymmetric hydrogenation of functionalizedand unfunctionalized olefins, providing good to excellent enantioselectivity.Thus,weenvisionedthepossibilitytotesttheseligandsincycloisomerizations,which would add a new set to already existing catalyst reported in theliterature.

5.1.2 Mechanismofpalladiumcatalyzedcycloisomerization

Figure5.2Mechanisticpathways.[86]

The mechanism of the transition metal catalyzed cycloisomerization of 1,6-enynescanbecategorizedinthreedistinctcatalyticpathwaysA,BorC(Figure

O

CO2Me Pd(OCOCF3)2(R)-BINAP

O

CO2Me

O

I Ot-BDMS

O

O OHOH

Phomactin A

X

X M

X

X

M

M

X

A

B

C

Metallacycle

π-Allyl complex

Hydrometallation

H

50

5.2) depending on the reaction conditions and the choice of the precatalystused.SinceinthisstudyPdIImetalprecursorswereusedinpresenceN,P-ligandandahydridesource;thereactionpathwayCismostlikelytooccur(Figure5.3).Thus,it will be discussed in further detail. In 1998 Trost proposed this reactionmechanism, suggesting that the Pd0 metal precatalyst in combination with aprotonsourcefavorsaPd0-PdIIcatalyticcycle(PathC),whileaPdIIprecatalystinthe absence of a reducing agentwould promote a PdII-PdIV catalytic pathway(PathA).[87]However, PdII precatalysts inpresenceof P,P-ligands alongwith ahydridesourcearealsoknowntotakepartinaPd0-PdIIcatalyticcycle.In2001Mikami proposed a Pd0-PdII catalytic cycle when Pd(OCOCF3)2 orPd(CH3CN)4(BF4)2precatalystsareusedtogetherwith(R)-SegPhos ligandinthepresence of D2O as the proton source.[83a] From deuterium experiments theyruledoutthatthePdIIhydridespecieswouldbetheactivecatalyst.InsteadtheysuggestedthatthePdIIgetsreducedtoPd0inpresenceoftheligandandoxidizeback to PdII hydride by a hydrogen source. Nevertheless, one cannot entirelyrule out the PdII-PdIV catalytic cycle since both paths will form identicalproducts.

Figure5.3Proposedcatalyticcycleforthepalladium-catalyzedcycloisomerization.

The reaction between the palladium precusor and a hydride donor (HCOOH)first generatesapalladiumhydride species (119),whichuponcoordination tothe alkyne and subsequent hydrometallation gives a vinyl palladiumintermediatethatisconcurrentlycoordinatedtothealkene(122).Thefollowing

[(MeCN)4Pd](BF4)2

PdN

PH

HCOOHN,P-ligand

O

R2R1

R3

O

R1 R2

PdNP

R3

O

R2H R3

PdNP

O

R2 R3

O

R1

PdNP

R2R3

H

120

121

122

123

124

119

51

stepcomprisestheinsertionofthealkeneinthevinylpalladiumtoprovide123,andβ-hydrideeliminationtofurnishtheene-typecyclizedproduct124.


The synthesis of substrates[88] and ligands[89] were carried out as previouslyreported in the literature. The screening of N,P-ligands for the asymmetriccycloisomerizationof1,6-enynesissummarizedinTable5.1.Theallylpropargylether125wasusedasstandardsubstratefortheasymmetric isomerization inpresence of Pd(CH3CN)4(BF4)2 and a chiral N,P-ligand. The reaction proceedssmoothlyat80°CinDMSOin18hourstogivetheene-typecyclicproduct126.It was observed that both the reactivity and the selectivity of the reactiondepend on the ligand structure, as shown in Table 5.1. Imidazole ligandR-L1gave good enantioselectivity (88% ee) but low reactivity and the desiredproductwas isolatedonly in27%yield.Switchingtoa ligandhavingathiazolemoietyR-L2gaveslightlyhigherenantioselectivity(92%ee).

Table5.1EvalutionofthechiralN,P-ligands.a

aReaction conditions: Substrate 125 (0.25 mmol), [(CH3CN)4Pd](BF4)2 (5 mol%), N, P-ligand(10mol%),HCOOH(0.25mmol)andDMSO(2ml),80°C,18h.

However, the yield was low allowing only 23% isolated yield of the product.LigandS-L3 providedan increase in yield, but adecrease in enantioselectivitywas observed (62% ee). Surprisingly, by replacing the phenyl group on the

O

CO2Me

O

CO2Me

[(MeCN)4Pd](BF4)2 (5 mol%)N,P-ligand (10 mol%)HCOOH (1.0 equiv.)

DMSO 18 h, 80 ºC

N

NPh

PPh2

R-L1

27% yield, 88% ee (S)

S

NPh

PPh2

R-L223% yield, 92% ee (S)

NPPh2

S

NPh

S-L352% yield, 62% ee (R)

S

NPh

P(o-Tol)2

S-L468% yield, 99% ee (R)

S

NPh

P(o-Tol)2

R-L5

77% yield, 90% ee (S)

O

NPh

NP(o-Tol)2


NP(o-Tol)2

O

N

R-L7

52% yield, 67% ee (S)

O

N

P(o-Tol)2


125 126

52

phosphine in ligand R-L2 with an o-tolyl (S-L4) gave an increase inenantioselectivity as well as reactivity. The desired product was obtained in68% isolated yield and in 99%ee. The open chain thiazole ligandR-L5with ahigherdegreeof flexibilitygrantedslightly improvedyieldbutcauseadrop inselectivity. The bicyclic ligands containing the oxazoline moiety (R-L6 – R-L8)werealsoscreened.Thereactionprovidedlowtomoderateselectivity,andtheyieldwas foundtodependonthesubstitutionontheoxazolinegroup.Finallyligand S-L4 proved to be the best both regarding enantioselectivity andreactivityproviding99%eeand68%isolatedyield

5.2.1 Substratescope

LigandS-L4was then chosen to screen a rangeof differently substituted allylpropargylethers(Table5.2).Replacingthemethylestergrouponsubstrate125totrimethylsilane(127) leadtoadramaticdecrease inenantioselectivity (55%ee). Gratifyingly, the high catalytic activity was maintained and the startingmaterial was converted entirely to the product in 18 h, providing 80% ofisolated yield. No improvement in enantioselectivity and reactivity wasobserved when the trimethylsilane group was changed to an isopropyl ester(129) (Table 5.2, entry 2). The substrate affordedmoderate enantioselectivity(52%ee)and78%isolatedyield.IntroducingethylgroupontheC-2carbonofthe olefin (131) resulted in low enantioselectivity (80% ee) whilemaintainingcomparable reactivity to that of substrates 129. A slight increment inenantioselectivityto81%wasalsoobservedwhentheethylwasreplacedwithbenzyl group on the C-2 position of the olefin (133). The substrates withoutmethyl substituent on the C-1 carbon of the olefin (135) resulted in lowenantioselectivity(31%ee)aswellassubstrateswithamorestericallycrowdeddoublebond(137).Nonetheless,highreactivitywasretainedgivingupto80-84%yield.Thesubstratebearingan isopropylgroup introducedat theC-2positionoftheolefin(E/Z139)didnotisomerizeunderstandardconditions.

53

Table5.2Substratestudyofcycloisomerizationof1,6-enyneswithS-L4.a

aReaction conditions: Substrate (0.25 mmol), [(CH3CN)4Pd](BF4)2 (5 mol%), N,P-ligand(10mol%),HCOOH(0.25mmol)andDMSO(2ml),80°C,18h.bNMRyield.

Raising the reaction temperature and a higher loading of catalyst failed toimprovetheresult.Thepossibleexplanation for thisobservationcouldbethestericbulkinessoftheisopropylgroup,whichisinhibitingthecyclizationorthebeta-hydrideeliminationstepinthecatalyticcycle.

O

R3

R4

O

R3 R4

[(MeCN)4Pd](BF4)2 (5 mol%)S-L4 (10 mol%)

HCOOH (1.0 equiv.)

DMSO 18 h, 80 ºC

R2

R2R1

Entry Substrate Product Yield (%) ee (%)

O

CO2i-Pr

O

CO2i-Pr

O

TMS

O

TMS

O

CO2Me

O

CO2Me

O

CO2Me

O

CO2Me

O

CO2Me

O

CO2Me

O

CO2Me

O

CO2Me

O

CO2Me

O

CO2Me

Ph Ph

1

2

3

4

5

6

7

80 55

78 52

75b 80

75 81

84 31

80b 22

- -E-139Z-139

R1

127

129

131

133

135

137

140

138

136

134

132

130

128

C-2

C-1

54

5.2.2 Investigationofthehydrogensource.

IthasearlierbeensuggestedbyMikamithattheactivecatalyticspeciesconsistof the palladium hydride, which in turn can be readily generated frompalladium precatalysts in the presence of a hydrogen source. A range ofadditives has been screened under standard conditions using ligandR-L5 and[(CH3CN)4Pd](BF4)2 with substrate 135 (Table 5.3). Under standard conditionsligandR-L5gave84%isolatedyieldand31%ee(entry1).Withoutanyadditives,the reaction still proceeded smoothly, providing complete conversion to thecyclic product in 18 h. However, using freshly dried DMSO the reactionproceedsconsiderablyslowercomparedtowetDMSO.Fromthisresult itwasconcluded that the water present in the wet DMSO was sufficient to act ashydrogen source to generate the palladium hydride species, which in turnacceleratesthereactionrate.

Table5.3Investigationofthehydrogensources.a

aReaction conditions: Substrate 135 (0.25 mmol), [(CH3CN)4Pd](BF4)2 (5 mol%), N,P-ligand(10mol%),HCOOH(0.25mmol)andDMSO(2ml),80°C,18h.

Asimilarresultwasobservedwhenwaterwasdirectlyemployedasanadditive.In almost all cases full conversionwereobserved,with 80-84% isolated yield.However, the enantioselectivity was significantly affected giving 31% to 12%and 10% ee respectively (entries 1-3). The effect of the hydride source wasfurther examined using methanol and trifluoroethanol. The high catalyticactivitywasstillmaintained inbothcases,andan increasedenantioselectivitywasobservedwhencomparedtotheadditionofwaterorremovalofadditives

O

CO2Me

O

CO2Me[(MeCN)4Pd](BF4)2 (5 mol%)

(R)-L5 (10 mol%)additiveDMSO

18 h, 80 ºC

Entry Additive Amount (equiv.) Conversion (isolated yield (%)) ee (%)

1 HCOOH 1.0 99 (84) 31

2 - - 99 (80) 12

3 H2O 50 99 (82) 10

4 MeOH 50 99 (82) 25

5 TFE 50 99 (79) 29

135 136

55

(entries4-5);usingtrifluoroethanolresultedinslightlyhigherenantioselectivitycomparedtomethanol.

5.3 Enantioselectivityandabsoluteconfiguration

Figure5.4Selectivitymodelforenantioselectivity.

TheabsoluteconfigurationoftheproductgeneratedwiththeuseofligandR-L2and S-L4 can be predicted from a quadrant selectivity structuremodel. Themodeltakes intoaccountthedegreeofsterichindranceinthefourquadrantsaroundthemetalcenter,accordingtotheligandandthemodeofcoordinationoftheincomingolefin(transtophosphorous).ThephenylsubstituentontheN-heterocyclic and the phosphine occupy two of the four quadrants (i and iv);makingthemrespectivelyhinderedi,andsemi-hinderediv,whiletheothertwoquadrants are left relatively open (ii and iii). In the stereodetermining step(Figure 5.3 122) the olefin is arranged in such a way that the hydrogen, thesmallest substituent, resides in the most hindered quadrant i (Figure 5.4b),whileitsbulkysubstituentremainsintheopenquadrant(iiandiii).AnewC-Cbondisformed,andonestereogeniccenterisgeneratedintheproductduringthecyclizationstep(Figure5.3123).Theabsoluteconfigurationoftheproductcanbederivedfromthequadrantmodelasseen inFigure5.4band5.4e.ThehinderedquadrantiofligandR-L2favorstheformationofS-126andligandS-L4

PS

N

i ii

iii iv

PdN

S

P

i ii

iii iv

Pd

N

S

PPd PS

N Pd

i ii

iii iv

i ii

iii ivR-L2 S-L4

NS

PPd

i ii

iii iv

Sterically favored Sterically unfavored

HO

CO2Me

O

CO2Me

a d

b c e

O

CO2Me

O

CO2MeO

CO2MeS-126 R-126 R-126

H

HO

CO2Me

56

(holdingoppositeconfigurationcomparedtoR-L2generatesmostthehinderedquadrant at iii, resulting in the formation of R-126. All the absoluteconfiguration predicted by this model was found in agreement withexperimentalmeasurementasshowninTable5.1.

5.4 Conclusion

ArangeofN,P-ligandswerestudied in theasymmetricene-typecyclizationof1,6-enynesusingapalladiumprecatalystwithHCOOH.The cycloisomerizationof allyl propargyl ethers took place efficiently by the catalytic system, givingmoderatetogood isolatedyields.Theenantioselectivitywas foundtodependbothon the ligand structure and thehydride source. The ligandS-L4was thebestinordertodeliverhighenantioselectivity(upto99%ee)usingHCOOHashydride source. The reaction provides a challenging quaternary stereogeniccenter inproximityofdifferentfunctionalities,whichinturncanbeappliedtofurtherchemicaltransformation.

57

6 PopulärvetenskapligSammanfattningpåSvenska

Arbetet som presenteras i denna avhandling avser asymmetrisk katalysmedanvändningavkiralaN,P-liganderochiridiumellerpalladiummetaller.Den första delen (kapitel 2 och 3) behandlar N,P-iridiumkatalyseradasymmetrisk hydrogenering av 1,4-cyklohexadiener som harfunktionaliseradeoch/ellerofunktionellasubstituenter,inklusiveallylsilan-sidokedjor. En serie N,P-iridiumkatalysatorer syntetiserades ochutvärderades på ett antal cyklohexadiener. De utvecklade N,P-iridiumkatalysatorerna resulterade i utmärkt kemo-, regio- ochenantioselektivitet för de flesta av de erhållna produkterna. För substratsom har en allylsilan sidokedja användes de bildade kirala cykliskaallylsilanerna för att inducera stereokontroll i en efterföljande Hosomi-Sakurai-reaktionmed användning av TiCl4 som Lewis-syra och aldehydersom elektrofiler. Produkterna, homoallyliska alkoholer, erhölls i god tillutmärktdiastereoselektivitet.Denandradelen(kapitel4)beskriverN,P-iridiumkatalyseradasymmetriskhydrogenering av olika vinylfluorider. Ett antal tri- och tetrasubstitueradevinylfluorider syntetiserades och utvärderades i den asymmetriskahydrogeneringen. Produkterna, mättade kirala fluorföreningar, erhölls imyckethögenantioselektivitet(upptill99%ee).Defluorinering,somärenvanlig sidoreaktion under de katalytiska hydrogeneringsförhållandena,observeradesejförmajoritetenavsubstraten.Slutligenbeskriverkapitel5tillämpningenavN,P-liganderidenasymmetriskacykloisomeriseringenav1,6-enyner med användning av en palladium-katalysator.Enantioselektivitetenförprodukternabefannsberobådepåsubstratetochvätekällan.De utvecklade katalytiska reaktioner som beskrivs i denna avhandlingtillhandahållerattraktivametoderförattskapaflerastereogenacentraienmolekylirelativtfåstegochfrånlättillgängligautgångsmaterial.

58

AppendixA:Contributionlist

I. Enantio-andRegioselectiveIr-CatalyzedHydrogenationofDi-andTrisubstitutedCycloalkenesSynthesized six catalysts and five substrates and took part in thescreeningofthereaction.Participatedinthepreparationofthesupportinginformation.

II. Ir-Catalyzed Asymmetric and Regioselective Hydrogenation ofCyclicAllylsilanesandGenerationofQuaternaryStereocentersviatheHosomi-SakuraiAllylationSynthesizedthemajorpartofthesubstratesandperformed≈80%oftheexperiments.Participatedinthepreparationofthemanuscriptandthesupportinginformation.

III. N,P-IridiumCatalyzedAsymmetricHydrogenationofVinylFluoridesSynthesisofallsubstratesandtookpartinscreening.Participatedinthepreparationofthesupportinginformation.

IV. Thiazole,ImidazoleandOxazolineBasedN,P-LigandsforPalladium-CatalyzedCycloisomerizationof1,6EnynesSynthesizedathirdoftheligandandsomesubstrates.Participatedinthepreparationofthesupportinginformation.

59

Acknowledgements

Iwouldliketoexpressmydeepestappreciationtothoseenthusiasticandhighlydevotedpeoplearoundme:First and foremost, my utmost gratitude to my supervisor, Prof. Pher GAndersson, for accepting me as a Ph.D. candidate in his group. Your help,inspiring suggestions, and encouragement helpedme all the time during theresearch.Youhavesupportedmethroughoutmystay inthedepartmentwithyour patience and knowledge, whilst providing me with an excellentatmospherefordoingresearch.Thankyouforalltheeffortsyouhaveputintomakemeabetterresearcher.Specialthankstomyco-advisorProf.BjörnÅkermarkforhisexcellentguidance,caring, patience and providing a comfortable environment to discuss. Dr.MarkusKärkäsforbeingawonderfulcollaboratoraswellasbeingmyguidanceandthanksforintroducingmetoartificialphotosynthesis.Dr. Janjira Rujirawanich (Nan), for your help and suggesting me to Pher.Dr.Pushpesh Upadhyay, for being wonderful lab colleague and an encouragingperson.Dr.VijaySinghParihar,IreallyappreciateyourhelpwhenIfirstmovedtoSweden.Dr.ThishanaSingh,thankyouforyouradviceandsupport.Dr.ByronPeters, the most knowledgeable chemist in the group whom I admire andrespect a lot. Always ready to give a helpinghand andprovide thenecessarysupport, both in and outside the lab. Thank you for helping me withinstrumentsandIhopeonedaywewillmeetagain.Dr.XuQuan,thehumoristand charismatic twin brother. Thank you for being supportive and I enjoyedyourcompanybothinandoutsideworkinghours.Dr.JianguoLiu,aninnocentbut cheerful colleague, I really enjoyed talking and sharing about our lifeexperiences and I will cherish it forever. Sutthichat Kerdphon, the loudestperson in the lab, I enjoyed your company and will cherish our friendshipforever. Cristiana Margarita, a conscientious and diligent person, I reallyenjoyedworkingtogetherwithyou.Thankyouforproofreadingmythesisandgiving suggestions. Suppachai Krajangsri, the DJ, and vocalist of the group,thanksforbeingniceandverysupportivecolleague.HaiboWu,atalkativeand

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sociable person, my brother, thank you for your help. Jiangping Yang, thequietest and hard-working person, thanks for your help. Dr. Sudipta Ponra,thanksforbeingsupportiveandIreallyenjoyedworkingtogetherwithyou.Dr.JiaZheng,aniceandsupportivecolleaguethanksforthehelp.I would like to acknowledge the financial, academic and technical support oftheuniversityandtheirstaff.CarinLarsson,KristinaRomare,MartinRoxengren,andOlaAndersson.fortheirtechnical support. Jenny Karlsson, Louise Lehto, Sigrid Mattsson and GülsünKücükgölfortheirsupportinadministrativework.Manythankstomycolleaguesinthedepartment:Dr.AnonBunrit(IenjoyedyourcompanybothinSwedenandThailandandnottomentionaboutyourwonderfulanddeliciousfood),Dr.SunisaAkkarasamiyo,Dr. Rahul Watile, Elena Subbotina, Pemikar Srifa, Phakinee Khunsirikulwanit,Jasmine Ingboon, Dr. Jéssica Margalef, Dr. Supaporn Sawadjoon, AndreyShatskiy,Dr.TanjaLaine,Dr.AhmedF.Abdel-Magied,AlessandroRuda,StalinReddyPathipati,Dr.MarcMontesinos,ViolaHobiger,Dr.GrecoGonzalezMiera(Mybrother,thankyouforyoursupport,adviceandforalwaysbeingtheretohelpme),HaniMobarak,SamuelMartinezErro,DongWang,DavidBitar,AitorBermejoLópez,youguysmademystayhereinthisdepartmentunforgettable.ThankstomyfriendsinSweden:SonamChokey,Dorji Tshomo,PemaYeshi,AlfPersson,PaulKrusic,NunnapudWilliam Jörgensen, Bo William-Jorgensen and Chatchai Vongpratoom formakingmystayinSwedenmorehomely. Profound appreciation goes tomy uncleDophu and auntDechen Choden fortheir immensesupport,andlove.WithouttheirhelpIwouldnothavemadeitthisfarinmylife.Thankyousomuch.Finally, I would like to thank my mother (Pema Dema) and my late father(Rinzin),theirloveisimmeasurableandtheirsupportsissounthinkablethatishard to express in words. They have providedme not just with the financialmeans, but also with moral and spiritual support, for which I am forevergrateful.TomywifeUma,thankyoudarlingfortheloveandsupport.

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