DEVELOPMENT OF CATALYTIC ENANTIOSELECTIVE C-Cmiun.diva-portal.org/smash/get/diva2:768971/FULLTEXT01.pdfvaluable structural scaffolds, namely poly-substituted spirocyclic oxindoles

Thesis for the degree of Doctor of Philosophy, Sundsvall 2014

DEVELOPMENT OF CATALYTIC ENANTIOSELECTIVE C-C

BOND-FORMING AND CASCADE TRANSFORMATIONS BY

MERGING HOMOGENEOUS OR HETEROGENEOUS

TRANSITION METAL CATALYSIS WITH ASYMMETRIC

AMINOCATALYSIS

Samson Afewerki

Supervisor:

Professor Armando Córdova

Department of Natural Sciences

Mid Sweden University, SE-851 70 Sundsvall, Sweden

ISSN 1652-893X,

Mid Sweden University Doctoral Thesis 206

ISBN 978-91-87557-90-3

ii

Akademisk avhandling som med tillstånd av Mittuniversitetet i Sundsvall

framläggs till offentlig granskning för avläggande av filosofie doktorsexamen

fredag, 24 oktober, 2014, klockan 10:15 i sal M108, Mittuniversitetet Sundsvall.

Seminariet kommer att hållas på engelska.


BOND-FORMING AND CASCADE TRANSFORMATIONS BY

MERGING HOMOGENEOUS OR HETEROGENEOUS

TRANSITION METAL CATALYSIS WITH ASYMMETRIC

AMINOCATALYSIS

Samson Afewerki

© Samson Afewerki, 2014


Mid Sweden University, SE-851 70 Sundsvall Sweden

Telephone: +46 (0)771-975 000

Printed by Mid Sweden University, Sundsvall, Sweden, 2014

iii

I hated every minute of training, but I said, “Don’t quit.

Suffer now and live the rest of your life as a champion.”

- Muhammad Ali (World Boxing Champion)

iv

v


BOND-FORMING CASCADE TRANSFORMATIONS BY MERGING

HOMOGENEOUS OR HETEROGENEOUS CATALYSIS WITH

ASYMMETRIC AMINOCATALYSIS

Samson Afewerki


Mid Sweden University, SE-851 70 Sundsvall, Sweden

ISSN 1652-893X, Mid Sweden University Doctoral Thesis 206;

ISBN 978-91-87557-90-3

ABSTRACT

Chiral molecules play a central role in our daily life and in nature, for instance

the different enantiomers or diastereomers of a chiral molecule may show

completely different biological activity. For this reason, it is a vital goal for

synthetic chemists to design selective and efficient methodologies that allow the

synthesis of the desired enantiomer. In this context, it is highly important that the

concept of green chemistry is considered while designing new approaches that

eventually will provide more environmental and sustainable chemical synthesis.

The aim of this thesis is to develop the concept of combining transition metal

catalysis and aminocatalysis in one process (dual catalysis). This strategy would

give access to powerful tools to promote reactions that were not successful with

either transition metal catalyst or the organocatalyst alone. The protocols presented

in this thesis based on organocatalytic transformations via enamine or iminium

intermediates or both, in combination with transition metal catalysis, describes

new enantioselective organocatalytic procedures that afford valuable compounds

with high chemo- and enantioselectivity from inexpensive commercial available

starting materials.

In paper I, we present a successful example of dual catalysis: the combination of

transition metal activation of an electrophile and aminocatalyst activation of a

nucleophile via enamine intermediate. In paper II, the opposite scenario is

presented, here the transition metal activates the nucleophile and the

aminocatalyst activates the electrophile via an iminium intermediate. In paper III,

we present a domino Michael/carbocyclisation reaction that is catalysed by a chiral

vi

amine (via iminium/enamine activation) in combination with a transition metal

catalysts activation of an electrophile. In paper IV, the concept of dual catalysis

was further extended and applied for the highly enantioselective synthesis of

valuable structural scaffolds, namely poly-substituted spirocyclic oxindoles.

Finally, in paper V the concept of dual catalysis was expanded, by investigating

more challenging and environmentally benign processes, such as the successful

combination of a heterogeneous palladium and amine catalysts for the highly

enantioselective synthesis of functionalised cyclopentenes, containing an all carbon

quaternary stereocenter, dihydrofurans and dihydropyrrolidines

Keywords: asymmetric catalysis, transition metals, aldehydes, heterogeneous

catalysis, amino acid, organocatalysis, α-allylation, β-alkylation, dynamic

transformations, polysubstituted, carbocycles, spirocyclic oxindoles, all-carbon

quaternary stereocenters

vii

SAMMANDRAG

Kirala molekyler spelar en central roll i vårt dagliga liv och i naturen, exempelvis

kan de olika enantiomererna eller diastereomererna av en kiral molekyl uppvisa

helt olika biologiska aktiviteter. Därför är ett ytterst viktig mål för syntetiska

kemister att utforma selektiva och effektiva metoder som möjliggör att syntetisera

den önskade enantiomeren. I detta sammanhang är det också mycket viktigt att

man tar hänsyn till begreppet grön kemi vid utformning av nya syntetiska

strategier, vilket kommer att leda till en mer miljövänlig och hållbar kemisk syntes.

Syftet med denna avhandling har varit att utveckla konceptet att kombinera

användandet av övergångsmetaller samt aminosyror som katalysatorer i en

gemensam process. Denna strategi skulle kunna ge tillgång till ett kraftfullt

verktyg för att gynna reaktioner som inte är möjliga att genomföra med enbart

övergångsmetallkatalysatorer eller organokatalysatorer. De protokoll som

presenteras i denna avhandling bygger på organokatalytiska transformationer via

enamin eller iminium intermediär eller båda dessa i kombination med

övergångsmetallkatalysatorer. De syntetiska metoderna beskriver nya

enantioselektiva organokatalytiska tillvägagångssätt som ger tillgång till viktiga

substanser med hög kemo- samt enantioselektivitet genom att starta från billiga

och kommersiellt tillgängliga utgångsmaterial.

I artikel I presenterar vi ett lyckat exempel där en synergistisk kombination av

övergångsmetall som aktiverar en elektrofil samt aktivering av en nukleofil via

enamin intermediär med hjälp av en aminokatalysator. I artikel II presenteras det

motsatta scenariot, där övergångsmetallen istället aktiverar en nukleofil och

aminokatalysatorn en elektrofil via iminium aktivering. I artikel III, utnyttjas

iminium och enamin aktivering i kombination med att

övergångsmetallkatalysatorn aktiverar en elektrofil i en domino reaktion. I artikel

IV utvidgas konceptet att kombinera de två katalytiska systemen och tillämpas för

enantioselektiv syntes av de strukturellt viktiga byggstenarna nämligen poly-

substituerade spirocykliska oxindoler.

Slutligen, i artikel V vidareutvecklar vi konceptet med dubbla katalytiska system

genom att undersöka en mer utmanande och miljövänlig process. Här presenteras

en lyckad kombination av en heterogen palladiumkatalysator och

organokatalysator för enantioselektiv syntes av funktionaliserade cyklopentener

bestående av ett kvartärt stereogent kol, dihydrofuraner och dihydropyrrolidiner.

viii

TABLE OF CONTENTS

ABSTRACT ....................................................................................................................... V

SAMMANDRAG .......................................................................................................... VII

LIST OF PAPERS ............................................................................................................ XI

PAPERS NOT INCLUDED IN THIS THESIS: ........................................................................... XII

LIST OF ABBREVIATIONS ...................................................................................... XIII

1. INTRODUCTION ...................................................................................................... 1

1.1. ASYMMETRIC SYNTHESIS ........................................................................................ 1

1.2. ASYMMETRIC CATALYSIS ........................................................................................ 1

1.3. ORGANOCATALYSIS ................................................................................................ 2

1.4. AMINOCATALYSIS ................................................................................................... 2

1.4.1. ENAMINE ACTIVATION CATALYSIS ...................................................................... 4

1.4.2. IMINIUM ACTIVATION CATALYSIS ....................................................................... 6

1.4.3. SOMO ACTIVATION CATALYSIS .......................................................................... 7

1.5. ORGANOCATALYTIC DOMINO REACTIONS ............................................................... 7

1.6. TRANSITION-METAL CATALYSIS .............................................................................. 9

1.7. HETEROGENEOUS CATALYSIS ............................................................................... 10

1.8. COOPERATIVE DUAL CATALYSIS ........................................................................... 10

1.8.1. COOPERATIVE AMINO AND TRANSITION METAL CATALYSIS .............................. 12

1.9. DYNAMIC KINETIC ASYMMETRIC TRANSFORMATION (DYKAT) ......................... 14

1.10. LEWIS ACID CATALYSIS ..................................................................................... 18

2. COOPERATIVE COMBINATION OF TRANSITION METAL- AND

ENAMINE ACTIVATION CATALYSIS (PAPER I) .................................................. 19

2.1. INTRODUCTION ..................................................................................................... 19

2.2. RESULTS AND DISCUSSION .................................................................................... 20

2.2.1. OPTIMISATION STUDIES ..................................................................................... 20

2.2.2. SUBSTRATE SCOPE ............................................................................................ 21

2.2.3. PROPOSED REACTION MECHANISM .................................................................... 22

2.2.4. SHORT TOTAL SYNTHESIS OF (S)-ARUNDIC ACID ............................................... 24

2.3. CONCLUSION ......................................................................................................... 24

3. COOPERATIVE COMBINATION OF TRANSITION METAL- AND

IMINIUM ACTIVATION CATALYSIS (PAPER II) ................................................. 25

3.1. INTRODUCTION ..................................................................................................... 25


ix


3.2.2. SUBSTRATE SCOPE ............................................................................................ 29


3.2.4. TOTAL SYNTHESIS OF THE NATURAL PRODUCT BISABOLANE SESQUITERPENES . 31

3.3. CONCLUSION ......................................................................................................... 32

4. COOPERATIVE DUAL CATALYSIS IN DOMINO REACTIONS (PAPER

III) 33

4.1. INTRODUCTION ..................................................................................................... 33



4.2.2. SUBSTRATE SCOPE ............................................................................................ 37


4.3. CONCLUSION ......................................................................................................... 41

5. THE CONSTRUCTION OF HIGHLY ENANTIOSELECTIVE

POLYSUBSTITUTED SPIROCYCLIC OXINDOLES BY COOPERATIVE DUAL

CATALYSIS (PAPER IV) ................................................................................................ 42

5.1. INTRODUCTION ..................................................................................................... 42



5.2.2. SUBSTRATE SCOPE ............................................................................................ 47


5.3. CONCLUSION ......................................................................................................... 50

6. COOPERATIVE COMBINATION OF HETEROGENEOUS- AND

AMINOCATALYSIS FOR ENANTIOSELECTIVE CHEMICAL

TRANSFORMATION (PAPER V) ................................................................................ 51

6.1. INTRODUCTION ..................................................................................................... 51



6.3.2. SUBSTRATE SCOPE FOR THE SYNTHESIS OF CYCLOPENTENES ............................ 53

6.3.3. SCOPE FOR THE SYNTHESIS OF DIHYDROFURANS AND DIHYDROPYRROLIDINES . 53

6.3.5. EVALUATION OF THE RECYCLABILITY AND LEACHING ...................................... 56

6.4. CONCLUSION ......................................................................................................... 57

CONCLUDING REMARKS ........................................................................................... 58

APPENDIX A - AUTHOR CONTRIBUTION TO PUBLICATION I-V ................. 59

APPENDIX B – CRYSTAL STRUCTURE .................................................................... 60

APPENDIX C – NOESY SPECTRA ............................................................................... 61

x

APPENDIX D – CRYSTAL STRUCTURE ................................................................... 62

APPENDIX E – NOESY SPECTRA ............................................................................... 63

ACKNOWLEDGEMENTS ............................................................................................. 64

REFERENCES ................................................................................................................... 65

xi

LIST OF PAPERS

This thesis is mainly based on the following publications, herein referred to by

their Roman numerals I-V:

I Direct Regiospecific and Highly Enantioselective Intermolecular

α-Allylic Alkylation of Aldehydes by a Combination of

Transition-Metal and Chiral Amine Catalysts

Samson Afewerki, Ismail Ibrahem, Jonas Rydfjord, Palle Breistein

and Armando Córdova.

Chem. Eur. J. 2012, 18, 2972.

II Catalytic Enantioselective β-Alkylation of α,β-Unsaturated

Aldehydes by Combination of Transition-Metal- and

Aminocatalysis: Total Synthesis of Bisabolane Sesquiterpenes

Samson Afewerki, Palle Breistein, Kristian Pirttilä, Luca Deiana,

Pawel Dziedzic, Ismail Ibrahem and Armando Córdova.

Chem. Eur. J. 2011, 17, 8784.

III A Palladium/Chiral Amine Co-catalyzed Enantioselective

Dynamic Cascade Reaction: Synthesis of Polysubstituted

Carbocycles with a Quaternary Carbon Stereocenter

Guangning Ma, Samson Afewerki, Luca Deiana, Carlos Palo-Nieto,

Leifeng Liu, Junliang Sun, Ismail Ibrahem and Armando Córdova.

Angew. Chem. Int. Ed. 2013, 52, 6050.

IV Highly Enantioselective Control of Dynamic Cascade

Transformations by Dual Catalysis: Asymmetric Synthesis of

Poly-Substituted Spirocyclic Oxindoles

Samson Afewerki, Guangning Ma, Ismail Ibrahem, Leifeng Lui,

Junliang Sun, and Armando Córdova.

Manuscript.

V Highly Enantioselective Cascade Transformations By Merging

Heterogeneous Transition Metal Catalysis with Asymmetric

Aminocatalysis

Luca Deiana, Samson Afewerki, Carlos Palo-Nieto, Oscar Verho,

Eric V. Johnston and Armando Córdova.

Sci Rep. 2012, 2, 851. www.nature.com, DOI:10.1038/srep00851.

Reprints were made with permission from the respective publishers.

http://www.nature.com/

xii

Papers not included in this thesis:

Palladium/Chiral Amine Co-catalyzed Enantioselective β-Arylation of

α,β-Unsaturated Aldehydes

Ismail Ibrahem, Guangning Ma, Samson Afewerki and Armando Córdova.

Angew. Chem. Int. Ed. 2013, 52, 878.

Combined Heterogeneous Metal/Chiral Amine: Multiple Relay Catalysis for

Versatile Eco-Friendly Synthesis

Luca Deiana, Yan Jiang, Carlos Palo-Nieto, Samson Afewerki, Celia A. Incerti-

Pradillos, Oscar Verho, Cheuk-Wai Tai, Eric V. Johnston and Armando Córdova.

Angew. Chem. Int. Ed. 2014, 53, 3447.

Efficient and Highly Enantioselective Aerobic Oxidation-Michael-

Carbocyclization Cascade Transformations by Integrated Pd(0)-CPG

Nanoparticle/Chiral Amine Relay Catalysis

Luca Deiana, Lorenza Ghisu, Oscar Córdova, Samson Afewerki, Renyun Zhang

and Armando Córdova.

Synthesis 2014, 46, 1303.

Total Synthesis of Capsaicin Analogues from Lignin-Derived Compounds by

Combined Heterogeneous Metal, Organocatalytic and Enzymatic Cascade in

One Pot

Mattias Anderson, Samson Afewerki, Per Berglund and Armando Córdova.

Adv. Synth. Catal. 2014, 356, 2113.

Enantioselective Heterogeneous Synergistic Catalysis for Asymmetric Cascade

Transformations

Luca Deiana, Lorenza Ghisu, Samson Afewerki, Oscar Verho, Eric V. Johnston,

Niklas Hedin, Zoltan Bacsik and Armando Córdova.

Adv. Synth. Catal. 2014, 356, 2485.

xiii

LIST OF ABBREVIATIONS

AmP Aminopropyl

Ar Aryl

Bn Benzyl

Cat. Catalyst

CH3CN Acetonitrile

Conv. Conversion

Dba Dibenzylideneacetone

DFT Density functional theory

DKR Dynamic kinetic resolution

DMF Dimethylformamide

DMSO Dimethyl sulfoxide

Dppe 1,2-Bis(diphenylphosphino)ethane

d.r diastereomeric ratio

DYKAT Dynamic Kinetic Asymmetric Transformation

E Electrophile

EDG Electron donating group

e.e Enantiomeric excess

e.r Enantiomeric ratio

Et Ethyl

EWG Electron withdrawing group

GC Gas chromatography

HOMO Highest occupied molecular orbital

HPLC High performance liquid chromatography

HRMS High resolution mass spectroscopy

KR Kinetic resolution

L Ligand

LG Leaving group

LUMO Lowest unoccupied molecular orbital

MCF Mesocellular foam

Me Methyl

MeO Methoxy

MOF Metal-organic frameworks

MS 4Å Molecular sieves (4 Ångström)

MeOH Methanol

NaBH4 Sodium borohydride

n.d Not determined

NMO N-Methylmorpholine-N-oxide

NMR Nuclear magnetic resonance

Nu Nucleophile

Bpin Pinacolato boron

xiv

Ph Phenyl

r.t Room temperature

SOMO Single occupied molecular orbital

TBDMS tert-butyldimethylsilyl ether

tBu tert-butyl

Temp. Temperature

TES Triethylsilyl

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TMS Trimethylsilyl

TPAP Tetrapropylammonium perruthenate

TsCl 4-Toluenesulfonyl chloride

1

1. INTRODUCTION

1.1. Asymmetric Synthesis

An important aim within organic synthesis is to target and develop new highly

efficient catalytic and asymmetric routes to enantiopure complex and valuable

compounds from inexpensive and readily available starting materials. Asymmetric

synthesis is an important method for enantioselective synthesis of desired

compounds.[1] Within asymmetric synthesis, various strategies have been

developed to introduce stereoselectivity into a reaction by using: chiral auxiliary,

chiral reagent, chiral pool and chiral catalyst. The chiral auxiliary is an enantiopure

chiral molecule temporarily incorporated in the substrate to introduce chirality.

The major drawback of this method is the extra synthetic steps required to

introduce and remove the chiral unit. Of the known methods for generating

enantiomerically pure compounds from achiral starting materials, asymmetric

catalysis is an efficient and economic strategy.[2]

1.2. Asymmetric catalysis

Nature is our source of inspiration and the ultimate paragon in designing

efficient and powerful catalytic chemical reactions. All the dynamic, efficient, and

highly selective processes that take place in nature, the chemists desire to create in

the laboratory. Enzymes catalyse most of the chemical synthesis in nature, giving

access to enantiomerically pure biologically active molecules. Because the different

enantiomers or diastereomers of a molecule often have different biological activity,

enantiomerically pure compounds are important in the field of pharmaceuticals.

The critical importance of obtaining pure enantiomers can be demonstrated in

the example of naproxen. The (S)-enantiomer is an anti-inflammatory drug,

whereas the (R)-enantiomer is a liver toxin (figure 1). Therefore, methods for

preparation of enantiomerically pure compounds are of major importance. Other

areas where pure enantiomers play an important role are in agrochemicals,

flavours and fragrances (figure 2).[3]

H3CO

OH

O

CH3

(S)-Naproxen (R)-Naproxen

Mirror planeAn anti-inflammatory drug A liver toxin.

CH3

HO

OOCH3

Figure 1. The two enantiomers of naproxen, with different biological activity.

2

(R)-Limonene Smells of oranges

(S)-Limonene Smells of lemons

H2N

O

OH

O

NH2

(R)-Asparagine Bitter

H2N

(S)-Asparagine Sweet

O

O

(R)-Olean Attracts male olive flies

O

O

(S)-Olean Attracts female olive flies

Mirror plane

OH

O

NH2O

Figure 2. Three compounds and their enantiomers showing completely different biological

outcomes.

Asymmetric catalysis is the most efficient procedure for the synthesis of

enantiomerically pure compounds.[2] A small amount of a chiral catalyst converts

large quantities of achiral starting materials into enantiopure compounds.

Asymmetric catalysis can be divided into three fields: Metal catalysis, Biocatalysis

and Organocatalysis.

1.3. Organocatalysis

In the last decade, the field of organocatalysis received great attention among

chemists around the world, because most of the reactions are easily performed,

insensitive to moisture and air, and employ readily available and non-toxic

materials. The pursuit of mimicking the catalytic mechanisms and stereoselectivity

of enzymes[4] is one of the breakthroughs in the field of organocatalysis.[5] A small

organic molecule is used to catalyse advanced organic transformations in the

absence of any metal.[6] Furthermore, organocatalysis can contribute as a powerful

tool for creating complex molecular frameworks in an efficient and

environmentally friendly approach, especially for the pharmaceutical companies

around the globe implementing a policy towards green chemistry.[7]

1.4. Aminocatalysis

Already in 1963, Stork realised the importance of enamine activation and

employed a stoichiometric amount of amine for the generation of the more reactive

enamines than the corresponding enolate of unmodified ketones.[8]

One of the first and most famous enantioselective organocatalytic

transformations disclosed in 1971 is the proline catalysed intramolecular aldol

reaction by Hajos and Parish.[5],[9] Subsequent acid mediated dehydration of the

3

corresponding aldol product such as 3 gives product 4 (scheme 1). Shortly after

this Eder, Sauer and Wiechert reported a similar one-pot reaction procedure to 4

using stoichiometric amounts of the proline catalyst.[10]

O

DMF, r.t., 72hO

OH

O

O

O

p-TsOH

C6H6

1 3100% yield, 93% ee

O

O

4

NH

CO2H

2a (3 mol%)

Scheme 1. The Hajos-Parish reaction.

This pioneering research increased the interest in the field of organocatalysis and

the vide supra described transformations were used in industry and applied to total

synthesis of natural products.[11] However, it was not until 2000 that aminocatalysis

began to be applied to a wider array of organic transformations.[6] Here, Barbas,

Lerner and List,[12] described the first intermolecular aldol reaction involving

ketones as donors (scheme 2). The same year MacMillan and co-workers disclosed

the first chiral amine-catalysed enantioselective Diels-Alder reaction (scheme 3).[13] O

R H

O

+Cat.2a (30 mol%)

DMSO, r.t.

O

65 7R

OH

54-97% yields60-96% ee's

R = Ar or iPr

Scheme 2. Proline-catalysed direct aldol reaction reported by List, Barbas and Lerner.

Ph O+

NH

NO

Bn

HCl

(5 mol %)

MeOH/H2O, 8h, 23 oCCHO

Ph

10-endo, 93% ee

Ph

CHO

10-exo, 93% ee

Ratio 1:1.3, yield 99%

+

8a 9

2b

Scheme 3. A catalytic enantioselective Diels-Alder reaction disclosed by MacMillan and co-

workers.

The use of primary or secondary amine catalyst for activation of different

carbonyl compounds, such as aldehydes and ketones, via different activation

modes, is one of the most dominant and amplified branches within asymmetric

organocatalysis, providing important and valuable chiral scaffolds.[6],[14],[15] The

condensation of the amine catalyst with the carbonyl moiety provides reactive

intermediates such as enamine, iminium and enamine radical cation via HOMO

(highest occupied molecular orbital), LUMO (lowest unoccupied molecular

orbital), respective SOMO (singly occupied molecular orbital) activation (scheme

4).

4

N

R

N

R

+N

RE+

Nu-

O

R

H

H H H

E

functionalised aldehyde

Enamine activation catalysis

Iminium activationcatalysis

SOMO activationcatalysis

O

H


R Nu

O

R

H


Nu

Nu-

Scheme 4. The different activation modes in aminocatalysis.

1.4.1. Enamine activation catalysis

Carbonyl compounds can be activated towards addition to several of

electrophiles at their α-carbon, through the formation of a nucleophilic enamine

species. The formation of iminium species I, by condensation of a chiral amine

catalyst with the aldehyde will increase the acidity of the α-proton (scheme 5,

intermediate I) and lead to a fast deprotonation, which results in HOMO-raising

and the formation of the active nucleophilic enamine intermediate (scheme 5,

intermediate II). The equilibrium is shifted toward the more stable (E)-trans

enamine due to steric repulsion between the R-group and the proton adjacent to

the nitrogen atom in the pyrrolidine ring.[16] The enamine can further react with a

range of electrophiles, delivering α-functionalised chiral aldehydes after

subsequent regeneration of the chiral amine catalyst through hydrolysis.

5

H2O

R

O

O

R

E

OH-

N

R

E

NH

N

R

N

R

H H+

N

R

(E)-s-cis enamineless stable

(E)-s-trans enaminemore stable

I

trans-II cis-II

III

E+

Scheme 5. Catalytic cycle of enamine mediated α-functionalisation.

The use of chiral cyclic secondary amines as catalysts has played a pivotal role for

the development of new chemical transformations of carbonyl compounds. There

are two possible ways, by which stereoinduction can be employed, depending on

the substituents on the aminocatalyst.[17] When an aminocatalyst containing a

hydrogen-bond-donating group is employed for promoting stereoselectivity, this

will proceed through hydrogen-bond directing as illustrated in scheme 6. The

hydrogen-bond will direct the electrophile to approach from above resulting in Re-

face attack. The second pathway is when the stereocontrol is achieved with the aid

of steric shielding. An aminocatalyst, which carries a bulky substituent will

sterically shield the electrophile and prevent it from attacking the shielded side.

Hence, the attack occurs from below via Si-face attack, which gives the opposite

enantiomer.

N

RY

Z

XH

N

R

Y

Z

Hydrogen-bondingstereocontrol

Face-shieldingstereocontrol

Re-faceattack

Si-faceattack

O

R

O

R

Z Z

YHYH

Scheme 6. Stereoinduction through two different pathways, hydrogen-bond directing and

steric shielding.

6

1.4.2. Iminium activation catalysis

Another important approach for the activation of carbonyl compounds is

through the formation of iminium intermediates. The concept of iminium catalysis

follows the same as Lewis acid catalysis (scheme 7), where the formation of

iminium intermediate lowers the LUMO of the electrophile. The difference is the

formation of a covalent intermediate. Thus, higher catalyst loadings may be

necessary. Scheme 8 exemplifies the catalytic cycle of iminium-mediated β-

functionalisation of α,β-unsaturated aldehyde. The equilibrium of the iminium ion

IV, formed after condensation of α,β-unsaturated aldehyde with the chiral amine

catalyst will be shifted towards the more stable (E)-iminium ion which can react

with a diverse range of nucleophiles.[18]

+ Lewis acid (LA)

+

LUMO-activation

O

R2 R1

O

R2 R1

LA

O

R2 R1

N

R2 R1

+

+

NH

Nu-

Nu-

Scheme 7. LUMO-activation with the assistance of a secondary amine or Lewis acid

catalysis of α,β-unsaturated carbonyl compound.

Nu-

H2O

N

NH

N

OH-

N(E)-iminium ion

more stable

R R

(Z)-iminium ionless stable

R Nu

+H+

N

R Nu

-H+

O

R Nu

H

(E)-IV

V

VI (Z)-IV

O

R

Scheme 8. Catalytic cycle for β-functionalisation of α,β-unsaturated aldehyde through

iminium activation catalysis.

7

1.4.3. SOMO activation catalysis

The activation modes of aminocatalysis have been further extended to SOMO

activation catalysis.[19],[20] This allows for polarity inversion (umpolung) of the

nucleophilic enamine forming radical cation intermediate via single electron

transfer. The intermediate can react with a variety of π-nucleophiles affording α-

functionalised carbonyl compounds.

1.5. Organocatalytic domino reactions

An inspirational goal of a synthetic chemist is to become as efficient and selective

as the creation of molecules in Nature. One synthetic strategy taking the chemist

closer to this goal is to employ biomimetic approaches. Nature uses highly efficient

cascade or domino reactions for biosynthesis of natural products, which

successfully generate complex structures with multiple stereocenters and the

reactions simultaneously proceed with excellent chemo-, regio- and

stereoselectivity.[21] Nature’s arsenal and sophisticated structural design have

fascinated and guided chemists to invent new synthetic methodologies, and has

elevated their knowledge to a whole new level.[22]

The cascade or domino reaction postulated by Tietze, is a reaction in which two

or more chemical bonds are formed based on the functionalities formed in the

previous step, under the same reaction conditions.[23] This strategy has several

advantages. It offers less purification steps, and has time and economic benefits,

when compared to traditional “stop and go approaches”, where purification and

isolation are performed after each chemical transformation before the next step.

Furthermore, Tietze’s strategy also gives access to molecules with high

complexity and a shorter synthetic route starting from simple materials.[24]

The use of aminocatalysis allows for the generation of two active intermediates,

the nucleophilic enamine and electrophilic iminium ones (vide supra, section 1.4.1

and 1.4.2), and therefore there are possibilities to combine these two activation

modes in one reaction in a domino fashion, which allows the formation of two new

bonds. For example, as depicted in scheme 9, is the use of iminium and enamine

subsequent activation involves both the electrophile and the nucleophile.[25]

Additionally, there are also possibilities to employ the opposite scenario enamine

and iminium activation for conjugate addition as depicted in scheme 10.

8

H2O

R

O

E+

OH-

N

R Nu

E

NH

N

R

N

R Nu

Nu-

O

R Nu

E

Scheme 9. The concept of iminium/enamine activation manifold in domino reactions

H2O

R

O

H2O

NH

N

R

N

R

R'

R'

X Y

R'

+

XY

N

R

R'

XY

O

R

R'

XY

Scheme 10. The concept of enamine/iminium activation manifold in domino reactions.

9

1.6. Transition-metal catalysis

Transition metal catalysis in organic synthesis is undoubtedly one of the most

powerful tools in the synthesis of valuable organic molecules in an efficient

manner. They have been extensively employed for various industrial applications,

in particular for the pharmaceutical industries.[26]

The presence of incomplete filled d-orbitals in transition metals gives them their

unique features for the use as catalysts in different chemical transformations.

The ability to obtain several oxidation states by accepting or giving electrons,

allows them to form different bonds and complexes which are important aspects in

catalytic reactions. Generally, transition metal catalysis can be divided into

homogeneous or heterogeneous catalysis. Compared to heterogeneous catalysis,

where the catalyst is immobilised onto heterogeneous supports with the catalyst

and the substrate in different phases, homogeneous catalysis, i.e. catalysis in

solution, offers a number of advantages, such as higher activity and selectivity,

because the catalyst is usually dissolved in the reaction mixture, which makes all

the catalytic sites accessible.[27] An example of a successful transition metal

catalysed reaction is the palladium catalysed Tsuji-Trost reaction.[28] The palladium

catalysed allylation reaction can occur via two different pathways depending on

the nature of the nucleophile. The use of stabilized (soft) nucleophiles such as

malonates and enamines usually add directly to the allyl moiety, which eventually

leads to an overall retention of configuration. Whereas the use of non-stabilized

(hard) nucleophiles such as organometallic reagents first attack the metal center,

and finally leads to an overall inversion of configuration followed by reductive

elimination to give the allylation product (scheme 11).

R2R1

X

PdLnR2R1

-X (II)Pd+

soft Nu-

L L

hard Nu-

R2R1

(II)PdL L

R2R1

Nu

R2R1

+

reductive elimination R2R1

Nu

R2R1

+

Nu

decomplexation-PdLn

-PdLn

retention

inversionNu

Nu

Scheme 11. Stereochemical outcome with soft and hard nucleophiles.

10

1.7. Heterogeneous catalysis

The endeavour of developing environmentally friendly and sustainable chemical

reactions that follow the concept of green chemistry is a focal goal for the chemical

society.[29] The concept of green chemistry is formulated as follows:

The “design of chemical products and processes to reduce or eliminate the use and

generation of hazardous substances”.[30] In this context, the use of catalysis is one of

the criteria for green processes. Despite the advantages of homogeneous catalysis,

it has drawbacks; when it comes to special handling, inert atmosphere and water

free solvents are required in some cases. Catalyst recovery and recyclability are

other aspects. To avoid these problems heterogeneous catalysis can be employed,

and it offers many advantages. The catalyst usually has higher stability both in

terms of storage and handling, the reaction can be performed in air atmosphere

and the catalyst is possible to recover and recycle by simple methods such as

filtration, decantation, extraction or through centrifugation and can be further

reused in multiple cycles, which makes the process more cost-effective. In addition,

heterogeneous catalysis offers a greener process because waste of toxic and

expensive catalysts can be avoided.[31] Due to the advantages with heterogeneous

catalysis and also because metal contamination is avoided it is attractive for

applications in both academia and industry.

The choice of support materials for designing efficient heterogeneous catalysts

are a key factor, and several solid supports have been used for immobilising

homogeneous catalysts, such as silica, dendrimers, zeolites and metal-organic

frameworks (MOFs).[32] In particular, mesoporous silica materials have been

attractive due to their unique features, such as high surface area, chemical,

thermal, and mechanical stability, highly uniform pore distribution and tuneable

pore size.[33]

1.8. Cooperative dual catalysis

Dual catalysis, where two different catalysts are used to allow for new unsolved

and challenging chemical transformations, not possible by a single catalyst alone,

has attracted an increasing number of researchers.[34]

However, one aspect to be considered when designing a suitable catalytic system

is the compatibility of the two catalysts to avoid catalyst inhibition.[35] This type of

strategy can be seen in nature were different enzymes can react by synergistic

cooperation, to form several bonds in a single sequence.[36]

The power of cooperative dual catalysis is demonstrated in figure 3, where two

separate catalysts activate two reactive species, one electrophile and the other a

nucleophile. As illustrated in figure 3, lowering the LUMO activates the

electrophile, whereas increasing the HOMO activates the nucleophile. Compared

to the case when a single catalyst is used, when two catalysts are employed, they

11

reduce the activation energy of the reaction to a larger extent. Hence, the

transformation is more prone to be efficient and successful.[34c]

LUMOA

A

E

BHOMO

Catalyst 1

+

Catalyst 1

B

C

LUMOA

E

BHOMO

Catalyst 1

+

Catalyst 2

+

Reaction where only one catalyst is employed Reaction where two catalysts are employed in a cooperative mode

B

Catalyst 2C

A

Catalyst 1

Figure 3. Illustration of the fundamentals of cooperative dual catalysis, when two catalytic

systems are utilised in a compatible way, compared to when single catalyst alone is

employed.

In other words dual catalysis is when separate catalysts activates the reactive

species in separate catalytic cycles and later on the two catalytic cycles are merged

together to form the chemical bond (figure 4).[37]

Dual catalysis

P

A + B

Catalyst 1

Catalyst 2

Figure 4. Clarification of the term dual catalysis.

12

1.8.1. Cooperative amino and transition metal catalysis

The organocatalysis field has grown to become one of the three-pillars within

asymmetric catalysis for obtaining complex chiral compounds.[6] Despite the many

advantages the field has shown (vide supra, section 1.3), it has, like every champion,

its own weaknesses and limitations, e.g. the activation through the employment of

aminocatalysis is restricted to carbonyl functionalities. To overcome this limitation

and broaden the chemical transformations of organocatalysis, cooperative dual

catalysis with metal or enzyme catalysts was introduced. At the same time the

introduction of organocatalysis to these fields also broadens their spectra of

applications.

Consequently a win win situation is created. In this thesis, cooperative dual

catalysis is achieved by a combination of aminocatalysis and transition metal

catalysis. This has been shown to be a powerful and important approach. In 2006

our group published the first successful simultaneous use of aminocatalysis and

transition metal catalysis by introducing a one-pot combination of transition metal

activation of an electrophile and an amine to enamine activation of an aldehyde or

ketone (scheme 12 and 13).[38]

Ph

H

O

+OAc

(10 mol%)

[Pd(PPh3)4] (5 mol%)

DMSO, 22 oC, 16h Ph

H

ONaBH4

MeOH, 0 oC

Ph

OH

72% yield

+OAc

(30 mol%)


DMSO, 22 oC, 16h

90% yield

O O

11a 12a

2c

13m 14m

15 16

2c

12a

NH

NH

Scheme 12. The first one-pot combination of a transition metal and an amine catalysts in

synergistic manner, where the amine generates the nucleophilic enamine and the transition

metal activates the electrophilic species.

Ph

H

O

+OAc

NH

(20 mol%)


DMSO, r.t

NaBH4

Ph

OH

3h, 25% yield, 87:13 er20h, 45% yield, 60:20 er

Ph

Ph

OTMS 2d

14m12a11a

Scheme 13. Selected examples from the attempt of enantioselective α-allylic alkylation back

in 2006.

13

Since this seminal work was published, this concept has become an attractive tool

and has further extended the potential and scope of catalysis. The influence this

work is revealed by the immense number of reports made on the combination of

aminocatalysis and transition metal catalysis since it was published.[39]

However, the possibility of merging amine catalyst activation of carbonyl

compounds through formation of electrophilic iminium in combination with the

transition metal activation of a nucleophile remained unsolved until recently,

when our group reported the first enantioselective conjugate silyl addition to α,β-

unsaturated aldehydes.[40] Since then, this newly developed concept has been

further expanded. It was further applied for the catalytic enantioselective β-

alkylation of α,β-unsaturated aldehydes (paper II), the catalytic enantioselective

synthesis of homoallylboronates and for the co-catalysed enantioselective β-

arylation of α,β-unsaturated aldehydes (scheme 14).[41]

R1 H

O

R1 H

OSi

PPh3 (20 mol%)

THF, 9-18h, 60 oC

Chiral amine 2d (25 mol%)Cu(OTf)2 (10 mol%)

R2Zn (2.0 equiv.)

4-NO2C6H4CO2H (10 mol%)

PhMe2Si-B(pin) (1.0 equiv.)

CH2Cl2, 22oC, 4h

Chiral amine 2d (25 mol%)

CuCl (10 mol%)

KOtBu (5 mol%)

R1 H

OR

MeMePh

R1 H

OBpin

B2(pin)2 (1.1 equiv.)

PPh3 (10 mol%)

MeOH (3.0 equiv.)

2-F-C6H4CO2H (10 mol%)

Et2O, 22oC, 45 min

Chiral amine 2d (20 mol%)

Cu(OTf)2 (5 mol%)

NaOtBu (5 mol%)

Transition Metal Catalysis

Iminium Catalysis

Borolation

Alkylation

Silylation

+

Chiral amine 2d (20 mol%)Pd(OAc)2 (5 mol%)

Ar-BH(OH)2 (1.5 equiv.)

R1 H

OAr

Arylation

Cs2CO3 (25 mol%)

MeOH (5.0 equiv.)

Toluene, 2h, 220C

NH

Ph

Ph

OTMS

2d

Scheme 14. The concept of combining amine catalyst activation of carbonyl compounds

through formation of electrophilic iminium and transition metal activation of nucleophile were

expanded for formation of different types of chemical bonds.

14

1.9. Dynamic Kinetic Asymmetric Transformation (DYKAT)

The conversion of racemic mixture into an enantiopure compound in 100%

theoretical yield, overcomes the drawbacks of kinetic resolution (KR). In the case of

KR only a theoretical yield of 50% can be obtained and the method relies on the

differences in reaction rate of the two enantiomers. There are different de-

racemisation methods that can be employed for the complete transformation of

racemic mixture into a single enantiomeric product, for instance dynamic kinetic

resolution (DKR) or dynamic kinetic asymmetric transformation (DYKAT).[42] In

DKR both enantiomers are converted to a single product through racemisation of

the slower enantiomer to the more reactive one, whilst in the case of DYKAT the

process occur via diastereomeric intermediates.

The de-racemisation method DYKAT is defined as: “The de-symmetrisation of

racemic or diastereomeric mixtures involving interconverting diastereomeric

intermediates-implying different equilibration rates of stereoisomers”[42d] There are

four types of DYKAT processes, type I and II relate to de-racemisation of

enantiomers, whereas type III and IV relate to de-epimerisation of diastereomers.

The differences between type III and type IV is that in the former, de-epimerisation

of a diastereomeric mixture of enantiomeric pairs take place, whereas in type IV

de-epimerisation occurs via a diastereomeric mixture of enantiomeric pairs

through achiral intermediates (scheme 15).

15

SR

Cat.*

kA

SRCat.*

SCat.*

SCat.* complex of chiral catalyst with achiral intermediate

kC

kD

Cat.*

kB

SSCat.*

kE PR

kF PS

majorproductfast

slow

SS

fast

slowminor

product

SR

Cat.*kA

SCat.*

Cat.*

kB

kC

PR

kD

PS

SS

fast

slow

DYKAT Type I DYKAT Type II

kSS

fast

DYKAT Type III DYKAT Type IV

PSS

slow

SSS

kSS/SRSSR

PSR

kSR

slow

SRS

PRS

kRS

slow

kRR/RSSRR

PRR

kRR

kRS/SS kSR/RR

kSS'PSS

slowPSR

kSR'

slow

kRR'PRR

slowPRS

kRS'

fast

SSS SSR

A + Bachiral

SRR SRS

kSSkSR

kRR kRS

Scheme 15. The four different types of DYKAT mechanisms

In 2010, continuing to devise enantioselective transformations based on the

combination of aminocatalysis and transition metal catalysis, our group disclosed

the first example of one-pot highly chemo- and enantioselective dynamic kinetic

asymmetric transformation (DYKAT) between α,β-unsaturated aldehydes and

propargylated carbon acids (scheme 16a).[43] Shortly after, the concept was

extended to the enantioselective synthesis of dihydrofurans (scheme 16b).[44]

16

R

O NC CO2Me

[Pd(PPh3)4] (5 mol%) CH3CN, 16-72h, r.t.

R

NC

O

+

CO2Me

8 17a 19

2d (20 mol%)

H

H

55-60 yields up to 12:1 d.r. and 86-95 ee´s

a)

R

O OH

PhCO2H (20 mol%) CHCl3 or THF, 18-144h, 4 oC

O R

O

+

8 17b 20

HH

40-77 yields and up to 91-99 ee´s

b)

2d (20 mol%), PdCl2 (5 mol%)

Scheme 16. a) Examples of the dynamic kinetic asymmetric transformation by combined

amine- and transition metal catalysed enantioselective cycloisomerisation, reported by our

group. b) Examples of the dynamic kinetic asymmetric oxo-Michael/carbocyclisation

reaction, reported by our group shortly after.

The Michael-cyclisation DYKAT process proceeds via a reversible Michael

addition and provides, after hydrolysis of the amine catalyst, the corresponding

Michael products 18 and ent-18 in racemic mixture. The chiral enamine

intermediates VIIa and VIIb undergo a palladium-catalysed cycloisomerisation on

the activated alkyne. Note that one step is faster than the other, which is indicated

by a solid arrow in scheme 17; the slower step is signified by a dotted arrow. The

enantioselective cascade transformation gives access to highly diastero- and

enantiopure compounds.

17

R

O

XH

+8

17

H NH

2

-H+

-H+

N

R

X

Pd-catalyst

fastX R

O

H

Michael addition

Michael addition

Carbocyclisation

Pd-catalyst

slowX

R

O

H

Carbocyclisation

O

R

XH

O

R

XH

Hydrolysis H2O

Hydrolysis H2O

X = C(CO2R)2, CNCO2R, O, NTs

18

ent-18

VIIa

VIIb

19

ent-19

N

R

X

Scheme 17. Pd and amine catalysed DYKAT transformation

18

1.10. Lewis acid catalysis

A Lewis acid is a species with a vacant orbital and can therefore accept an

electron pair and promote a chemical reaction. Lewis acids have been used as

catalysts for different organic reactions.[45] For example, transition metals such as

palladium with electron deficient metal center can be used as a Lewis acid catalyst

for activation of olefins and enynes toward nucleophilic addition. As depicted in

scheme 18 a functionalised cyclic structure could be obtained when the Lewis acid

palladium was used as catalyst in a cyclisation reaction.[43],[44],[46]

N

R

X

Pd-catalyst

X R

O

H

Lewis acid activation of alkyne

VII

19

N

R

X

VIII

PdII

Scheme 18. Lewis acid activation of alkyne for the Pd and amine catalysed carbocyclisation

DYKAT transformation.

19

2. COOPERATIVE COMBINATION OF TRANSITION METAL- AND ENAMINE ACTIVATION CATALYSIS (PAPER I)

2.1. Introduction

The α-alkylation of carbonyl compounds is an important and useful approach for

the C-C bond formation.[47] In this context, the Tsuji-Trost allylation reaction is a

very powerful strategy, because an allyl-group is introduced, which is a valuable

moiety for further transformations. However, due to competing side reactions,

such as aldol condensation, Cannizzaro and Tishchenko reactions and N- or O-

alkylations, this reaction is mainly restricted to direct α-allylic alkylations of non-

stabilised ketones and aldehydes (scheme 19a).[28],[48],[49] Another challenge when

using this type of reaction is that one have to consider how to control

regioselectivity (scheme 19b). Here it is known that the use of a Pd-catalyst

provides the linear product whereas the use of an Ir-catalyst provides the branched

isomer.[50],[51]

Despite all the many challenges that hinder the development of a suitable

methodology, our group devised a protocol for the direct catalytic intermolecular

α-allylic alkylation of aldehydes and ketones, providing the desired products with

high chemo- and regioselectivity (vide supra, section 1.8.1, scheme 12).[38]

LGRMetal catalyst, Nu-

NuR + R

Nu

H

O

R

Aldol condensation

H

O

RR

Cannizzaro reaction

OH

O

R

OH

R

+

Tishchenko reactiona)

b)

O

O

R R

Linear Branched-LG

Scheme 19. a) The challenging side reactions of non-stabilised aldehydes.

b) Regioselectivity issues.

At the time our group also attempted to develop a catalytic enantioselective

version, unfortunately without impressive results (vide supra, section 1.8.1, scheme

13). This is due to racemisation of the -stereocenter of the carbonyl compound.

20

Thus, it is challenging to both control the stereoselectivity of the C-C bond-forming

step and next avoid racemisation of the corresponding -allylic alkylated products.

Recently, we went back and re-examined the enantioselective version of the α-

allylation reaction of carbonyl compounds. As a model for further studies we

investigated the reaction of 3-phenylpropionaldehyde 11a with phenyl allyl acetate

12b, catalysed by the chiral amine catalyst 2d in combination with

tetrakis(triphenylphosphine)palladium(0) ([Pd(PPh3)4]) as co-catalyst.

2.2. Results and discussion

2.2.1. Optimisation studies

To optimise the reaction, we considered amine and transition metal catalyst

compatibility and inhibition, solvent and temperature. From this study we

concluded that the correct solvent and temperature were crucial for obtaining high

reactivity and enantioselectivity (table 1). DMSO was the solvent of choice,

providing the highest reactivity, whereas DMF gave the highest enantioselectivity

(table 1, entries 2 and 3). Hence, we envisioned that a mixture of these two solvents

probably would give the optimal results. To our delight this worked well and the

optimal condition turned out to be a 1:1 mixture of DMSO and DMF at -20 °C for

40h (table 1, entry 9). We tried different leaving groups in the phenylallyl moiety

but this did not improve the results (table 1, entries 10 and 11).

21

Table 1. Selected examples of the screening studies.[a]

Entry Conv. [%][b]

1 70

Pd-cat. e.r.[%][c]

75:25

Ph LG

Solvent

DMSO

+ Ph

Ph

OHIn situ. Red.

NaBH4, MeOH

-15 oC, 15 min.

[Pd(PPh3)4]

Time [h]

13

Ligand T [oC]

22

2d (20 mol%)Ligand(10 mol%)

14a

LG

OAc

Ph

O

H

-

2 93 81:19DMSOPd(OAc)2 2922OAc PPh3

Pd-cat. (5 mol%) Solvent

11a 12

Ph

Ph

H

13a

O

3 63 87:13Pd(OAc)2 2422OAc PPh3

4 66 85.5:14.5Pd(OAc)2 484OAc PPh3 DMSO

5 43 95:5Pd(OAc)2 484OAc

6 65 92:8DMF/DMSOPd(OAc)2 244OAc PPh3

7 95 83:17244OAc

8 11 n.d.Pd(OAc)2 40-20OAc PPh3 DMF/DMSO

PPh3

DMF

DMF

[Pd(PPh3)4] - DMF/DMSO

9 96 96:4DMF/DMSO 40-20OAc

10 40 96:448-20Br [Pd(PPh3)4] - DMF/DMSO

[Pd(PPh3)4] -

11 21 88:1248-20Cl [Pd(PPh3)4] - DMF/DMSO

[a] Under N2 atmosphere; final concentration = 0.5 M. [b] Determined by 1H NMR

spectroscopy on the crude reaction mixture. [c] Determined by analysis of chiral phase

HPLC.

2.2.2. Substrate scope

By using diverse aldehydes 11 and allyl acetates 12 we expanded the generality

of this transformation. Examination of the substrate scope showed that having an

electron-donating group (EDG) in the para-position on the phenylallyl acetate 12 or

using unsubstituted allyl acetate, the reactivities were lower, although the

enantioselectivity remained high (scheme 20: 14i, 14j, 14m and 14n). Electron-

withdrawing groups (EWG) in the para-position on the phenyl-allyl acetate 12

increased the reactivity and the isolated yield was nearly doubled (scheme 20: 14k

and 14l). Furthermore, the transformation also tolerated various aldehydes. Thus

reacting aliphatic aldehydes with different lengths and side-chain functionalities,

we obtained good to high yields, 70-83%, and high enantioselectivities 94:6-98:2

(scheme 20: 14b-h).

22

R1 H

O

+R2

[Pd(PPh3)4] (5 mol%) NaBH4, -15 oC

MeOH, 15 min

R1

OHOAc

(20 mol%)

R2

NH OTMS

Ph

Ph

3.0 equiv. 1.0 equiv.

Ph

OHPh OHPh OHPh OHPh

14a, 80% yield, 96:4 er 14b, 71% yield, 94:6 er 14c, 79% yield, 97:3 er 14d, 70% yield, 95:5 er

OHPh OHPh OHPh OHPh

14e, 83% yield, 98:2 er 14f, 81% yield, 96:4 er 14g, 75% yield, 97:3 er 14h, 83% yield, 95:5 er

BnO

Ph

OHOH

14i, 30% yield, 98:2 er 14j, 50% yield, 98:2 er

MeOMeO

OH

14k, 78% yield, 96.5:3.5 er

PhCl

OHOH

14l, 81% yield, 97.5:2.5 er 14m, 58% yield, 92:8 er

PhCl

OH

14n, 55% yield, 97:3 er

DMSO:DMF-1:1

-20 oC, 40-48h

2d

11 12 14

Scheme 20. Substrate scope of the direct catalytic enantioselective intermolecular α-allylic

alkylation of aldehydes.

2.2.3. Proposed reaction mechanism

The catalytic asymmetric C-C bond formation occurs via dual cooperative

catalysis, where the nucleophile and electrophile are simultaneously activated

through distinct catalysts with directly coupled catalytic cycles. The proposed

reaction mechanism is presented in scheme 21, where the nucleophilic enamine

intermediate II is formed through condensation of the chiral amine catalyst 2 and

the aldehyde 11. In parallel, the electrophilic η3-π-allylpalladium complex IX is

generated through a separate catalytic cycle, after oxidative addition of the

palladium catalyst. The two active intermediates are merged; resulting in

23

formation of intermediate X. The chiral product 13 is formed after regeneration of

the chiral amine and palladium catalysts.

Oxidative addition

Nucleophilicaddition

CondensationReductive elimination

Hydrolysis

H

O

H2O

R2

Pd+

[Pd]0

R2

12

-OAc

H2O

IX

AcONH

11R1

2

N

R1

HII

L

L

(II)

N

R1

HX

R2

+

N

R1

HXI

R2

+O

R1

H13

R2

Pd(0)L2

Decomplexation

Scheme 21. The proposed reaction mechanism for the direct catalytic enantioselective

intermolecular α-allylic alkylation of aldehydes.

However, an additional challenge that can lead to low stereoselectivity is the

problem with racemisation or epimerisation that can occur by either the chiral

amine catalyst or through enolization forming ent-13 (scheme 22).

through enolization

N

R1

HXI

R2

+

N

R1

H R2

N

R1

HXIa

R2

+

O

R1

H

13

R2

H2O

NH2

O

R1

H

ent-13

R2

H2O

NH2

+H+ -H+

XII

-H+

+H+

Scheme 22. Main problems that can lead to low stereoselectivity for the direct catalytic

enantioselective intermolecular α-allylic alkylation of linear aldehydes.

24

2.2.4. Short total synthesis of (S)-arundic acid

To demonstrate the importance and simplification of this methodology, we

applied it to a short total synthesis of arundic acid. Here the (R)-enantiomer is a

very interesting target due to its biological activity. It is active against inter alia

Alzheimer’s and Parkinson’s diseases and is currently undergoing clinical

studies.[52] The co-catalytic asymmetric reaction between octanal 11i and allyl

acetate 12a, gave after in situ reduction of the corresponding alcohol 14o in high

enantioselectivity albeit in moderate yield. After catalytic hydrogenation with

Pd/C and subsequent catalytic oxidation, we had completed the three-step

synthesis of (S)-arundic acid 22 in 96% yield from 14o (scheme 23). The absolute

configuration of product 14 was confirmed by comparing the [α]D value with that

reported of 22.[52b]

OAc+H

O

OHi)-ii) iii) OH iv) CO2H

46% yield, 96.5:3.5 e.r. 98% yield 98% yield, (S)-arundic acid

Conditions: i) chiral amine 2d (20 mol%), [Pd(PPh3)4] (5 mol%), DMF/DMSO 1:1, -20 oC, 48h; ii) NaBH4, MeOH, -15 oC,

15min; iii) cat. Pd/C, H2 (balloon), MeOH, r.t.; iv) NaClO2, cat. NaClO, cat. TEMPO, CH3CN/Buffer (pH 6.5).

11i 12a 14o 21 22

[]D20 = +6.6 (c = 0.5, EtOH)

(Litt. []D20 = +6.6 (c = 0.54, EtOH)

Scheme 23. The total synthesis of (S)-arundic acid in three steps.

2.3. Conclusion

In conclusion, the work presented vide supra offers a more promising

enantioselective protocol than those previously reported, giving access to highly

regio- and enantioselective α-allylated products in all examples, starting from

simple and readily available starting materials. The importance of the

methodology to the short total synthesis of the valuable natural product arundic

acid was further demonstrated. A future expansion of this dual catalysis strategy is

to challenging catalytic asymmetric domino reactions (See chapter 4 and 5).

Another important future application of this concept would be its

implementation with Iridium catalysis, which would open up for the formation of

the branched regioisomers (Scheme 19b) and the creation of -allylated aldehydes

with two newly formed stereocenters. This was recently beautifully accomplished

by Carreira and co-workers.[53]

25

3. COOPERATIVE COMBINATION OF TRANSITION METAL- AND IMINIUM ACTIVATION CATALYSIS (PAPER II)

3.1. Introduction

An additional versatile methodology for enantioselective formation of carbon-

carbon bonds is enantioselective Cu-catalysed conjugate addition (ECA) of

organometallic reagents to Michael acceptors.[54] However, the use of α,β-

unsaturated aldehydes as Michael acceptors is very challenging due to their high

reactivity and their ability to undergo competing undesired 1,2–additions (scheme

24).[55]

R H

O

1,4-addition

1,2-addition

R H

Ocat. Cu-salt

R1-M

R1

R R1

OH

+

Scheme 24. The two competing pathways for Cu-catalysed conjugate addition of

organometallic reagents to α,β-unsaturated aldehydes.

Chiral β-methylated arylalkylaldehydes are important building blocks for the

enantioselective synthesis of bioactive natural products such as bisabolane

sesquiterpenes (e.g., (S)-(+)-curcumene 27, (S)-(+)-dehydrocurcumene 30, (S)-(+)-

turmerone 31), but these compounds still remain challenging to construct (scheme

25). Therefore access to these compounds via an efficient asymmetric methodology

is of great interest. Bisabolane sesquiterpenes exhibit cytostatic and antibiotic

activities, and are also used as additives in perfumes, flavours and cosmetics.[56]

H

OO

(S)-(+)-turmerone (S)-(+)-curcumene

31 27

(S)-(+)-dehydrocurcumene

30

23k

Scheme 25. Retrosynthetic analysis for the synthesis of bisabolane sesquiterpenes 27, 30

and 31.

In 2011, our research group successfully reported the first example of further

expansion of the concept of dual catalysis, and merged the catalytic cycle of

26

transition metal activation of a nucleophile and a chiral iminium activation of an

enal.[40] We hypothesised that this methodology of dual catalysis could be applied

for the synthesis of β-alkyl substituted aldehydes by enantioselective conjugate

addition of alkylreagents to α,β-unsaturated aldehydes.

In 2010, Aleksakis and co-workers reported the first protocol for asymmetric Cu-

catalysed conjugate addition of dialkylzinc and Grignard reagents to α,β-

unsaturated aldehydes in the presence of phosphine ligands inducing chirality.[57]

The desired products were obtained with moderate to excellent 1,4-

regioselectivity and up to 90% ee’s. However, the work by Aleksakis et al. was

restricted to aliphatic α,β-unsaturated aldehydes, only two examples of aromatic

α,β-unsaturated aldehydes with low to moderate enantioselectivity were reported

(scheme 26). This report encouraged us to investigate whether our methodology

could be successful in this transformation.

An elegant idea would be to use the ability of a chiral amine catalyst to lower the

LUMO of the α,β-unsaturated aldehydes via iminium activation as a platform in

combination with copper catalysed conjugate addition of organometallic reagents

to control the regioselectivity and enantioselectivity.

OPh

CuTC, (R)-BINAP

Et2Zn

Et2O, -20 oC, 6h OPh

EtCuTC, (R)-Tol-BINAPEtMgBr, TMSCl

Et2O, -78 oC, 8hO

Et

Ph

81 % yield 44% ee

Ratio (1,4/1,2): 20:8053% ee

Scheme 26. Selected results from the report of Aleksakis and co-workers.



We started our investigation of the catalytic asymmetric 1,4-addition of

alkylmetal to α,β-unsaturated aldehydes by one-pot combination of the chiral

amine catalyst 2 and copper salt as the co-catalyst. To avoid the undesired 1,2-

addition, we anticipated the use of dialkylzinc as the nucleophilic source, because

compared to the corresponding Grignard reagents they are known to be less

reactive, more stable and also exhibit a high functional group tolerance. The

nucleophilicity of organozinc reagents can be increased through transmetallation

to form more reactive organometallic reagents.[58]

We selected cinnamic aldehyde 8a as the model substrate, THF as the solvent and

2d as the amine catalyst for our optimisation study (table 2). As we had predicted,

a reaction performed in the absence of the chiral amine catalyst 2d was not

selective and it gave only traces of the desired product 23a with no

enantioselectivity (table 2, entry 1). When we carried out the reaction in the

presence of 2d but in the absence of a copper source, slightly higher enantio- and

regioselectivity were obtained (table 2, entry 2), corroborating the impact of the

27

chiral amine catalyst 2d. Although lower reactivity was obtained when the two

catalysts were combined together, the synergistic effect can be revealed by the

significant increase in stereoselectivity (table 2, entry 3). Shifting to the more

reactive Grignard reagent (EtMgBr) as the nucleophilic source failed in promoting

the reaction successfully, instead it almost exclusively gave the undesired product

24a as a racemic mixture (table 2, entry 5). A more promising result was obtained

when the ligand L1 was added (table 2, entry 6). Hoping to increase the reactivity

and selectivity we used p-nitro-benzoic acid as an additive to drive the formation

of the iminium ion (scheme 28: intermediate IV) but this did not improve the

results (table 2, entry 7). We also found that CuTC and CuCl were less effective

than Cu(OTf)2 (table 2, entries 4 and 9).

Table 2. Optimisation studies for the Cu-catalysed conjugate addition of organometallic

reagents to cinnamic aldehyde 8a.[a]

Entry Conv. [%][b]

1[e] 91

e.r.[%][d]

50:50

t [h]

12

ligand L1 (mol%)

Cat. 2d (25 mol%)

Ph

O

H

Cu(OTf)2 (10 mol%)

Et2Zn (2.0 equiv.)

8aPh

O

H23a

Ratio 23a/24a[c]

3:97

Ph

OH

24a

+

3 18 82:1812 84:16

4[g] 23 71:294 16:84

6 58 96:417 62:38

7[i] 64 82:1812 67:33

8 72 88:1216 34:66

9[j] 24 91:923 76:24

T [oC]

60

60

50

60

60

22

60

-

-

-

L1 (20)

L1 (20)

L1 (20)

L1 (4)

ligand L1, Temp., THF

5[h] 100 51:496 8:9222-

2[f] 29 78:229 22:7860-

[a] Under N2 atmosphere; final concentration = 0.5 M. [b] Determined by

1H NMR

spectroscopy on the crude reaction mixture. [c] Determined by GC and 1H NMR of the crude

reaction mixture. [d] Determined by chiral-phase GC. [e] The reaction was performed without

amine catalyst 2d. [f] The reaction was performed without Cu(OTf)2 catalyst. [g] CuCl (10

mol%) was used as the copper source. [h] EtMgBr as the nucleophilic source (2.0 equiv.). [i]

p-nitro-benzoic acid (25 mol%) was added as additive. [j] CuTC (2 mol%) was used as the

copper source.

28

P

L1

NN

Cl-

L6

P

L3

PPh2

PPh2

PPh2

PPh2

L4 L5

P

L2 2b

NH

N

Bn

O

2d

NH

Ph

Ph

OTMS

2e

2f 2g 2h

NH

N

Bn

O

HCl NH

OTMS

F3C CF3

CF3

CF3

NH

Ph

Ph

OH NH

Ph

Ph

Figure 5. The structures of the different ligands and catalysts used during screening studies.

To understand the importance of the ligand for the transformation from the

optimisation studies, we decided to screen additional ligands (figure 5). Of the

investigated ligands only L5 improved the results in terms of regio- and

enantioselectivity, but failed in increasing the reactivity of the reaction (table 3,

entry 5).

Table 3. Ligand screening.[a]

Entry Conv. [%][b]

1 58

e.r.[%][d]

96:4

Time [h]

12

Ligand

Cat. 2d (25 mol%)Ligand L (20 mol%)

Ph

O

H

L1

Cu(OTf)2 (10 mol%)

Et2Zn (2.0 equiv.)

THF, 60 0C

8aPh

O

H23a

Ratio 23a/24a[c]

62:38

Ph

OH

24a

+

2 11 82:189L2 36:64

3 38 87:1312L3 76:24

4 27 89:1111L4 49:51

5 19 94:612L5 86:14

6 8 76:248L6 77:23


spectroscopy on the crude reaction mixture. [c] Determined by GC and 1H NMR on the

crude reaction mixture. [d] Determined by chiral-phase GC.

Furthermore, we studied different chiral secondary amine catalysts 2 (figure 5),

in the model reaction without improving the results (table 4).

29

Table 4. Catalyst screening.[a]

Entry Conv. [%][b]

1 38

e.r.[%][d]

47:53

Time [h]

17

Catalyst

Cat. 2 (25 mol%)Ligand L1 (20 mol%)

Ph

O

H

2b

Cu(OTf)2 (10 mol%)

Et2Zn (2.0 equiv.)

THF, 60 0C

8aPh

O

H23a

Ratio 23a/24a[c]

8:92

Ph

OH

24a

+

2 58 96:4122d 62:38

3 >98 47:53142e 19:81

4 53 61:39172f 8:92

5 60 90:10182g 48:52

6 75 62:38152h 12:88


spectroscopy on the crude reaction mixture. [c] Determined by GC and 1H NMR on the

crude reaction mixture. [d] Determined by chiral-phase GC.


We then applied the optimised catalytic system to a variety of aldehydes (scheme

27). The co-catalytic ECA of Et2Zn to enals 8 with an aryl substituent at the β-

position with different electronic and steric properties proceeded with good 1,4-

selectivities and high enantioselectivities up to 98:2 e.r. (scheme 27). Aromatic enals

bearing an EDG such as a methoxy substituent at meta- or para-position gave

products with the highest 1,4-selectivities (scheme 27: 23b and 23h). Further on, by

simply changing the nucleophilic to Me2Zn, we obtained the chiral aldehyde 23k

containing a stereogenic benzylic center with a methyl group. Products 23j and 23k

were obtained with high regio- and enantioselectivity.

However, the transformation showed to be less enantioselectivity, when aliphatic

α,β-unsaturated aldehydes were employed, but still we obtained acceptable results

(scheme 27: 23l).

30

23b, 83% yield, ratio 85:15, 98:2 er

H

O

MeO

23c, 44% yield, ratio 75:25, 98:2 er

H

O

23d, 60% yield, ratio 63:37, 95:5 er

H

O

Cl

23e, 47% yield, ratio 78:22, 96:4 er

H

O

Br

23f, 62% yield, ratio 64:36, 98:2 er

H

O

23g, 71% yield, ratio 83:17, 97:3 er

H

O

23h, 79% yield, ratio 80:20, 98:2 er

H

O

23i, 44% yield, ratio 79:21, 97:3 er

H

O

23j, 76% yield, ratio 91:9, 98:2 er

H

O

MeO

MeO Cl

23k, 65% yield, ratio 93:7, 97:3 er

H

O

23l, 60% yield, ratio 80:20, 83:17 er

H

O

Cat. 2d (25 mol%), Ligand L1 (20 mol%)R1

O

HCu(OTf)2 (10 mol%), R2Zn (2.0 equiv.),

THF, 9-18h, 60 0C

8R1

O

H23

R1

OH

R24

+

R

Scheme 27. The substrate scope of the catalytic enantioselective β-alkylation of α,β-

unsaturated aldehydes by combination of transition metal and aminocatalysis.


A plausible reaction mechanism is illustrated in scheme 28, based on the absolute

configuration of 23k (vide infra) and previous DFT calculations by our group on the

similar enantioselective conjugate silyl addition to α,β-unsaturated aldehydes.[40]

We also performed HRMS analysis. After transmetallation, where the alkylzinc

reagent is transformed to the copper reagent, the catalytic cycle starts with the

formation of intermediate XIII. In parallel, intermediate IV is formed by

condensation of the chiral amine catalyst 2 and the α,β-unsaturated aldehyde 8.

Intermediates XIII and IV are merged, leading to coordination of the reactive

copper species XIII to iminium intermediate IV. Next, 1,4-alkyl addition occurs

from the less sterically hindered Si face (R = Ar) of the chiral iminium intermediate

XIV. Subsequent protonation of intermediate XV, gives the chiral β-alkylated

product 23. The regenerated chiral amine catalyst 2 and copper complex XIII

continue their duty in the catalytic cycle.

31

R1

H

N

R1

O

H

R1

H

N

L-CuII-R

R2Zn

R-Zn-L

OH-

IV

NH CuI

R

L

XIV

R1

H

N

XV

Cu

R

H2O

H+

R

R1H

O

L2CuII

XIII

L

R2Zn

2

8

23 Scheme 28. The proposed reaction mechanism for the catalytic enantioselective β-

alkylation of α,β-unsaturated aldehydes by combination of transition metal catalysis and

aminocatalysis.

3.2.4. Total synthesis of the natural product bisabolane sesquiterpenes

One of the main intentions with designing new synthetic methods is to provide

new or complementary solutions to difficult problems in chemical synthesis.

Herein, we present an efficient enantioselective total synthesis of three bisabolane

sesquiterpenes, (S)-(+)-curcumene 27, (S)-(+)-dehydrocurcumene 30 and (S)-(+)-

turmerone 31 (scheme 29), where our methodology plays an important role for the

introduction of enantioselectivity. All three total synthesis starts from the β-

methylated benzylic aldehyde 23k obtained from the catalytic enantioselective β-

methylation of the α,β-unsaturated aldehyde 8c by merging aminocatalysis and

transition metal catalysis.

The short total synthesis of (S)-(+)-curcumene 27 begins with the reduction of

23k, followed by tosylation and subsequent iodination. This gives product 25 in

65% overall yield. Completion of the synthesis by Grignard addition to 25

furnished (S)-(+)-curcumene 27 in 57% yields.

The Wittig reaction of 23k gave compound 29 (64%), and an additional Wittig

reaction completed the synthesis of (S)-(+)-dehydrocurcumene 30 in 68% yield.

32

Turmerone 31 was easily obtained in 51% overall yield in two steps from 23k by

Grignard addition to 23k and then TPAP oxidation. The absolute configuration of

23k was established by these total syntheses.

O

(S)-(+)-turmerone

MgBr

O

H

O

Ph3P

O

MgBr

I

(S)-(+)-curcumene

23k25

26

29

31

a)-c)

Conditions: a) NaBH4, CH2Cl2, MeOH, 0 o C; b) TsCl, Pyridine, CH2Cl2, r.t, 5h; c) NaI,

acetone, reflux, 2h; d) 26, CuI, THF, 0 o C, 5h; e) 28, CHCl3, reflux, 16h; f) Ph3PMeBr, BuLi, Et2O; g) 26,

THF, 0 o C, 1h; h) TPAP, NMO, CH2Cl2, M.S (4Å), 3h.

d)

e)

27

28

f)

(S)-(+)-dehydrocurcumene

30

26g)-h)

65% yield 57% yield

64% yield 68% yield

51% yield

Scheme 29. The total synthesis of three bisabolane sesquiterpenes, (S)-(+)-curcumene 27,

(S)-(+)-dehydrocurcumene 30 and (S)-(+)-turmerone 31, starts from the key compound 23k.

3.3. Conclusion

In conclusion, we have achieved the enantioselective β-alkylation of α,β-

unsaturated aldehydes by combining aminocatalysis and transition-metal catalysis

(dual catalysis). Hence, simple commercially available chiral amine catalyst in

combination with copper salt could be used for the asymmetric addition of

dialkylzinc reagents to α,β-unsaturated aldehydes. The transformation was highly

1,4-selective and the corresponding products were obtained with high

enantiomeric ratios. The developed methodology was successful for aromatic α,β-

unsaturated aldehydes and thus give a complementary tool to the previous vide

supra described transformation. The approach was then used as a key step to the

short total synthesis of three biological active sesquiterpenes, (S)-(+)-curcumene 27,

(S)-(+)-dehydrocurcumene 30 and (S)-(+)-turmerone 31.

33

4. COOPERATIVE DUAL CATALYSIS IN DOMINO REACTIONS (PAPER III)

4.1. Introduction

In the course of our designing of new approaches and methodologies for the

synthesis of valuable chiral and complex molecules, we envisioned that the dual

catalysis of amino- and transition metal catalysis could be successfully applied in a

one-pot domino reaction. Numerous natural and unnatural products contain

frameworks with contiguous multiple stereocenters and these products often have

biological activity.[59] In this context, polysubstituted carbocycles with contiguous

stereocenters, are synthetically interesting products.[60]

In addition, the enantioselective one-pot domino reaction proved to be a

powerful tool for the synthesis of valuable complex molecules. A domino reaction

does not only give access to compounds with excellent levels of stereocontrol in

simple operational procedures from simple starting materials, but also other

benefits such as cost reduction for solvents and chemicals, as well time. The need

for purification after each step is also avoided. All are important parameters both

in academia and industry (vide supra, section 1.5).

To make the vision reality, to avoid problems such as catalyst incompatibility

between the transition-metal catalyst and the amine catalyst leading to inefficiency,

a careful design of a suitable catalytic system and appropriate reagent is necessary.

Furthermore, allyl acetate 32 offers possibilities for double activation, consisting

of a nucleophilic part and an allyl moiety that can be activated by Pd(0) to generate

an electrophilic site as in the Tsuji-Trost reaction. The concept of iminium and

enamine subsequent activation of α,β-unsaturated aldehydes 8, in combination

with metal-catalyst activation, will hopefully deliver products with high level of

complexity in a one-pot reaction. In this chapter we present a highly diastereo- and

enantioselective in one-pot transformation for the construction of poly-

functionalised cyclopentanes and cyclohexanes, with four contiguous

stereocenters, including a chiral quaternary carbon. In scheme 30 the co-catalytic

dynamic cascade reaction of 32 and 8 is depicted. After reversible conjugate

addition leading to the corresponding Michael products 33 and ent-33 and further

oxidative addition of palladium catalyst gives XVIIa and XVIIb.

Subsequently stereoselective intramolecular reaction gives mainly 34, after

regeneration of chiral amine and palladium catalysts.

34

R

O

H

NH2

8

LG

NC

CN32

O

R

NC

NC

LG

33

NR

NC

NC

LG

H2O

H2O

H2O

CNNC

R

O

34XVIa

+

Pd cat.

self-alkylationpolymerisation

Pd cat.

R

H

N

IV

NR

NC

NC

LG

XVIb

+

O

R

NC

NC

LG

ent-33

-LG

NR

NC

NC

XVIIa

NR

NC

NC

XVIIb

+

-LG

Pd

Pd

+

+

fast

chiral amine cat.Pd cat.

H2OCNNC

R

O

ent-34

slow

chiral amine cat.Pd cat.

n

n

n

n

n

n

n

LG = Leaving group

n

n

Scheme 30. Pd/chiral amine co-catalytic dynamic cascade reaction between 32 and 8.



Our optimisation study started with the reaction of allyl acetate 32 and cinnamic

aldehyde 8a in the presence of chiral amine catalyst 2d and different palladium

catalysts, with ligand L7. When the reaction was catalysed by only the amine

catalyst 2d in acetonitrile for 48h, only the corresponding Michael product 33 was

detected (table 5, entry 1). In the absence of chiral amine catalyst 2d, Pd2(dba)3 and

L7 failed in promoting a successful reaction (table 5, entry 2). To our delight, a

successful synergistic cooperation was noticed when the reaction was performed in

the presence of both the chiral amine 2d and Pd(PPh3)4 in toluene for 17h, 55%

conv., 91:9 d.r. and 98:2 e.r. To further improve the results, we varied the solvent.

Results indicated that acetonitrile was the solvent of choice, slightly higher

reactivity was observed compared to the reaction performed in toluene, 8h, 62%

conv. (table 5, entries 4, 5 and 6). Employment of palladium complex Pd2(dba)3 in

acetonitrile gave more a promising result (table 5, entry 9). However, with the best

results in terms of reactivity, diastereoselectivity and enantioselectivity were

obtained when the reaction concentration was lowered from 0.5 to 0.2 M (table 5,

entry 10).

35

Table 5. Optimisation study for the palladium and chiral amine catalysed enantioselective

synthesis of polysubstituted cyclopentane 34.

OAc

NC

NC

32

Entry Conv. [%][a]

1[c] 57

Pd-cat. e.r.[%][b]

n.d.

Solvent

+

Time [h]

48

Ligand

2d (20 mol%) L7 (10 mol%)

34a

-

2[d] <1 n.d.[Pd2(dba)3] 48

Pd-cat. (5 mol%)

Solvent, 22 oC

time

d.r.[%][a]

n.d.

n.d.

Ph

O

H

8a

CNNC

O

H

Ph

34a'

+

- CH3CN

CH3CN

3 55 98:217-

6 62 97:3[Pd(PPh3)4] 8

91:9

91:9

toluene

CH3CN-

7[c] 72[Pd(OAc)2] 22tolueneL7

[Pd(PPh3)4]

n.d.n.d.

8 958

9 90[Pd2(dba)3] 5

91:9toluene

CH3CN

[Pd2(dba)3] >99.5:0.5L7

L7 96:4 >99.5:0.5

CNNC

O

H

Ph

L7

90[Pd2(dba)3] 5CH3CN 96:4 >99.5:0.5

10[e] [Pd2(dba)3] 5CH3CNL7 96:4 >99.5:0.598

4 10[Pd(PPh3)4] 26DMF-

5 14[Pd(PPh3)4] 22DMSO n.d.n.d.-

n.d.n.d.

[a] Determined by

1H NMR spectroscopy on the crude reaction mixture. [b] Determined by

analysis of chiral-phase HPLC. [c] Conversion to the corresponding Michael product 33 with

50:50 e.r. [d] The reaction was performed without catalyst 2d. [e] The concentration of the

reaction was changed from 0.5 M to 0.2 M.

P

L7

2j

NH

Ph

Ph

OTBDMS

2b

P

NH

N

2k

2i

NH

Ph

Ph

OTESNH

N

Bn

O

HCl

Figure 6. The structures of the ligand and catalysts employed for the reaction during

optimisation studies.

36

Further optimisation attempts by screening different amine catalysts 2 were not

successful; amine catalyst 2d was to be the most effective for this transformation

(table 6, entry 2).

Table 6. Screening of different chiral catalysts 2.

OAc

NC

NC

32

Entry Conv. [%][a]

1[c] 22

e.r.[%][b]

+

2 (20 mol%) L7 (10 mol%)

34a

[Pd2(dba)3] (5 mol%)

CH3CN, 22 oC, 5h

d.r.[%][a]

Ph

O

H

8a

CNNC

O

H

Ph

34a'

+

CNNC

O

H

Ph

n.d.n.d.2b

Catalyst 2

3 14 92:891:92e

4 50 99:197:32i

5 272j

6 932k 25:7596:4

98:291:9

2 98 >99.5:0.596:42d

[a] Determined by


analysis of chiral-phase HPLC. [c] Conversion to the corresponding Michael product 33 with

50:50 e.r.

Next, the creation of enantioselective quaternary stereogenic centers is an

important and challenging task in organic synthesis due to the high steric

repulsion between the substituents on the carbon center.[61] To introduce a

quaternary center in our polysubstituted carbocycles, we chose another allyl

acetate substrate. Allyl acetate 35 allows the introduction of a stereogenic

quaternary center in the product 37 and by that increasing the complexity of the

product 37, which contains four stereogenic centers including the chiral quaternary

center. A new short screening study of the reaction condition using substrate 35 is

summarised in table 7, indicating that the optimal reactions condition is the same

as for allyl acetate 32. Both (Z)- and (E)-allyl acetate 35 were reactive in the one-pot

domino reaction (table 7, entries 4 and 6). Decreasing the amine catalyst 2d loading

to 10 mol%, resulted in low reactivity, but with maintained high enantio- and

diastereoselectivity (table 7, entry 5).

37


synthesis of polysubstituted cyclopentane 37 containing a chiral quaternary center.

OAc

NC

MeO2C

35

Entry Conv. [%][a]Pd-cat. e.r.[%][b]

+

Time [h]Ligand

2d (20 mol%) L7 (10 mol%)

37a

Pd-cat. (5 mol%)

CH3CN 22 oC

time (h)

d.r.[%][a]

Ph

O

H

8a

CNMeO2C

O

H

Ph

37a'

+

1 95 98.5:1.524-

4[d] 95 >99.5:0.5[Pd(PPh3)4] 19

84:16

93:7

5[d,e] [Pd2(dba)3] 24L7

[Pd(PPh3)4]

6[d,f] 9124 95:5[Pd2(dba)3] >99.5:0.5L7

2 85[Pd2(dba)3] 19

3[c] 6924

91:9L7 >99.5:0.5

[Pd2(dba)3] L7 90:10 99.5:0.5

L7

58 >99.5:0.592:8

CNMeO2C

O

H

Ph

[a] Determined by


analysis of chiral-phase HPLC. [c] Catalyst 2i was used. [d] The concentration of the

reaction was changed from 0.5 M to 0.2 M. [e] The reaction was conducted using 10 mol%

of catalyst 2d. [f] The reaction was performed using (E)-35.


The developed palladium chiral amine catalysed enantioselective methodology

for synthesis of polysubstituted cyclopentane 37 tolerated a wide range of α,β-

unsaturated aldehydes 8. The substrate scope showed that the reaction tolerates

α,β-unsaturated aldehydes bearing EDG or EWG at the phenyl group providing

the desired products with four stereogenic centers including an all carbon

quaternary with moderate to high yields, high diastereoselectivity and excellent

enantioselectivity (Scheme 31: 37b-37i). Moreover, varying the position of the

substituents on the phenyl group at ortho-, meta- and para-position worked well,

even though a slight decrease in reactivity could be noticed for substituent on the

ortho-position, probably due to the steric repulsion (Scheme 31: 37g-37i). When the

reaction was performed using aliphatic or heteroaromatic α,β-unsaturated

aldehydes, a considerable decrease in reactivity and in diastereoselectivity was

obtained, but still controlled enantioselectivity (Scheme 31: 37k-37l).

We extended the methodology further to the synthesis of the cyclohexane

derivative 40, which was obtained in good yield and with excellent diastereo- and

enantiocontrol (Scheme 32).

38

OAc

NC

MeO2C

35

+

2d (20 mol%) L7 (10 mol%)

37

[a] The reaction was conducted using (E)-35. [b] The reaction was performed using (Z)-35.

[c] The reaction was performed at 4 oC for 60h and the e.r. determined by Chiral GC analysis.


CH3CN (0.2 M) 22 oC

23-30h

R

O

H

8

CNMeO2C

O

H

R

37a, 75% yield,

95:5 d.r., >99.5:0.5 e.r.[a]

CNMeO2C

O

H

37b, 77% yield,

93:7 d.r., 99.5:0.5 e.r.[b]

CNMeO2C

O

H

37c, 86% yield,

93:7 d.r., 99.5:0.5 e.r.[b]

CNMeO2C

O

H

37d, 88% yield,

92:8 d.r., 99.5:0.5 e.r.[b]

CNMeO2C

O

H

OMe

OMe

37e, 82% yield,

93:7 d.r., >99.5:0.5 e.r.[b]

CNMeO2C

O

H

37f, 76% yield,

95:5 d.r., >99.5:0.5 e.r.[b]

CNMeO2C

O

H

CNBr

37g, 82% yield,

93:7 d.r., >99.5:0.5 e.r.[b]

CNMeO2C

O

H

37h, 82% yield,

92:8 d.r., 99.5:0.5 e.r.[b]

CNMeO2C

O

H

37i, 69% yield,

96:4 d.r., 99.5:0.5 e.r.[b]

CNMeO2C

O

H

37j, 72% yield,

93:7 d.r., >99.5:0.5 e.r.[b]

CNMeO2C

O

H

37k, 66% yield,

80:20 d.r., 99.5:0.5 e.r.[b]

CNMeO2C

O

H

37l, 70% yield,

80:20 d.r., 99.5:0.5 e.r.[b,c]

CNMeO2C

O

H

Cl

Cl Cl

O

Scheme 31. The substrate scope of the palladium and chiral amine catalysed

enantioselective synthesis of polysubstituted cyclopentane with four stereogenic centers 37.

MeO2C

CN

38

+

2d (20 mol%) L7 (10 mol%)

40, 65% yield, >97:3 d.r., 99.5:0.5 e.r.


CH3CN, 24h, 60 oC

Ph

O

H

8a

OAc

H

O

PhCNMeO2C

Scheme 32. The application of the methodology for the synthesis of polysubstituted

cyclohexane 40.

39


When an organic chemist carries out a chemical reaction, it is vital to understand

how the reaction proceeds. Thus, we wanted to understand the highly

enantioselective domino reaction. Hence we monitored the reaction by HPLC and

NMR to analyse the formation of the Michael products 33a, 36a and 36a’. When

allyl acetate 32 was employed as the substrate, the enantiomeric ratio of the

Michael product 33a was determined to 50:50 (0% e.e., a racemic mixture) (table 8).

The same enantiomeric ratio was obtained for the Michael products 36a and 36a’

and the diastereoselectivity was 65:35 (table 9). Because the isolated yield of the

corresponding cyclopentane 34a and 37a was 70%, and 74% respectively, and the

related Michael products were racemic, we propose that the reaction proceeded via

a DYKAT mechanism. In our case, the enantioselective cascade transformation

proceeds via the DYKAT type IV mechanism.[42]

Table 8. The monitoring of the crude reaction mixture with 1H NMR and chiral phase HPLC

analysis for the palladium and chiral amine catalysed enantioselective synthesis of

polysubstituted cyclopentane 34.

OAc

NC

NC

32

+

2d (20 mol%) L7 (10 mol%)

33a


CH3CN (0.2 M) 22 oC

time

Ph

O

H

8a

CNNC34a

CNNC

O

H

Ph+Ph

O

H

*

OAc

Time (h)[a] Ratio (33:34)[c]

2 15:85 96:443

Conv.(%)[b] dr (34a:34a')[c] er[d]

33a

50:50[e]

34a

>99.5:0.5[e]

5 8:92 96:490 n.d. 99.5:0.5[f]

[a] Reaction mixture. [b] Combined conversion of the corresponding Michael product 33 and

cyclopentane 34 as determined by 1H NMR of crude reaction mixture. [c] Determined by

1H

NMR analysis. [d] Determined by chiral-phase HPLC analysis. [e] The sample was isolated

by preparative TLC. [f] The sample was isolated by flash column chromatography. 34a was

obtained in 70% yield.

.

40

Table 9. The monitoring of the crude reaction mixture with 1H NMR and chiral phase HPLC

analysis for the palladium and chiral amine catalysed enantioselective synthesis of

polysubstituted cyclopentane 37.

OAc

NC

MeO2C

35

+

2d (20 mol%) L7 (10 mol%)

36a + 36a'


CH3CN (0.2 M) 22 oC

time

Ph

O

H

8a

CO2MeNC37a

CNMeO2C

O

H

Ph+Ph

O

H

* *

OAc

Time (h)[a] Ratio (36:37)[c]

4 28:72 94:665:3525

Conv.(%)[b] dr (36a:36a')[c] dr (37a:37a')[c] er[d]

36 36a'

50:50[e] 50:50[e]

37a

>99.5:0.5[e]

8 22:78 94:665:3534 n.d. n.d. >99.5:0.5[e]

24 9:91 93:763:3790 n.d. n.d. >99.5:0.5[f]

[a] Reaction mixture. [b] Combined conversion of the corresponding Michael product 36 and

cyclopentane 37 as determined by 1H NMR of crude reaction mixture. [c] Determined by

1H

NMR analysis. [d] Determined by chiral-phase HPLC analysis. [e] The sample was isolated

by preparative TLC. [f] The sample was isolated by flash column chromatography. 37a was

obtained in 74% yield.

The proposed reaction mechanism is depicted in scheme 33. It starts with the

condensation of the chiral amine 2 and the aldehyde 8, forming the corresponding

Michael products 36, ent-36, 36’ and ent-36’, through a fast equilibrium via enamine

intermediates XVIIIa-XVIIId. The least favoured enamine intermediates XVIIIb-

XVIIId are interconverted to the more favoured enamine intermediate XVIIIa via a

fast de-epimerisation process. Then oxidative addition of palladium catalyst occurs

predominantly to the favoured enamine intermediate XVIIIa, resulting in the

electrophilic π-allylpalladium complex XIXa.

This undergoes an irreversible stereoselective intermolecular nucleophilic Si-

facial attack by the chiral enamine followed by protonation and reductive

elimination furnishing the intermediate XXa simultaneously regenerating the

palladium catalyst. Afterwards, chiral amine 2 is regenerated and after hydrolysis

of intermediate XXa the final product 37 is obtained. The reaction mechanism was

further established, by HRMS analysis on the crude reaction mixture, which

determined the presence of the intermediates IV, XVIII, XX. The absolute

configuration of products 37 were determined by single-crystal X-ray analysis of

37i and the relative stereochemistry of the minor diastereomer 37’ was determined

by NOE experiments (see appendix B and C).

41

R

O

HNH

28

OAc

NC

CO2Me

35

N

R

NC

MeO2C

OAc

H2O

O

R

NC

MeO2C

OAc

ent-36

H2O

NR

MeO2C

NC

OAc

H2O

OR

MeO2C

NC

OAc

36

H2O

N

R

CNMeO2C

OAc

O

R

CNMeO2C

OAc

H2O

H2O

N

R

MeO2C

NC

OAcH2O

H2O

-OAc-

[PdLn]NR

MeO2C

NC

-[PdLn]

NC

MeO2C

N

R

+

H2O

CNMeO2C

R

O

+

37

NH

2

XVIIIa

XIXa

XXa

XVIIIb

XVIIIcXVIIId

[PdLn]+

36'

ent-36'

O

R

MeO2C

NC

OAc

Scheme 33. The proposed reaction mechanism for the highly diastereoselective and

enantioselective palladium and chiral amine co-catalytic transformation for the synthesis of

polysubstituted cyclopentane via a dynamic kinetic asymmetric cascade transformation.

4.3. Conclusion

In this chapter, we present an efficient and practical one-pot domino reaction by

a synergistic integration of amino- and transition metal catalysis for the synthesis

of highly diastereo- and enantioselective polysubstituted cyclopentanes 37 and

cyclohexane 40, containing four stereocenters including an all carbon quaternary

center. The reaction is performed under mild reaction conditions, with a

straightforward performance, starting from simple starting materials without the

need for isolation of intermediates. A plausible mechanism for the chemical

transformation is through a DYKAT process, where the iminium and enamine

activation modes through aminocatalysis play crucial roles.

42

5. THE CONSTRUCTION OF HIGHLY ENANTIOSELECTIVE POLYSUBSTITUTED SPIROCYCLIC OXINDOLES BY COOPERATIVE DUAL CATALYSIS (PAPER IV)

5.1. Introduction

In recent years chemists have devoted considerable time to the development of

new and efficient asymmetric methods for the synthesis of spirocyclic oxindols.

Due to their biological activities and their synthetic challenging structures these

ubiquitous structures are of high importance but difficult to create.[62] The

characteristic framework of spiro-oxindol consist of an oxindol scaffold containing

a cyclic motif at the 3-position on the oxindol core structure (figure 7).

N

R1

R2

X cyclic motif

oxindole scaffold

X = C, N, O, S, etc.

O

Figure 7. Spiro oxindol characterised by the oxindol core including a cyclic scaffold on the

3-position of the oxindol.

In this context, spiro-oxindols containing a five member ring scaffold is of great

interest, since they can be found in many natural products; some examples are

shown in figure 8.[63] However, so far direct asymmetric synthetic methods for the

construction of these valuable scaffolds are limited and need to be further

expanded.

N

O

MeO

O

N

H

NO2

H

HN

O

O

N

OH

NHMe

H

O

Cyclopiamine B Citrinadin B

N

O

N

H

Notoamide A

HO

O

NH

O

O

Figure 8. Representative natural products containing spirocyclopentane oxindol scaffolds.

Inspired by the efforts that have been made towards development of new

asymmetric methodologies for the synthesis of the valuable spirocyclopentane

oxindole,[64],[65] we began to design and develop practical and efficient

methodologies for the enantioselective synthesis of valuable spirocyclopentanes.

Based on our previous research and careful retrosynthetic analysis, we envisioned

that the concept of one-pot domino reaction by a synergistic combination of amino-

and palladium catalysis could be applied to the enantioselective synthesis of highly

43

functionalised spirocyclopentane oxindoles. According to the retrosynthetic

analysis illustrated in scheme 34, a plausible combination of oxindol 41 and α,β-

unsaturated aldehyde 8, on the basis of our research on α-allylic alkylation and

Michael addition would hypothetically deliver compound 43, with four contiguous

stereocenters including a spiroquaternary stereocenter. At the same time this will

also provide synthetically valuable functional groups, an aldehyde and an allyl

group, which should be useful in further transformations.

R H+

O

N

O

R'

O

H

R

allylic alkylation

Michael addition

* *

* *

N

O

R'

LG

84143 Scheme 34. Retrosynthetic analysis for the construction of spirocyclopentane oxindole 43.



We begun our study with the reaction of the oxindol 41a and cinnamic aldehyde

8a, in the presence of catalytic amount of Pd(PPh3)4 and amine catalyst 2d, in

toluene at room temperature. To our delight, the reaction proceeded well giving

excellent conversion after 60 h, with high enantioselectivity but unfortunately with

poor diastereoselectivity 58:42 (table 10, entry 1). Altering the solvent to

acetonitrile did not improve the diastereoselectivity, but resulted in poor reactivity,

only 20% conversion (table 10, entry 2). Utilising Pd2(dba)3 as co-catalyst in

combination with ligand L7, slightly increased the enantioselectivity (table 10,

entry 3). Further optimisation on the basis of temperature or by addition of

additive 2p did not bring about any improvements (table 10, entries 4-6). Based on

previous work we knew the importance of ligands for these types of reactions (vide

supra, section 4.2.1). Hence we started to screen new ligands (table 10, entries 7-9

and 11-12). Only ligand L9 gave a significantly higher diastereoselectivity 74:26

(table 10, entry 9). Increased temperature did not improve the results, but slightly

decreased the diastereoselectivity (table 10, entry 10).

44


synthesis of polysubstituted spirocyclic oxindoles 43a and 43a’.[a]

Entry Conv. [%][b]

1 >95

Pd-cat. d.r.[%][b]

58:42

Ph H

Solvent

+

Time [h]

60

Ligand T [oC]

22

2d (20 mol%)Ligand (10 mol%)

43a'

-

2 20[Pd(PPh3)4] 6522-

Pd-cat. (5 mol%)time, temp., Solvent

41a 8a 43a

3 75 58:42Pd2(dba)3 3822L7

4 75 58:42Pd2(dba)3 104-20L7 CH3CN

5 81 57:43Pd2(dba)3 2060

6[e] <1 n.d.Pd2(dba)3 7522L7

7 68 67:333822

8 22 57:43Pd2(dba)3 7222L1 CH3CN

L7

CH3CN

CH3CN

Pd2(dba)3 L8

9 59 74:263622

10 54 64:362440Pd2(dba)3 L9

Pd2(dba)3 L9

11 63 50:508022Pd2(dba)3 L10

CH3CN

CH3CN

CH3CN

CH3CN

CH3CN

e.r.[%][d]

90.5:9.5

95:5

n.d.

63:37

n.d.

98:2

94:6

94:6

96:4

>99.5:0.5

e.r.[%][c]

98:2

99:1

n.d.

96:4

n.d.

98.5:1.5

>99.5:0.5

98.5:1.5

97.5:2.5

99:1

N

O

OAc

O

N

O

O

H

Ph

N

O

O

H

Ph

+

[Pd(PPh3)4] toluene

CH3CN 57:43 n.d.n.d.

12 <10 50:504822Pd2(dba)3 L5

13 <5 50:503622Pd2(dba)3 L9

CH3CN

toluene

n.d.

n.d.

n.d.

n.d.

[a] The reaction was performed with 41a (0.2 mmol) and 8a (0.1 mmol) in solvent (0.5 mL).

[b] Conversion to and d.r. of 43 as determined by 1H NMR spectroscopy on the crude

reaction mixture. [c] E.r. of 43a as determined by analysis of chiral-phase HPLC. [d] E.r. of

43a’ as determined by analysis of chiral-phase HPLC. [e] The reaction was performed with

2l (20 mol%) as additive.

45

O

PPh2PPh2

L8

P

OMe

OMe

MeO

L9

P

L10

NH

NH

S

CF3

F3C

CF3

CF3

2l Figure 10. The structures of the ligands and additives considered this chapter.

With these results in hand we started to investigate the size of the N-protecting

group of the oxindole from methyl 41a to benzyl 41b, hoping to improve the

diastereoselectivity. Initially, we tested the background reaction in the presence of

chiral amine catalyst 2d but in the absence of Pd2(dba)3 and ligand. No desired

product 43b was obtained, only the corresponding Michael products 42b and 42b’

in 66% conversion and in 57:43 ratio (table 11, entry 1). Performing the reaction in

absence of catalyst 2d, but in the presence of Pd2(dba)3 and ligand L9, was not

successful (table 11, entry 2). Performing the reaction at 40 °C, in combination with

2d, Pd2(dba)3 and L9 for 12 h, gave the best optimal results (table 11, entry 5), a

slight increase in terms of diastereo- and enantioselectivity comparable to previous

results (table 10, entry 9). We also used benzoic acid or triethylamine as additives

(table 11, entries 6-7) and screened different amine catalysts 2 (table 11, entries 8-

10), but obtained no improvements.

46


synthesis of polysubstituted spirocyclic oxindoles 43b and 43b’.[a]

Entry Conv. [%][b]

1[e] 0

Catalyst d.r.[%][b]

-

Ph H+

Time [h]

12

T [oC]

40

2 (20 mol%)L9 (10 mol%)

43b'

2 0- 1240

Pd2(dba)3 (5 mol%)

CH3CN, time, temp.

41b 8a 43b

3 80 64:362d 2422

4 >95 73:272d 460

5 >95 77:232d 1240

6[f] 42 58:422d 7240

7[g] 83 70:302040

8 <10 n.d.2e 1260

2d

9 85 75:251240

10 83 76:2412402j

2i

e.r.[%][d]

-

99:1

94:6

98:2

98:2

98:2

n.d.

98:2

98:2

e.r.[%][c]

-

>99.5:0.5

98.5:1.5

99.5:0.5

99:1

99.5:0.5

n.d.

99.5:0.5

99.5:0.5

N

O

Bn

OAc

O

N

O

Bn

O

H

Ph

N

O

Bn

O

H

Ph

+

2d

- - -

[a] The reaction was performed with 41b (0.2 mmol) and 8a (0.1 mmol) in CH3CN (0.5 mL).


reaction mixture. [c] E.r. of 43b as determined by analysis of chiral-phase HPLC. [d] E.r. of

43b’ as determined by analysis of chiral-phase HPLC. [e] The reaction was performed

without Pd2(dba)3 and L9 and the corresponding Michael products 42b and 42b’ were

obtained in 66% conversion and in 57:43 ratio. [f] The reaction was performed with benzoic

acid (20 mol%) as additive. [g] The reaction was performed with triethylamine (25 mol%) as

additive.

In an attempt to further increase the diastereoselectivity we screened different

solvents, without any improved results (table 12). Using the best conditions (table

11, entry 5), we decided to probe the scope, by using different α,β-unsaturated

aldehydes 8 and oxindole 41 for the Pd/chiral amine co-catalytic one-pot domino

transformation.

47

Table 12. Further optimisation by solvent screening.[a]

Entry Conv. [%][b]

1 >95

d.r.[%][b]

77:23

Ph H

Solvent

+

2d (20 mol%)L9 (10 mol%)

43b'

2 67

Pd2(dba)3 (5 mol%)

solvent, 12h, 40 oC

41b 8a 43b

3 >95 71:29

4 61 56:44CH2Cl2

5 >95 73:27

THF

DMSO

e.r.[%][d]

98:2

88:12

93:7

63:37

e.r.[%][c]

99.5:0.5

96.5:3.5

96:4

96:4

N

O

Bn

OAc

O

NO

Bn

O

H

Ph

NO

Bn

O

H

Ph

+

CH3CN

DMF 74:26 93:796:4

[a] The reaction was performed with 41b (0.2 mmol) and 8a (0.1 mmol) in CH3CN (0.5 mL).


reaction mixture. [c] E.r. of 43b as determined by analysis of chiral-phase HPLC. [d] E.r. of

43b’ as determined by analysis of chiral-phase HPLC.


To expand the substrate scope we tested a wide range of enals 8 (scheme 35). The

reaction tolerated aromatic α,β-unsaturated aldehydes with no substituents, EWG

or EDG at the para-position on the aromatic ring. These resulted in high yields,

good diastereo- and excellent enantioselectivities (scheme 35: 43b, 43c, 43e and

43g). Moving the EWG on the aromatic moiety to the meta-position also worked

well (scheme 35: 43d). When a heteroaromatic group was employed, it gave a

decrease in diastereoselectivity 54:46. It was, however, possible to isolate the two

diastereomers 43f and 43f’ separately in pure forms and good yields and with

excellent enantiopurity. When aliphatic α,β-unsaturated aldehydes were employed

the transformation showed enhanced reactivity, and gave slightly increased

diastereoselectivities and at the same time excellent enantioselectivities (scheme 35;

43i and 43j). The oxindol core structure could also be varied; having both EWG

and EDG at the 6-position on the oxindol core structure resulted in high yields,

good diastereoselectivity and excellent enantiocontrol (scheme: 35, 43k and 43l).

48

Scheme 35. Investigation of the substrate scope for the Pd/chiral amine co-catalytic one-pot

domino transformation.

[a]The reaction was conducted using 41 (0.4 mmol) and 8 (0.2 mmol) in CH3CN (1.0 mL) for 6h. [b]Same as [a] but reaction time was 12h. [c]Determined by 1H NMR analysis on the crude reaction mixture. [d]Determined by chiral-phase HPLC analysis. [e]Determined by 1H

NMR analysis on the pure isolated product.

43b:[b] 86% yield,

77:23 d.r.[c], 99.5:0.5 e.r.[d]

43c: 87% yield,

71:29 d.r.[c], 99:1 e.r.[d]

43d: 79% yield,

74:26 d.r.[c], 98.5:1.5 e.r.[d]

R H+

2d (20 mol%)L9 (10 mol%)

Pd2(dba)3 (5 mol%)

CH3CN, 40 oC, 6h

41b: X = H41c: X = Cl41d: X = Me

8 43

N

O

Bn

OAc

O

N

O

Bn

O

H

R

N

O

Bn

O

H

N

O

Bn

O

H

N

O

Bn

O

H

X X

43f: 41% yield,

>19:1 d.r.[e], 98.5:1.5 e.r.[d]

43f': 35% yield,

>19:1 d.r.[e], 97:3 e.r.[d]

N

O

Bn

O

H

N

O

Bn

O

H

43i: 88% yield,

82:18 d.r.[c], 99:1 e.r.[d]

N

O

Bn

O

H

43j: 89% yield,

84:16 d.r.[c], 98.5:1.5 e.r.[d]

43k: 76% yield,

75:25 d.r.[c], >99.5:0.5 e.r.[d]

43l: 90% yield,

82:18 d.r.[c], >99.5:0.5 e.r.[d]

N

O

Bn

O

H

N

O

Bn

O

H

N

O

Bn

O

H

O O

Cl

43e: 84% yield,

72:28 d.r.[c], 98.5:1.5 e.r.[d]

N

O

Bn

O

H

43g: 78% yield,

75:25 d.r.[c], 99.5:0.5 e.r.[d]

43h: 81% yield,

73:27 d.r.[c], 99:1 e.r.[d]

N

O

Bn

O

H

N

O

Bn

O

H

OMe

OMe

Br

Cl

43f:43f' = 54:46[c]


The proposed reaction mechanism for the synthesis of spirocyclopentane

oxindoles 43 is similar to the one proposed in paper III (vide supra, section 4.2.3).

The transformation occurs through a DYKAT like process, which “fishes out” one

major stereoisomer out of 16 possible. It is like since the equilibrations of Michael

intermediates 42 are slow and thus they are not racemic. In scheme 36, the

proposed reaction mechanism is demonstrated, where only two out of the 16

possible stereoisomers of 43 are shown. It should be highlighted that it is a very

challenging task to construct these spiro oxindol skeletons containing four

contiguous stereocenters including a spiro quaternary stereocenter, which due to

49

steric reasons is normally difficult to create. In that way this designed

methodology makes it even more important, allowing one to obtain one major

stereoisomer out of many possible. After condensation to the iminium ion IV

followed by Michael addition, enamine intermediates XXIa-XXId are formed,

which through equilibrium will shift towards the most favourable intermediate

XXIa. Subsequently, oxidative addition of the palladium catalyst will form

predominantly π-allyl complex intermediate XXIIa, which after an irreversible

intermolecular nucleophilic addition by the enamine, followed by reductive

elimination and hydrolysis will regenerate both 2 and the palladium catalysts,

delivering chiral product 43. Furthermore, the reaction mechanism was further

established, by HRMS analysis on the crude reaction mixture, which determined

the presence of the intermediates IV, XXI and XXIII. The absolute configuration of

products 43 were determined by single-crystal X-ray analysis of 43g and the

relative stereochemistry of the minor diastereomer 43’ was determined by NOE

experiments of 43d’ (see appendix D and E).

N

R'

O

RO

ent-42'

N

R'

O

RN

H2O

-H+41

N

NH

RIV

+

-H+

41

N

R'

O

RN

H2O

OAc

OAc

N

R'

O

RO

OAc

42'

[PdLn]

-OAc-

N

R'

O

R

[PdLn]+

N

N

R'

O

RO

[PdLn]

H2O2

43'

-H+

41

N

R'

O

RN

OAc

H2O

N

R'

O

RO

OAc

ent-42

XXIb

XXIc

XXId

XXIIc

N

R'

O

RN

OAc

XXIa

[PdLn]

OAc-

R

[PdLn]+

NXXIIa

N

O

R'

XXIIIa

N

OR'

R

N+

-H+41

[PdLn]

N

OR'

R

O

43

2

8

-OH-

H2O

H2O

N

R'

O

RO

OAc

42

Scheme 36. The proposed reaction mechanism for the enantioselective Pd/chiral amine co-

catalytic transformation for the synthesis of polysubstituted spirocyclopentane oxindoles 43

via a dynamic kinetic asymmetric cascade transformation.

50

5.3. Conclusion

In conclusion, we have presented a one-pot domino procedure for the

construction of the very challenging synthetic valuable frameworks of

spirocyclopentane oxindoles, by further extension of our concept presented on the

synergistic combination of transition metal- and aminocatalysis. The reaction

demonstrated in this chapter provides spirocyclopentane oxindoles 43 with four

contiguous stereocenters including a spiro quaternary stereocenter; it also gives

synthetically valuable functional groups, an aldehyde and an allyl group, which

should be useful in further transformations. The demonstrated chemical

transformation gives a tool to “fish out” one stereoisomer out of 16 possible, in

high yields, acceptable to good diastereoselectivity and excellent enantioselectivity.

51

6. COOPERATIVE COMBINATION OF HETEROGENEOUS- AND AMINOCATALYSIS FOR ENANTIOSELECTIVE CHEMICAL TRANSFORMATION (PAPER V)

6.1. Introduction

To further develop the concept of aminocatalysis towards a preeminent tool in

enantioselective synthesis, we wondered if the aminocatalyst could be merged

with heterogeneous palladium catalyst in a productive way. This would take the

concept a step closer towards a greener process.

We selected the homogeneous Michael/carbocyclisation reactions presented in

scheme 16 as a model reaction for the examination of the feasible integration of

heterogeneous palladium- and aminocatalysts. We prepared the heterogeneous

palladium catalysts Pd(0)- and Pd(II)-Amp-MCF catalysts as described by Bäckvall

and co-workers[33d] and wanted to use them to explore the concept.



To validate our hypothesis concerning the combination of heterogeneous

palladium catalyst and aminocatalyst, we initially started to investigate the

reaction between α,β-unsaturated aldehydes 8q and propargyl cyanoacetate 17a

and the amine catalyst 2d. Initially the reaction was performed with Pd(II)-AmP-

MCF (1.5 mol%) in acetonitrile for 22h and to our delight the reaction proceeded

smoothly with high diastereo- and enantioselectivity, 16:1 and 90% e.e.

respectively, but unfortunately in a low yield, only 37% (table 13, entry 1).

However, when the catalyst loading of Pd(II)-AmP-MCF was increased to 3.0

mol% an increase in reactivity and diastereoselectivity was observed (68% yield

and 21:1 d.r.), although with a slight decrease in enantioselectivity (86% e.e.) (table

13, entry 2).

We obtained optimal reaction conditions for this system when we changed

solvent to dichloromethane (table 13, entry 3). When we used Pd(0)-AmP-MCF for

the reaction, the solvent of choice turned out to be toluene (table 13, entry 10). To

compare the heterogeneous system with the homogeneous, we decided to

implement homogenous palladium catalyst. Evaluation of the Pd(II)-source

confirmed that the homogeneous system proved to be slightly more efficient in

terms of reactivity and diastereoselectivity (table 13, entries 4 and 6). On the other

hand, for the Pd(0)-source, the opposite scenario was observed, where higher

reactivity, diastereo- and enantioselectivity were obtained (table 13, entries 10 and

13). As anticipated from the synergistic effect, no desired product was observed,

when the palladium- and amine catalyst were not employed together (table 13,

entries 14 and 15).

52

Table 13. Exploration of the DYKAT transformation by integrated amino- and heterogeneous

palladium catalysts for the enantioselective Michael/carbocyclisation reaction.

O NC CO2Me

Pd-catalyst (3 mol%) Solvent, Time, r.t. NC

O

+

Entry Time (h) Solvent Pd-catalyst Yield (%)[a] dr[b] ee (%)[c]

1[d] 22 CH3CN Pd(II)-AmP-MCF 37 16:1 90

2

21 CH2Cl2 Pd(II)-AmP-MCF 80 16:1 943

4 CH2Cl2 81 18:1 94

4 3.5 CH2Cl2 Pd(II)-AmP-MCF 73 10:1 96

6

24 CH3CN Pd(II)-AmP-MCF 68 21:1 86

8 42 CH3CN Pd(0)-AmP-MCF 67 17:1 86

12 41 CH3CN Pd(PPh3)4 76 12:1 86

O2N

NO2

CO2Me

7 23 toluene 76 9:1 94

9 18 CH2Cl2 Pd(0)-AmP-MCF 70 16:1 91

10 18 toluene Pd(0)-AmP-MCF 75 15:1 95

11 18 p-xylene Pd(0)-AmP-MCF 72 15:1 92

13 18 toluene 71 10:1 91

5 18 toluene Pd(II)-AmP-MCF 67 10:1 94

14[e] 23 CH2Cl2

CH2Cl2

Pd(II)-AmP-MCF 0 - -

2315[f] - 0 - -

PdCl2

Pd(PPh3)4

PdCl2

8q 17a 19a

H

H2d (20 mol%)

[a] Isolated yield of pure 19a. [b] Determined by

1H NMR spectroscopy on the crude reaction

mixture. [c] Determined by analysis of chiral-phase HPLC. [d] The reaction was performed

with 1.5 mol% of Pd-catalyst. [e] The reaction was performed without chiral amine 2d. [f] The

reaction was performed with only chiral amine 2d. The conjugate addition intermediate 18a

and ent-18a were formed with 2:1 d.r.

53

6.3.2. Substrate scope for the synthesis of cyclopentenes

The substrate scope for the combined heterogeneous palladium- and

aminocatalysts, was explored employing both Pd(II)-AmP-MCF and Pd(II)-AmP-

MCF with different α,β-unsaturated aldehydes 8 and propargyl cyanoacetate 17a.

Conducting the reaction using either Pd(0)- or Pd(II)-AmP-MCF did not show

significant differences only a slightly higher reactivity when Pd(II)-AmP-MCF was

used (table 14, entries 1-2 and 6-7). When the enal was altered to para-Br-Phenyl

α,β-unsaturated aldehyde, an increase in enantioselectivity was observed, when

the reaction was carried out using Pd(0)-AmP-MCF (table 14, entries 3 and 4). In

general, the enantioselective DYKAT transformation worked well for different

enals, also for heteroaromatic and aliphatic aldehydes; albeit a drop in reactivity

and diastereoselectivity was observed for aliphatic aldehyde (table 14, entry 11).

6.3.3. Scope for the synthesis of dihydrofurans and dihydropyrrolidines

Dihydrofurans and dihydropyrrolidines could be obtained by changing the

alkyne to 17b and 17c. The substrate scope for the dual catalytic combination of

heterogeneous palladium and chiral amine catalysts was very encouraging; it

showed a tolerance toward different α,β-unsaturated aldehydes 8, providing

dihydrofurans 20 and dihydropyrrolidines 21, in good to high yields and high

enantioselectivity (table 15, entries 1-9). Also in this study a drop of

enantioselectivity could be noted, when aliphatic aldehyde was employed (table

15, entry 10).

54

Table 14. Substrate scope of the DYKAT transformation by integrated amino- and

heterogeneous palladium catalysts, delivering highly substituted, diastereo- and

enantioselective cyclopentenes, bearing an all carbon quaternary stereocenter.

R

O NC CO2Me

R Time (h) Yield (%)[a] dr[b] ee (%)[c]

O2N 18 75 15:1 95

O2N 20 80 16:1 94

Br 16 83 18:1 96

Cl 16 85 19:1 96

18 70 15:1 91

16 86 24:1 96

O2N

5 21:1 91

O18 81 12:1 91

n-Pr 23 67 5:1 96

R

NC CO2Me

O

+

74

Br 18 78 19:1 99

Entry

1[d]

2[e]

3[e]

4[d]

5[e]

6[d]

8[e]

9[e]

10[e]

11[d]

16 84 12:1 967[e]

H

H

8 17a 19

Pd-catalyst (3 mol%) Solvent, Time, r.t.

2d (20 mol%)

[a] Isolated yield of pure 19. [b] Determined by

1H NMR analysis on the crude reaction

mixture. [c] Determined by analysis of chiral-phase HPLC. [d] The reaction was performed

with Pd(0)-AmP-MCF in toluene. [e] The reaction was performed with Pd(II)-AmP-MCF in

CH2Cl2.

55

Table 15. Substrate scope of the co-catalytic enantioselective cascade reaction using

heterogeneous Pd and chiral amine catalysts, giving access to dihydrofurans and

dihydropyrrolidines.

R

O X

X R

O

+H

H

8 17b (X = OH)17c (X = NHTs)

Pd-catalyst (3 mol%) additive, Time, temp.

2d (20 mol%)

Alkyne (X) Time (h) Yield (%)[a] ee (%)[b]Entry

O2N

O2N

Cl

Cl

Br

O2N

O2N

OH 17 82 92

OH 17 69 89

40OH 85 93

OH 22 59 94

OH 25 59 98

NHTs 22 53 92

NHTs 20 59 94

NHTs 22 53 96

NHTs 20 67 94

Me NHTs 23 84 77

R

1[c]

2[c]

3[d]

4[e]

5[e]

6[f]

7[f]

8[f]

9[f]

10[f]

20 (X = O)21 (X = NTs)

[a] Isolated yield of pure 20 or 21. [b] Determined by chiral-phase HPLC analysis. [c] The

reaction was performed with Pd(II)-AmP-MCF (5 mol%) in CHCl3 (0.5 mL) and benzoic acid

(20 mol%) as additive and the reaction was stirred at 4 °C for the time shown. [d] The

reaction was performed with Pd(0)-AmP-MCF in toluene (0.5 mL) and benzoic acid (20

mol%) as additive and the reaction was stirred at r.t. for the time shown. [e] The reaction

was performed with Pd(II)-AmP-MCF in THF (0.25 mL) and benzoic acid (20 mol%) as

additive and the reaction was stirred at 4 °C for the time shown. [f] The reaction was

performed with Pd(II)-AmP-MCF (5 mol%) in toluene (1.0 mL), water (1.0 equiv.) and sodium

acetate (2.5 equiv.) as additive and the reaction was stirred at r.t. for the time shown.

56

6.3.5. Evaluation of the recyclability and leaching

Because the lifetime and recyclability of the heterogeneous catalyst are the

immense benefits for practical applications (vide supra, section 1.7), we started to

evaluate the recyclability for this co-catalytic enantioselective cascade reaction. The

model reaction selected for the study was 8q as the enal, Pd(II)-AmP-MCF, 2d as

chiral amine and CH2Cl2 as solvent at room temperature. After the completion of

each reaction the reaction mixture was centrifugated and the supernatant was

purified to give the product, while the solid heterogeneous catalyst was washed

with CH2Cl2, dried and further reused under the same reaction conditions. The

heterogeneous catalyst promoted the reaction in nine consecutive cycles without

losing its activity (table 16). To investigate if any palladium catalyst from the

heterogeneous catalyst had leached into the solution, we performed a hot filtration.

The reaction was conducted until 20% conversion was obtained, subsequently the

heterogeneous catalyst was filtered off and the solid free reaction mixture was

allowed to stir for 5h under the same reaction conditions. The reaction was

monitored by 1H NMR analysis and no further conversion was detected. Elemental

analysis by Inductively Coupled Plasma was performed on the solid free reaction

mixture and when the hot filtration was performed using Pd(0)-AmP-MCF no Pd

had leached into the solution. However, when the reaction was carried out using

Pd(II)-AmP-MCF, the elemental analysis showed a Pd content of 80 ppm. To

confirm whether the reaction was promoted by the heterogeneous catalyst or by

the leached palladium into the solution, a test reaction was performed. The

reaction was carried out using 80 ppm of the homogeneous palladium catalyst

PdCl2. To our delight only traces of the product was detected after 4h, whereas

when conducting the reaction with Pd(II)-AmP-MCF it was finished within this

time (table 13, entry 4). This confirms that the heterogeneous palladium catalyst

promotes the reaction and not the leached palladium.

57

Table 16. Recycling of the heterogeneous Pd-catalyst.

Cycle Time (h) Yield (%)[a] dr[b] ee (%)[c]

1 20 73 13:1 92

2

17 78 23:1 923

17 73 19:1 93

4 16 82 21:1 93

5

17 78 30:1 946

19 82 23:1 93

7 16 92 18:1 94

8

16 89 17:1 949

16 81 16:1 94

O NC CO2Me

Pd(II)-AmP-MCF (3 mol%) CH2Cl2, Time, r.t. NC

O

+

O2N

NO2

CO2Me

8q 17a 19a

H

H

2d (20 mol%)

[a] Isolated yield of pure 19a. [b] Determined by

1H NMR analysis on the crude reaction

mixture. [c] Determined by analysis of chiral-phase HPLC.

6.4. Conclusion

In conclusion, we have presented a new interdisciplinary concept, where the area

of aminocatalysis and heterogeneous catalysis are integrated in a successful

manner. This novel merged frontier allows us to develop the process to take one

step closer to more environmentally benign chemical transformations. Since the

concept of sustainability has become the focus of chemists during the last decades,

considerable efforts have been made towards improving different processes in a

greener direction. The implementation of the concept of the highly enantioselective

cascade transformation delivering well functionalised cyclopentenes, containing an

all carbon quaternary stereocenter, dihydrofurans and dihydropyrrolidines, gives

access to a greener process compared to those previously reported. The

heterogeneous palladium catalyst was effectively used in nine cycles without loss

of activity.

58

CONCLUDING REMARKS

The field of organocatalysis has had a successful journey and proven to be a

powerful methodology for the synthesis of valuable enantiomerically pure

compounds by the employment of simple and inexpensive chiral amine catalysts.

By dual combination of aminocatalysis and transition metal catalysis, the field

has been further extended to achieve unsolved chemical transformations that have

not been possible by either the amine catalyst or the transition metal alone. In the

same way, the field of transition metal catalysis has also been broadened by the

implementation of organocatalysis. The designed dual catalytic reaction by

merging the catalytic cycles of aminocatalysis and transition metal catalysis allow

various electrophiles to be employed in reactions involving enamine activation and

different nucleophiles in reactions involving iminium activation. Rather cheap,

simple and readily available starting materials were used in the presented chemical

transformations by the dual catalytic system. The dual catalytic design was further

applied in domino reactions and showed high efficiency delivering nearly

enantiopure highly complex molecules containing several stereogenic centers.

Sustainability has become an important subject for society and as chemist a main

goal is to contribute with new approaches following the concept of green

chemistry, leading to more environmental chemical synthesis. In this context we

have taken the dual catalytic combination of amino- and transition metal catalysis

towards a greener process by considering recyclability of the metal by the use of

heterogeneous transition metal catalysis leading to improved green chemistry

parameters such as atom economy and reduction of toxins.

The developed methodologies could provide a solution or complementary tools

for challenging transformations in the future.

59

APPENDIX A - AUTHOR CONTRIBUTION TO PUBLICATION I-V

I. Performed most of the experimental work, including the total synthesis of

arundic acid. Wrote the supporting information.

II. Performed a major part of the experimental work. Screened the reaction

conditions and probed the substrate scope. Supervised the work of the diploma

worker Kristian Pirttilä. Wrote the supporting information.

III. Carried out half of the experimental work. Prepared the starting materials and

the racemic substrates. Contributed in the screening studies, evaluation of the

scope, wrote the supporting information and contributed in writing of the

manuscript.

IV. Performed all the synthetic and nearly all of the experimental work. Wrote the

supporting information and contributed in writing of the manuscript.

V. Performed half of the experimental work, prepared the racemic substrates.

Contributed in the screening studies, evaluated the scope, writing of the

supporting information.

60

APPENDIX B – CRYSTAL STRUCTURE

Ortep diagram of Crystal 4k (with thermal ellipsoids set at 90% probability).[66]

61

APPENDIX C – NOESY SPECTRA

62

APPENDIX D – CRYSTAL STRUCTURE

Ortep picture of Crystal 4i.[67]

63

APPENDIX E – NOESY SPECTRA

64

ACKNOWLEDGEMENTS

I would like to start to extend my sincerest thanks to my supervisor Professor

Armando Córdova, for giving me the opportunity to perform my PhD studies in

his group and for introducing me to the very interesting field of asymmetric

catalysis and of course for his constant pushing the quality of my research,

presentation and writing skills towards excellence. I am greatly indebted to

Associate Professor Ismail Ibrahem for his help and guidance. All my co-workers

Palle Breistein, Guangning Ma (Marwin), Carlos Palo-Nieto, Luca Deiana, Jonas

Rydfjord, Kristian Pirttilä, Celia A. Incerti-Pradillos, Pawel Dziedzic, Oscar

Córdova, Moniruzzaman Mridha and Jonas Johansson, you all have left

memorable and knowledgeable footprints in me. I would like to thank Prof. Erik

Hedenström and his group members. I also thank Eric Johnston and Oscar Verho

from Bäckvall group.

I would like to give deeply and endless thanks to all the people at the University

who have been helpful, Håkan Norberg, Torborg Jonsson, Maria Torstensson,

Viktoria Lilja, Veronica Norman, Anna Parment, Anita Zetterström, Eva Olofsson

Anne Åhlin, Fredrik Carlsson, Bo Westerlind, Sören Sollén, Lars-Johan Bäckström,

Kristoffer Sjöbom, Fredrik Bodin, Christina Olsson and Caroline Wiklöf.

I would like to acknowledge my uncle Medhanie Wolderifael and his family.

As Lao Tzu said; “The journey of a thousand miles begins with one step”, and my first

step was taken at the end of junior high school in Valsätraskolan, when my

chemistry teacher, Gunilla Oskarsson, who believed in me and my capacity more

than I did, persistently advised me to choose natural science for my further

education in high school. Her advice taught me that a person is limitless and that

anything can be accomplished, no matter where you are in the eyes of others. I am

indebted for her important advice, which has been one of the main keys to

reaching this stage of my education.

I would like to give deep and endless thanks to all my friends during my master

studies at Uppsala University, all my friends at high school in Celsiusskolan, all

my friends from the time in Bäcklösa and Valsätraskolan, team Nakfa, all my

friends from the soccer team Uppsala IF and “Guzludi grabbarna”.

My basic knowledge in organic synthesis I gained during my diploma work and

research training at Uppsala University, which have helped me to smoothly adapt

to the new environment at the beginning of my PhD studies and for that I am

thanking all the people who have provided me with very valuable tools and

knowledge in organic synthesis.

I would like to give my sincerest and deep appreciation to the people that have

taken their time to proofread this thesis Hans-Erik Högberg and Italo Andres

Sanhueza. Last but not least I would like to send endless and many thanks to my

family, having you in my life is a privilege and indescribable for me.

65

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DEVELOPMENT OF CATALYTIC ENANTIOSELECTIVE C-Cmiun.diva-portal.org/smash/get/diva2:768971/FULLTEXT01.pdfvaluable structural scaffolds, namely poly-substituted spirocyclic oxindoles