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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.
DEVELOPMENT OF CATALYTIC ENANTIOSELECTIVE C-C
BOND-FORMING AND CASCADE TRANSFORMATIONS BY
MERGING HOMOGENEOUS OR HETEROGENEOUS
TRANSITION METAL CATALYSIS WITH ASYMMETRIC
AMINOCATALYSIS
Samson Afewerki
© Samson Afewerki, 2014
Department of Natural Sciences
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
DEVELOPMENT OF CATALYTIC ENANTIOSELECTIVE C-C
BOND-FORMING CASCADE TRANSFORMATIONS BY MERGING
HOMOGENEOUS OR HETEROGENEOUS CATALYSIS WITH
ASYMMETRIC AMINOCATALYSIS
Samson Afewerki
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
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
3.2. RESULTS AND DISCUSSION .................................................................................... 26
ix
3.2.1. OPTIMISATION STUDIES ..................................................................................... 26
3.2.2. SUBSTRATE SCOPE ............................................................................................ 29
3.2.3. PROPOSED REACTION MECHANISM .................................................................... 30
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. RESULTS AND DISCUSSION .................................................................................... 34
4.2.1. OPTIMISATION STUDIES ..................................................................................... 34
4.2.2. SUBSTRATE SCOPE ............................................................................................ 37
4.2.3. PROPOSED REACTION MECHANISM .................................................................... 39
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. RESULTS AND DISCUSSION .................................................................................... 43
5.2.1. OPTIMISATION STUDIES ..................................................................................... 43
5.2.2. SUBSTRATE SCOPE ............................................................................................ 47
5.2.3. PROPOSED REACTION MECHANISM .................................................................... 48
5.3. CONCLUSION ......................................................................................................... 50
6. COOPERATIVE COMBINATION OF HETEROGENEOUS- AND
AMINOCATALYSIS FOR ENANTIOSELECTIVE CHEMICAL
TRANSFORMATION (PAPER V) ................................................................................ 51
6.1. INTRODUCTION ..................................................................................................... 51
6.3. RESULTS AND DISCUSSION .................................................................................... 51
6.3.1. OPTIMISATION STUDIES ..................................................................................... 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.
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
functionalised aldehyde
R Nu
O
R
H
functionalised aldehyde
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%)
[Pd(PPh3)4] (5 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%)
[Pd(PPh3)4] (5 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.
3.2. Results and discussion
3.2.1. Optimisation studies
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
[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 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
[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 on the
crude reaction mixture. [d] Determined by chiral-phase GC.
3.2.2. Substrate scope
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.
3.2.3. Proposed reaction mechanism
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.
4.2. Results and discussion
4.2.1. Optimisation studies
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
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.
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
Table 7. Optimisation study for the palladium and chiral amine catalysed enantioselective
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
1H NMR spectroscopy on the crude reaction mixture. [b] 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.
4.2.2. Substrate scope
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.
[Pd2(dba)3] (5 mol%)
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.
[Pd2(dba)3] (5 mol%)
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
4.2.3. Proposed reaction mechanism
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
[Pd2(dba)3] (5 mol%)
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'
[Pd2(dba)3] (5 mol%)
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.
5.2. Results and discussion
5.2.1. Optimisation studies
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
Table 10. Optimisation study for the palladium and chiral amine catalysed enantioselective
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
Table 11. Optimisation study for the palladium and chiral amine catalysed enantioselective
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).
[b] Conversion to and d.r. of 43 as determined by 1H NMR spectroscopy on the crude
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).
[b] Conversion to and d.r. of 43 as determined by 1H NMR spectroscopy on the crude
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.
5.2.2. Substrate scope
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]
5.2.3. Proposed reaction mechanism
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.
6.3. Results and discussion
6.3.1. Optimisation studies
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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