DIPARTIMENTO DI CHIMICA, MATERIALI E INGEGNERIA CHIMICA “Giulio Natta” Dottorato di Ricerca in Chimica Industriale e Ingegneria Chimica (CII) XXII ciclo 2007 - 2009 ASYMMETRIC SYNTHESIS BY ENZYME AND SOFT LEWIS ACID CATALYSIS Tesi di Dottorato di ASSEM MAHMOUD El SAYED BARAKAT Matricola: 710744 Coordinatore: Prof. Dr. Renato Rota Tutore: Prof. Dr. Claudio Fuganti Relatore: Prof. Dr. René Peters POLITECNICO DI MILANO
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DIPARTIMENTO DI CHIMICA, MATERIALI E INGEGNERIA CHIMICA “Giulio Natta” Dottorato di Ricerca in Chimica Industriale e Ingegneria Chimica (CII) XXII ciclo 2007 - 2009
ASYMMETRIC SYNTHESIS BY ENZYME AND SOFT LEWIS ACID
CATALYSIS
Tesi di Dottorato di ASSEM MAHMOUD El SAYED BARAKAT Matricola: 710744
Coordinatore: Prof. Dr. Renato Rota Tutore: Prof. Dr. Claudio Fuganti Relatore: Prof. Dr. René Peters
POLITECNICO DI MILANO
This work is dedicated to my parents
A Gehad, mia moglie
& mio Figlio
ACKNOWLEDGEMENTS
It gives me great pleasure to express my deep sense of gratitude to Prof. Dr. Claudio Fuganti for
introducing me to the fascinating area of organic chemistry and his astute guidance. His receptive
attitude, untiring enthusiasm and positive approach will always remain a source of inspiration.
I am greatly thankful to Dr. Stefano Sera for his scientific guidance, stimulating suggestions and
encouragement related to this work. I am indebted for his kind care and concern in the lab.
My sincere thanks to Prof. Dr. Elisabetta Brenna for the valuable scientific discussions, during the
course of this work and for her excellent help in proofreading this manuscript .
I sincerely would like to thank Prof. Dr. René Peters for his support, encouragement, for his
guidance and numerous discussions during these years. I am grateful to him for giving me the
opportunity to work in his laboratory at ETH, Zurich, Switzerland and then at university of
Stuttgart, Germany as exchange student for one and half year.
I would like to thank Dr. Philip Kraft, Givaudan Schweiz AG, Fragrance Research, Dübendorf,
Switzerland, for the olfactory descriptions and for the threshold determinations.
My warmest thanks goes to my former and present colleagues from our research groups for
providing me a friendly and academically environment over the last years (Francesco G. Gatti,
Daneilla Acetti, Fabio Parmeggiani, José Cabrera-Crespo, Daniel Fischer, Simon Eitel, Haoxi
Huang, Florian Koch, Thomas Kull, Frank Maier, Helen Taylor, Paolo Tiseni, Manuel Weber,
Zhuoqun Xin). My special thanks to Dr. Daniel Fischer for helping me in various ways during the
course of this work at ETH, Zurich.
I would like to thank prof. Stefano srevi, head of department and his group for their kind
cooperation.
Moreover, I would like to thank all the people at the services of the Politecnico di Milano, ETH
Zürich and the University of Stuttgart for their help in recording the NMR spectra and the library
staff for excellent facilities.
A special thanks goes to prof. Dr. Renato Rota, coordinator of PhD students for his kind
cooperation. My special thanks to Mrs. Myriam Oggioni for her help and cooperation.
I am grateful to all the nice people with whom I shared many delightful moments and who made my
stay at Milano, Zurich, and Stuttgart pleasant.
A special thanks goes to Prof. Dr. Mohammed shaban, Prof. Dr. Adel Zaki, and Dr Mahmoud
Fawzi for helping me during master course.
A special thanks goes to Prof. Dr.Giuseppe Guanti, Prof. Dr. Luca Banfi, Prof. Dr. Renata Riva,
and Dr. Andrea Basso for their help during my stay for one year at university of genoa, Italy.
I gratefully acknowledge the financial support by the Politecnico di Milano and allowing me to go
to ETH, Zurich and University of Stuttgart for one and half year; more over for facilitating me to
attend the international conferences. My Special thanks goes to ETH and University of Stuttgart for
providing the necessary research facilities.
I am indebted to my parents and my family members who have constantly encouraged me and I am
grateful to them for all their sacrifices.
Finally, I would like to thank my wife for her patience, encouragement, and great support.
List of publications
Parts of this thesis have been published:
1. D. F. Fischer, A. Barakat, Z-q. Xin, M. E. Weiss, R. Peters., The Asymmetric Aza-Claisen
Rearrangement: Development of Widely Applicable Pentaphenylferrocenyl Palladacycle
Catalysts., Chem. Eur. J. 2009, 15, 8722. (VIP)
2. A. Barakat, E. Bernna, C. Fuganti, S. Serra, Synthesis, olfactory evaluation, and
determination the absolute configuration of the β- and γ-Iralia® isomers, Tetrahedron:
Asymmetry 2008, 18, 2316.
3. S. Serra, A. Barakat, C. Fuganti, Chemoenzymatic Resolution of Cis and Trans 3,6-
dihydroxy-α-ionone. Synthesis of the enantiomeric forms of dehydrovomifoliol and 8,9-
1. poster: Lipase mediated resolution of Cis and Trans-3,6-dihydroxy-α-ionone. Some
applications to the synthesis of dehydrovomifoliol and 8,9-dehydrotheaspirone. A. Barakat,
S. Serra. Organic chemistry “Target synthesis: challenges, Strategies and Methods”
Séminairehors-ville du 3éme cycle en chimie 2007 (CUSO-2007). Villars,
Switzerland, Sept, 2007.
2. attending: International symposium metal–catalyzed syntheses new ways forward for industrial processes). Accademia nationale dei lincei, fondazione “guido donegani” Roma, Italy, May, 2007.
I
Table of Contents
Abstract. 1
Chapter 1: Introduction 5
1.1 The Impact of Molecular Chirality 5
1.2 The Preparation of Enantiopure Molecules 6
1.2 Biocatalysis 8
1.2.1 Enzymes and Carbon-Carbon Bond Formation 9
1.2.3 Enzymes and Epoxidation 10
1.2.4 Enzymes and Redcution 11
1.2.5 Lipases as Biocatalysis in Organic Synthesis 11
1.2.6 Enzymes and Transamination 12
1.3 Application of Biocatalysis 12
1.3.1 Enzymes and Chiral Intermediates for Pharmaceuticals 13
1.3.2 Applications of Biocatalysis in Fragrance Chemistry 13
1.4 Chemocatalysis 14
1.4.1 Pd(II)- and Pd(0)-Catalyzed Reactions 16
1.4.2 Enantioselective Synthesis 17
1.4.2.1 Asymmetric Allylic Alkylation (AAA) 17
1.4.2.2 Asymmetric Heck Reactions 19
1.4.3 Palladacycles 19
1.4.4 Application of Palladacyles 20
1.4.4.1 Michael Additions 20
1.4.4.2 Asymmetric aza-Claisen Rearrangements 21
1.4.5 Platinacycles 25
1.5 Enzymes in Combination with Metal Catalysts for Asymmetric Catalysis 26
1.6 Conclusion 27
7.7 References and Notes 27
Chapter 2 33
Chemoenzymatic Resolution of cis- and trans -3,6-dihydroxy-α-ionone. Synthesis of the Enantiomeric
Forms of Dehydrovomifoliol and 8,9-Dehydrotheaspirone 33
2.1 Introduction 33
2.1.1 General Introduction, Motivation 33
2.2 Literature Overview. 33
2.2.1 known Ionone Isomers. 33
2.3 Results and Discussion 36
2.3.1 Preparation of Racemic Diols 36
II
2.3.2 Lipase-mediated Resolution of Diols 37
2.3.3 Determination of the Absolute Configuration of Acetates; Synthesis of
Dehydrovomifoliol.
2.3.4 Synthesis of the Enantiomeric Forms of 8,9-Dehydrotheaspirone. 40
2.3.5 Olfactory Evaluation of the Enantiomeric Forms of Dehydrotheaspirone 41
2.4 Conclusion 41
2.5 Reference 42
Chapter 3 45
Synthesis, Olfactory Evaluation and Determination of the Absolute Configuration of the β- and γ-
Iralia® Isomers 45
3.1 Introduction. 45
3.2 General Introduction, Motivation. 45
3.3 Literature Overview. 46
3.4 Results and Discussion. 47
3.4.1 Preparation of β-Isomers 47
3.4.2 Preparation of γ-Isomers 48
3.4.3 Synthesis of Enantioenriched γ-Iralia Isomers 50
3.4.4 Determination of the Absolute Configuration of γ-Iralia Isomers 51
3.4.5 Olfactory Evaluation of the Iralia Isomers 52
3.5 Conclusion 53
3.6 References 53
Chapter 4 55
The Asymmetric Aza-Claisen Rearrangement: Development of Widely Applicable
Pentaphenylferrocenyl Palladacycle Catalysts 55
4.1 Introduction 55
4.1.1 General Introduction and Motivation 55
4.1.2 Literature Overview 55
4.1.2.1 Structural Variety of Chiral Ferrocenyl Oxazoline Ligands 56
4.1.2.2 Chiral Ferrocenyl Oxazoline Ligands and Palladacycles 58
4.1.2.3 Direct Enantioselective and Diastereoselective Cyclopalladations 59
4.1.2.4 Chiral Ferrocenyl Oxazoline Derived Palladacycles and their Application 63
4.2 Results and Discussion 74
4.2.1 Synthesis of Oxazoline Palladacycles 74
4.2.2 Determination of the Absolute Configuration 76
4.2.3 Catalysis with Known Substrates 77
4.2.4 Catalysis 80
4.2.5 Challenging New Substrates 86
III
4.2.6 Rearrangement of Thiocarbamates 90
4.3 Modified Catalyst Design Model for the Asymmetric Aza-Claisen Rearrangement 90
4.4 Models for the Enantioselectivity Determining Step in the Aza-Claisen Rearrangement 91
4.5 Scale up of the Rearrangment of Trifluoroacetimidate and Recycling of PPFOP-Cl 93
4.6 Conclusion 94
4.7 References 95
Chapter 5 97
Intramolecular Hydroamination of Unactivated Olefins using a Highly Strained Planar Chiral
Platinacycle. 97
5.1 Introduction. 97
5.1.1 General Introduction and Motivation 97
5.1.2 Literature Overview 98
5.2 Results and Discussion 105
5.2.1 Synthesis of a Bisimidazoline Platinacycle 105
5.2.2 Synthesis of Amino Olefin 105
5.2.2.1 General Procedure for the Synthesis of 4-Mono-substituted Amino Olefins 100
5.2.2.2 4,5-Di-substituted Amino Olefins 106
5.2.3 Results and Discussion 108
5.2.3.1 Catalysis 108
5.2.3.2 Investigation of the Influence of the Silver Salt 109
5.2.3.3 Investigation of the Influence of the Amino Protecting Group 110
5.2.3.4 Investigation of the Influence of Additives 111
5.3 Attempts to the Development of an Improved Catalyst 113
5.4 Development of New Catalysts 114
5.4.1 Ligand Preparation. 115
5.4.2 Screening Different Conditions for Cycloplatination 116
5.5 Conclusion 118
5.6 References 118
Chapter 6 121
Miscellaneous. 121
6.1 Synthesis of a Methoxy-substituted Pentaphenyl Ferrocenyl Imidazoline Palladacycle 121
6.1.1 Literature Overview 121
6.1.2 Results and Discussion 122
6.2 Synthesis of a Pentaphenyl Ferrocenyl Oxazoline Palladacycle with a Pd(III) Center 125
6.2.1 Literature Overview 125
6.2.2 Results and Discussion 125
6.3 Intramolecular Hydroalkoxylation of Unactivated Olefins 127
6.3.1 Literature Overview 127
IV
6.3.2 Results and Discussion 127
6.3.2.1 Synthesis of Hydroxy Olefins 127
6.3.2.2 Optimization of the Reaction Conditions for Intramolecular Hydroalkoxylation of
Unactivated Olefins 128
6.4 Cyclization of Alkenyl β–diketone esters by Hydroalkylation. 131
6.4.1 Literature Overview 131
6.4.2 Results and Discussion 131
6.4.2.1 Synthesis of Alkenyl β-keto Esters 131
6.4.2.2 Optimization of Reaction Conditions for Cyclization of Alkenyl β-keto Esters 125
6.5 Synthesis of 4,5-Didehydroionone Stereoisomers. 135
6.5.1 Literature Overview. 135
6.5.2 Results and Discussion. 137
6.5.2.1 Synthesis of 4,5-Didehydro-α-ionone 137
6.5.2.2 Synthesis of 4,5-Didehydro-β and γ-ionone 137
6.6 Conclusion 139
6.7 References 139
Chapter 7 143
Experimental 143
General 143
Synthesis of the Enantiomeric Forms of Dehydrovomifoliol and 8,9-Dehydrotheaspirone. 145
Synthesis of racemic (3RS,6SR)-3,6-dihydroxy-γ-ionone and of (3SR,6SR)-3,6-dihydroxy-γ-ionone
145
(3RS,6SR)-3,6-Dihydroxy-γ-ionone (±) 145
(3SR,6SR)-3,6-Dihydroxy-α-ionone (±) 146
General Procedure for Lipase-mediated Resolution of Racemic Substrates (±)( GP1) 147
Resolution of (3RS,6SR)-3,6-dihydroxy-γ-ionone (±) 147
(3S,6R)-3-acetoxy-6-hydroxy-α-ionone (−) 148
(3R,6S)-3-acetoxy-6-hydroxy-α-ionone (+) 148
Resolution of (3SR,6SR)-3,6-dihydroxy-α-ionone (±) 148
(3S,6S)-3-acetoxy-6-hydroxy-α-ionone (+) 149
(3R,6R)-3-acetoxy-6-hydroxy-α-ionone (−) 149
General Procedure for Conversion of 3-acetoxy-6-hydroxy-α-ionone Isomers in the
Dehydrovomifoliol Enantiomers (GP2) 149
(−)-Dehydrovomifoliol 150
(+)-Dehydrovomifoliol 150
General Procedure for Conversion of 3-acetoxy-6-hydroxy-α-ionone Isomers in the 8,9-
Hammett-Plot of C-3-Aryl substituted allylic imidates 235
References 236
X
List of Acronyms and Abbreviations
Ac Acetyl aq. Aqueous Ar Aryl Bn Benzyl Boc tert-butyloxycarbonyl Bu Butyl BuLi n-butyllithium Cat. Catalyst Cbz Benzyl formate Cp Cyclopentadienyl DBU 1,8-Diazabicycloundec-7-ene DCM Dichloromethane DCE Dichloroethane DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DIBAL Diisobutylaluminium hydride DIPEA N,N-diisopropylethylamine DMAP Dimethylaminopyridine DMF Dimethylformamide DMPU 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone Dpa Dibenzylideneacetone Dppe 1,2-Bis(diphenylphosphino)ethane d.r. Diastereomeric ratio ee Enantiomeric excess e.g For example EI Electron impact ionisation Et Ethyl equiv. Equivalent ESI Electron spray ionisation FBI Ferrocene bisimidazoline Fc Ferrocene FIP Ferrocene imidazoline palladacycle GP General procedure H Hour(s) HB Hünig`s base HMPA Hexamethylphosphoric acid triamide HPLC High performance liquid chromatography HR-MS High resolution-mass spectroscopy I Iso IR Infrared spectroscopy L.A. Lewis acid LDA Lithium diisopropylamide LHMDS Lithium bis(trimethylsilyl)amide M Meta Me Methyl MP Melting point MS Mass spectroscopy MTBE Methyl tert-butylether NBS N-bromosuccinimide N. D. Not determined NMR Nuclear magnetic resonance
XI
NOE Nuclear overhauser effect O Ortho P Para Ph Phenyl PMP p-methoxyphenyl PPFOP Pentaphenylferrocenyl oxazoline palladacycles P.S. Proton sponge RT Room temperature SM Starting material t, tert Tertiary TBAF Tetra-n-butylammonium fluoride TBS Tert-butyldimethylsilyl TEMPO 2,2,6,6-Tetramethylpiperidine-1-oxyl Tf Trifluoromethanesulfonyl THF Tetrahydrofuran TLC Thin layer chromatography TMEDA N,N,N’,N’-tetramethylethylenediamine TMS Trimethylsilyl Ts p-toluenesulfonyl
Abstract
The subject of this thesis is the use of chiral catalysts which convert prochiral substrates into
enantiomerically pure (or enriched) compounds. A principal advantage of asymmetric catalysis as
compared to stoichiometric asymmetric synthesis is that a subequimolar quantity of a chiral entity
is sufficient for the enantioselective formation of a chiral product. This results in lower cost, fewer
reaction steps and less environmental pollution. Catalysis can be performed either by biocatalysts
or chemocatalysts. Biocatalysis was applied for the synthesis of enantiopure compounds by
enzymes. We have performed two examples by enzymes. The first example describes the
straightforward synthesis of both enantiomers of cis- and trans 3-acetoxy-6-hydroxy-α-ionone. The
compounds are prepared by resolution of the diastereoisomerically pure racemic 3,6-dihydroxy-α-
ionone isomers. The later process is based on two steps. The enantio- and regioselective lipase-
mediated acetylation of diols to afford the corresponding 3-acetoxy-derivatives, and the fractional
crystallization of the latter compounds increasing their optical purity. These building blocks were
used for the synthesis of both enantiomeric forms of the natural norterpenoids dehydrovomifoliol 1
and 8,9-dehydrotheaspirone 2. 8,9-Dehydrotheaspirone 2 is a natural flavor and its odour properties
were evaluated by professional perfumers (Scheme 1).
HO
O1) chemoenzymatic
resolution2) chemical
transformation O
O
OO
OH
cis and t rans diols 3 Dehydrovomifoliol Dehydrotheaspironeenantiomers 1 enantiomers 2
OH
Scheme 1
The second example performed by biocatalysis describes the regioselective synthesis of the methyl
ionones isomers. The enantiomers of the γ isomers are prepared by enzyme-mediated resolution of
the corresponding 4-hydroxy derivatives followed by reductive elimination of the hydroxy group.
Since all the obtained isomers are components of the artificial violet odorants sold under the trade
name of Iralia®, their odour properties have been evaluated by professional perfumers (Scheme 2).
2 Abstract
O
R
R'
O
R
R'O
R
R'
β -iralia isomers γ -iralia iosmers R = H, R' = MeR = Me, R' = H
Scheme 2
In modern synthetic chemistry, soft Lewis acids such as Pd(II), Pt(II) or Au(I) have become more
and more important, since coordination of these carbophilic cations to olefins or alkynes results in a
net transfer of electron density from the ligand to the metal center thus activating the unsaturated
system for the attack of the nucleophiles. The soft Lewis acid can thus be regarded as a
chemoselective (owing to its low oxophilicity) and possibly chiral proton substitute.
The Pd(II) catalyzed aza-Claisen rearrangement of allylic trichloro- and trifluoroacetimidates
enables the transformation of achiral allylic imidates 7, readily prepared from allylic alcohols 5 in a
single high yielding step, to chiral enantioenriched allylic amides 8. Since the trihaloacetamide
protecting groups can be readily removed, the overall transformation leads to allylic amines 9, the
valuable building blocks for the synthesis of important compound classes such as unnatural amino
acids. This is the second approach of this thesis (scheme 3).
R1
O
CX3
NR3
R1
O
CX3
NR2 R3
R2
Pd(II)
R1*
NH2R2
R3 = H, PMPX = Cl, F
R1
OHR2 CX3
NR3
Cl+
5 6 7 8 9
Scheme 3
To this end, pentaphenylferrocenyl oxazoline palladacycles PPFOP-Cl 4 have been created
(Scheme 4), affording the most active enantioselective catalyst for the aza-Claisen rearrangement
of trihaloacetimidates:
Introduction: BioCatalysis and Chemocatalysis 3
ON
Fe Ph
PhPhPh
Ph
iPr Pd Cl
2
ONR3
R1
CX3
R1
NR3
CX3
OR2
R2 1°/ 2°/ 3° allylic amines
3°/ 4° stereocenter s
[PdII]
PPFOP-Cl 4
1. Pd(OAc)2, AcOH,95 °C, 93%
2. LiCl, MeOH, PhH95%
Fe
PhPh
Ph
Ph PhHO
O
1. (COCl)2, DCM,cat. DMF
2. (S)-valinol, NEt3,DCM, 0 °Cto RT
3. TsCl, NEt3, DCM,cat. DMAP
91%
Fe
PhPh
Ph
Ph Ph
NO
i-Pr
11
10
Scheme 4
Nitrogen-containing saturated heterocyclic systems are important core structures in organic
chemistry because of their presence in many bioactive natural products. One of the most appealing
approach to these heterocycles is the intramolecular hydroamination, in which the nitrogen carbon
bond is formed by the addition of an amine to an olefin. In response to the limitations associated
with the hydroamination of unactivated C=C bonds, an effective Pt-catalyzed protocol for the
intramolecular hydroamination of amino alkenes has been applied (Scheme 5).
Fe
N
Pt
N
PhPh
Cl
Ts
NN
Ph
PhTs
(5 mol%) 12(5 mol%) Ag-salt,solvent, T,t
n = 1, 2
NHPGP N
R2
R1
R2
R1R3
PGP
R3
n n
12PGP = Protective group
Scheme 5
Chapter 1
Introduction.
1.1 The Impact of Molecular Chirality.
Chirality1 is an important aspect of the most fundamental processes of the life.2 The sugars that
constitute DNA and RNA possess a uniform stereochemical configuration. The proteins encoded
by these oligonucleotides, crucial for the chemical transformations in cells, consist of chiral α-
amino acids that occur exclusively in the L-configuration. Without this chiral homogeneity, the
biomachinery that makes up all known living organisms would not be able to function. Even in the
most elementary forms of life, such as bacteria3 a myriad of different chiral molecules are involved
in complex signaling pathways. Receptor proteins on the cell membrane or within the cytoplasm or
cell nucleus can specifically bind to one enantiomer of a chiral “messenger” molecule and initiate a
corresponding cellular response.
These diastereomeric interactions are the key to modern drug development.4 The interactions
between biological systems and synthetic chiral molecules has a huge impact on contemporary
everyday life and applications ranging from flavors, fragrances, and food additives to
agrochemicals and life-saving drugs. Homochirality in drugs is as old as the first therapeutic agents
isolated from natural sources, such as quinine and morphine. However, as products of synthetic
chemistry, until recently chiral drugs were manufactured as racemates. The assumption that only
one enantiomer of a drug has biological activity and the other serves as “isomeric ballast”4 has
turned out to be a rather dangerous one. The two enantiomers of a compound most frequently bind
to different receptors, and therefore have completely different physiological effects. The presence
of the “wrong” enantiomer has, in some cases, been known to cause serious side-effects. This has
resulted in severe restrictions5 to the production of bioactive molecules and at present time “single
enantiomer drugs have a commanding presence in the global pharmaceutical landscape”.6 The
development of efficient methodologies for the synthesis of the individual enantiomers of an
asymmetric target compound is, therefore, of continuous interest to scientists in both industry and
academia.
6 Chapter 1
1.2 The Preparation of Enantiopure Molecules.
The goal of asymmetric synthesis − whether it is done in an academic or an industrial setting − is to
prepare stereochemically-enriched compounds in the most efficient and practical manner possible.
However, the choice of strategy is rarely simple, because the ways in which efficiency and
practicality are defined can depend on a large number of factors. These can include scale, reagent
costs, time allotted and required, number of steps/manipulations, potential hazards, waste
generation, specifications for product purity, volumetric productivity and/or throughput,
availability of appropriate equipment, and even the scientific background of the synthetic chemists
involved.
In selecting a method for the preparation of an enantioenriched compound, one must therefore
consider the different alternatives. There are three fundamentally different approaches,7 and these
can be defined as follows:
● Chiral pool: use of enantiopure starting materials provided by Nature.
● Resolution: separation of enantiomers by chemical or physical means.
● Enantioselective synthesis: preparation from achiral precursors using chiral reagents or catalysts.
There are numerous instances where the chiral pool approach is unbeatable, either because the
requisite starting material is produced by Nature in great abundance or because the target is itself a
complex natural product and laboratory syntheses are very expensive relative to isolation from
natural sources. Unfortunately, the range of compounds provided by Nature is limited with respect
to structure and stereochemistry, and for this reason resolution and asymmetric synthesis will
certainly always be vitally important strategies for accessing enantiopure compounds. In figure 1.1
there are selected examples for the chiral pool approach.
HO2C
HO2C H
NH2
N
SH
CO2H
HN
MeMe
O
O
NH2
O
O
O
OH
Ampicllin: antibiotic 13 Bioallethrin 14
Glutamic acid 15 (+)-Limonene 16 (−)-Menthol 17 (−)-β -Pinene 18 Fig 1.1. Selected examples for the chiral pool approach.
Introduction: BioCatalysis and Chemocatalysis 7
Resolutions fall broadly into three classes. Classical resolutions involve the use of a stoichiometric
amount of a chiral resolving agent.8 The resolving agent is associated to the substrate, either
covalently or non-covalently, to generate a pair of diastereomers. The diastereomers are separated
and, through a separate chemical transformation, the substrate is released from the resolving agent.
This approach has proven to be especially useful if salt formation is straightforward, as in the case
of amines and carboxylic acids (e. g. Scheme 1.1).9
NH2H2N
HO OH
CO2HHO2C
H2O/HOAc90 to 5 °C
(±)-19 20 21 22
+NH3H3N
OOC COO
OHHO
K2CO3 (2.equiv.)H2O/EtOH
NH2H2N
> 98%ee
40-42%
Scheme 1.1. Classical resolution of trans-1,2-Cyclohexanediamine.
Chiral chromatography generally relies on the use of a chiral stationary phase to resolve
enantiomers contained in a mobile phase, and in principle it can be carried out on analytical or
preparative scale. In reality, the large solvent volumes, long separation times, and relatively high
costs of chiral chromatography often limit the scale at which chromatographic separations can be
carried out. Kinetic resolution involves using a chiral catalyst or reagent to promote selective
reaction of one enantiomer over the other giving a mixture of enantioenriched starting material and
product, and the desired component is then isolated (Scheme 1.2).10
SS + RR + Reagent SS + PR SS or PR
(racemic (isolated)substrat)
chiral catalyst separation
Scheme 1.2. Catalytic kinetic resolution.
The “classical” resolution of racemic mixtures by diastereomeric crystallisation, to date, often
constitutes the industrial method of choice to obtain large quantities of enantiopure compounds.11
However, unless it can be recycled, half of the racemic starting material (the “unwanted”
enantiomer) is a waste-product. This intrinsic property of classical resolutions poses a major
disadvantage from an atom-economy point of view.12 The same disadvantage applies to chemical
or enzymatic kinetic resolutions, involving a reaction in which one of the two enantiomers reacts
more rapidly than the other based on a difference in transition state Gibbs energy. Although in
certain cases, (dynamic) kinetic resolution can lead to complete conversion of the starting material
by in situ racemization, generally one enantiomer reacts whereas the other remains intact.
8 Chapter 1
The remaining option for the preparation of enantiopure molecules involves the introduction of
chirality to a prochiral substrate by asymmetric induction.13 This may involve the use of
stoichiometric amounts of a chiral reagent or a chiral auxiliary followed by the subsequent
diastereoselective introduction of a stereogenic center. However, the use of equimolar amounts of
valuable chiral auxiliary materials makes these approaches rather unappealing. A far more
attractive form of stereoselective synthesis involves the application of asymmetric catalysts. A
relatively small amount of enantiopure catalyst can, in an ideal scenario, produce large quantities of
enantiopure product. Although powerful biocatalytic methods exist, employing enzymes or
antibodies as catalysts,14 their biomolecular homochirality often poses a problem when the “non-
natural” enantiomer of the product is desired. Recently, directed evolution methods have resulted in
enzymes which produce the alternative enantiomers in excess.15 Alternatively, chemical catalysts
can be adapted to provide the desired enantiomer of the product by choosing the appropriate
enantiomer of the ligand. Although asymmetric organocatalysis – based on the use of small organic
molecules as catalysts − is an emerging field,16 in the last decades considerable progress has been
made in the development of highly active metal-catalyzed asymmetric transformations based on
enantiopure ligands complexed to a (transition) metal core.17 In 2001, Noyori, Knowles and
Sharpless received the Nobel prize in chemistry18 on asymmetrically catalyzed hydrogenation and
oxidation reactions opening the field of homogeneous asymmetric catalysis. Asymmetric
reductions and oxidations have been developed to an extent that they are in some cases used for
industrial production of enantiomerically enriched compounds. However, in catalytic asymmetric
carbon-carbon bond forming reactions high catalytic activity and enantioselectivity are less well
established.
1.2 Biocatalysis.
Biocatalysis has many attractive features in the context of green chemistry: mild reaction
conditions (physiological pH and temperature), an environmentally compatible catalyst (an
enzyme) and solvent (often water) combined with high activities and chemo-, regio- and
stereoselectivities in multifunctional molecules. Furthermore, the use of enzymes generally
circumvents the need for functional group activation and avoids protection and deprotection steps
required in traditional organic syntheses. This affords processes which are shorter, generate less
waste and are, therefore, both environmentally and economically more attractive than conventional
routes.
An illustrative example of the benefits to be gained by replacing conventional chemistry by
biocatalysis is provided by the manufacture of 6-aminopenicillanic acid (6-APA) 25, a key raw
material for semi-synthetic penicillin and cephalosporin antibiotics, by hydrolysis of penicillin G
Introduction: BioCatalysis and Chemocatalysis 9
23.17 Up until the mid-1980s a chemical procedure was used for this hydrolysis (scheme 1.3). It
involved the use of environmentally unattractive reagents, a chlorinated hydrocarbon solvent
(CH2Cl2) and a reaction temperature of – 40° C.19 In contrast, enzymatic cleavage of penicillin G
23 (scheme 1.1) is performed in water at 37 °C and the only reagent used is NH3 (0.9 kg per kg of
6-APA 25), to adjust the pH.
N
SHN
OO
HH
CO2H
N
SN
ClO
HH
CO2H
N
SH2N
O
HH
CO2H
i. Me3SiClii. PCl5/CH2Cl2 − 40 °CPhNMe2
Pen acylaseH2O, 37 °C
i. BuOH, − 40 °Cii. H2O, 0 °C
Penicillin G
6 APA 25
23
24
Scheme 1.3. Enzymatic versus chemical deacylation of Penicillin G.
Biocatalysis is growing rapidly, we will discus here briefly some topics which biocatalysis were
involved.
1.2.1 Enzymes and Carbon-Carbon bond formation.
The formation of carbon–carbon bonds is central to organic chemistry, indeed to chemistry in
general. The preparation of virtually every product, be it fine chemical or bulk chemical, will
include a carbon–carbon bond formation at some stage in its synthesis. Carbon-carbon bond
formation can be catalysed by enzymes and metal transition catalyst but is not really green as
enzyme catalyst. The key to making them green is that they have to be easily separable and
reusable.
One of the pleasant example discussed here is enzymatic synthesis of cyanohydrins 26.
Cyanohydrins are versatile building blocks that are used in both the pharmaceutical and
agrochemical industries20 Consequently, their enantioselective synthesis has attracted considerable
attention (scheme 1.4).
10 Chapter 1
R CN
OH
R CN
NPhthR CN
O
R COOH
OH
R CONH2
OH
R
OH
R CN
OSO2R'
R CN
FR CN
N3
R
OH O
R
OH
O
HNH2
R
OHNH2
R' 26
Scheme 1.4. Cyanohydrins are versatile building blocks.
In 2005, Anton Glieder et al,21 were described that site directed mutagenesis has led to a Prunus
amygdalus HNL that can be employed for the preparation of (R)-2-hydroxy-4-phenylbutyronitrile
28 with excellent enantioselectivity (ee > 96%). This is a chiral building block for the
enantioselective synthesis of ACE inhibitors such as enalapril 29 (scheme 1.5).
OHCN, PaHNL
CN
OH
NH
EtO2C
O
CO2HEnalapirlconv = 98%
ee >96%
27 28 29
Scheme 1.5. Modified Prunus amygdalus HNL catalyzes the enantioselective formation of potential
precursors for ACE inhibitors.
1.2.3 Enzymes and Epoxidation.
Ramesh N. Patel et al,22 were reported the synthesis of chiral intermediate (3S,4R)-trans-3,4-
dihydro-3,4-dihydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile [(+)-trans diol 32] by the
stereoselective microbial epoxidation of 2,2-dimethyl-2H-1-benzopyran-6-carbonitrile 30. This
compound is a potential intermediate for the total synthesis of potassium-channel openers. Several
microbial cultures were found which catalyzed the transformation of 30 to the corresponding
(3S,4S)-epoxide 31 and (+)-trans diol 32. The two best cultures, Corynebacterium sp. SC 13876
and Mortierella ramanniana SC 13840 gave reaction yields of 32 M% and 67.5 M% and optical
purities of 88 and 96 %, respectively, for (+)-trans diol 32.
Introduction: BioCatalysis and Chemocatalysis 11
O O
Omicrobialepoxidation
O
OHOH
30 31 3288%ee 96%ee
Scheme 1.6. Microbial epoxidation.
1.2.4 Enzymes and Redcution.
Baker’s yeast (Saccharomyces cerevisiae) has been used in the various transformations as an
environmentally benign reagent in organic synthesis. A. Yajima et al,23 reproted the first
biotransformations employing whole cells of baker’s yeast in fluorous media. The IBY-mediated
reductions of various ketones either with glucose or methanol as energy sources proceeded in
fluorous media without loss of stereoselectivity. The used fluorous solvent was easily and
sufficiently recovered by the filtration and methanol extraction, and was pure enough to be reused
without any purification. The combination of the biotransformation with fluorous chemistry can act
as an environmentally benign chemical process (Scheme 1.7).
O
R1 R2
immobilized bakers' yeastglucose or MeOH
in fluorous media(perfluorooctane)
OH∗
R1 R2
ee: 87-99%yield: 19-66%
Scheme 1.7. IBY mediated reduction of ketone.
1.2.5 Lipases as Biocatalysis In Organic Synthesis.
Considering their specific and limited function in metabolism, one should expect lipases to be of
limited interest for the organic chemist. However, chemists have discovered lipases to be one of the
most versatile classes of biocatalysts in organic synthesis for a few simple reasons: they can be
employed under mild reactions in common organic solvents, under atmospheric pressure, and at
room temperature. They generally safe for the environment, and can be recycled with out loss of
activity. Lipases can accommodate a wide variety of synthetic substrates, while still showing
chemo-, regio, and/or stereoselectivity.
Fuganti et al.26 applied lipases for the synthesis of enantiopure compounds in the fields of flavours
and fragrances.
12 Chapter 1
1.2.6 Enzymes and Transamination.
Optically active α-chiral primary amines are highly demanded in asymmetric synthesis owing to
the biological/pharmacological activity of many amines. Biocatalytic reductive amination or
transamination is well established for accessing α-amino acids. Wolfgang Kroutil et al,24 were
employed biocatalysis for such reductive amination of ketones. For this purpose, they combined
three enzymes: 1) an ω-transaminase transfers the amino group from alanine to the substrate to be
converted, to give the desired amine and pyruvate; 2) an amino acid dehydrogenase (for example,
alanine dehydrogenase) recycles alanine from pyruvate by consuming ammonium and NAD(P)H;
3) finally, the cofactor is recycled by using standard methods (for example, formate dehydrogenase
and formate, glucose dehydrogenase and glucose). In this concept, alanine is not consumed but
recycled.
O
R'R
ω-transaminasebuffer, pH 7.0/DMSO
NH2
R'R
NH2
CO2H
O
CO2HL-AADH
NH4 H2O
NAD(P)H NAD(P)
Formate CO2or orGlucose GluconolactoneFDH or GDH
ee: up to 99%
Scheme 1.8. Outline of the formal reductive amination concept for the preparation of optically
pure amines.
1.3 Application of Biocatalysis. There has been an increasing awareness of the enormous potential of microorganisms and enzymes
for the transformation of synthetic chemicals with high chemo-, regio- and enatioselective manner.
Chiral intermediates and fine chemicals are in high demand at pharmaceutical and agrochemical
industries for the preparation of the bulk drug substances and the agricultural products. Single
enantiomers can be produced by chemical or chemo-enzymatic synthesis. The advantages of
biocatalysis over chemical synthesis are that enzyme-catalyzed reactions are often highly
enantioselective and regioselective. They can be carried out at ambient temperature and
atmospheric pressure, thus avoiding the use of more extreme conditions which could cause
problems with isomerization, racemization, epimerization, and rearrangement. Microbial cells and
enzymes derived therefrom can be immobilized and reused for many cycles. Additionally, enzymes
Introduction: BioCatalysis and Chemocatalysis 13
can be over expressed to make biocatalytic processes economically efficient, and enzymes with
modified activity can be tailor-made. This section provides examples on the use of enzymes for the
synthesis of single enantiomers of key intermediates for drug substances.
1.3.1 Enzymes and Chiral Intermediates for Pharmaceuticals.
Biocatalytic processes have been described for the synthesis of chiral intermediates for β3- and β2-
Scheme 1.22. aza-Claisen rearrangments of allylic imidates using FIP 77.
1.4.5 Platinacycles.
Pt(II)52 and Au(I)52a,46 catalysis have experienced a boom over the past 5 years, as these late
transition metals have the unique property to catalyze highly atom economic reactions of
26 Chapter 1
unactivated alkynes, olefins or allenes creating a significant increase of molecular complexity in a
single step using simple starting materials. The catalysts are compatible with most functional
groups due to their low oxophilicity and are usually very robust towards moisture or air. Pt(II)-
olefin complexes have been reported to be highly reactive for outer-sphere attack by nucleophiles.
The resulting Pt(II)-alkyl intermediates undergo rapid protonolysis53 with Brønsted acids rather
than β-hydride elimination known to be the usually preferred pathway for Pd(II)-alkyl complexes.
In contrast, ligand exchange is relatively slow for Pt(II) complexes.52 Catalysts allowing for a more
rapid ligand exchange could thus lead to enhanced activity of this expensive metal and might
expand the scope to additional valuable applications. In addition to the reactivity issue and despite
considerable progress, asymmetric activation of π-ligands by Au or Pt complexes is still an area of
high development potential.52
Peters et al.54 synthesised platinacycle 12, which was employed in the intramolecular
enantioselective Friedel-Crafts alkylation of indoles 78 as a first example for a highly
enantioselective reaction catalysed by a platinacycle (Scheme 1.23).
Fe
N
Pt
N
PhPh
Cl
Ts
NN
Ph
PhTs
NY
RR
X
Z
NY
R
R
X
Z
(5.0 mol%) 12(5.0 mol%) AgO2CC3F7,CF3CH2OH, 50 °C, 60 h
7915 examples45-95% yield78-92% ee
78
12
Scheme1.23. Friedel-Crafts alkylation of indoles.
1.5 Enzymes in Combination with Metal Catalysts for Asymmetric Catalysis.
Enzyme catalysis (for the resolution of a racemate) and metal catalysis (for the racemization of the
slower reacting enantiomer) are a powerful combination for obtaining successful DKR processes.
The high efficiency of these processes makes them attractive alternatives to existing methods in
asymmetric catalysis for obtaining highly functionalized chiral alcohols and amines in
enantiomerically pure form.55
Introduction: BioCatalysis and Chemocatalysis 27
Reetz and co-workers demonstrated the first example of chemoenzymatic DKR for the preparation
of enantiopure amines.56 Thus, the combination of immobilized CALB as biocatalysts and
palladium on carbon as racemization catalysts was used for the synthesis of (R)-N-(1-
phenylethyl)acetamide 81 from 1-phenylethylamine 80 in moderate yield (64%) and
enantiomerically pure form (Scheme 1.24).
NH2Pd/C-CALBNEt3/AcOEt
NHAc
64% yield, 99% ee80 81
Scheme 1.24. Example of chemoenzymatic DKR for the preparation of enantiopure amines.
1.6 Conclusion.
In a summary, short overview about biocatalysis and chemocatalysis have been presented.
1.7 References and Notes.
1 Chirality (Greek, handedness, derived from the word stem χειρ~, ch[e]ir~, hand~) is a
“dissymmetry” property important in several branches of science. An object or a system is
called chiral if it differs from its mirror image. The term chirality was coined by Lord
Kelvin: (a) W. T. Kelvin, Baltimore Lectures on Molecular Dynamics and the Wave
Theory of Light, C. J. Clay and Sons: London, 1904. For further stereochemical definitions,
see (b) E. L. Eliel, S. H. Wilen, Stereochemistry of Organic Compounds, Wiley: New
York, 1994.
2 (a) F. Krick, Life Itself, McDonald & Co.: London, 1981; (b) M. Gardner, The
Ambidextrous Universe, 2nd Ed., C. Scribner: New York, Harmondsworth: UK, 1982.
3 For a review on chemical signaling among bacteria, see: G. J. Lyon, T. W. Muir, Chem.
Biol. 2003, 10, 1007.
4 E. J. Ariens, W. Soudijin, P. B. M. W. M. Timmermans (Eds.), Stereochemistry and
Biological Activity of Drugs, Blackwell Scientific Publications: Oxford, 1983.
5 Food and Drug Administration, Fed. Reg. 1992, 22, 249.
6 A. M. Rouhi, Chem. Eng. News 2003, 81, 45.
7 E. L. Eliel, S. H. Wilen, L. N. Mander, Stereochemistry of Organic Compounds, Wiley,
New York, 1994.
28 Chapter 1
8 J. Jacques, A. Collet, S. H. Wilen, Enantiomers, Racemates, and Resolutions, Krieger,
Malabar, FL, 1991.
9 J. F. Larrow, E. N. Jacobsen, Org. Synth. 1998, 75, 1. Reviews: (a) H. B. Kagan, J. C.
Fiaud In Topics in Stereochemistry (Eds.: E. L. Eliel, J. C. Fiaud), Wiley, New York, 1988;
Vol. 18, pp 249; (b) A. H. Hoveyda, M. T. Didiuk, Curr. Org. Chem. 1998, 2, 537.
10 (a) J. Jacques, A. Collet, S. H. Wilen, Enantiomers, racemates, and resolutions, Wiley:
New York, 1981; (b) A. N. Collins, G. N. Sheldrake, J. Crosby (Eds.), Chirality in Industry
II, Wiley: Chichester, 1997; (c) T. Vries, H. Wynberg, E. van Echten, J. Koek, W. ten
Hoeve, R. M. Kellogg, Q. B. Boxterman, A. J. Minnaard, B. Kaptein, S. van der Sluis, L.
Hulshof, J. Kooistra, Angew. Chem. Int. Ed. 1998, 37, 2349.
11 B. M. Trost, Angew. Chem. Int. Ed. Engl. 1995, 34, 259.
12 J. Seyden-Penne, Chiral Auxiliaries and Ligands in Asymmetric Catalysis, Wiley: New
York, 1995.
13 (a) J. Wagner, R. A. Lerner, C. F. Barbaras III, Science 1995, 270, 1797; (b) A. M.
Klibanov, Nature 2001, 409, 241.
14 For reviews on the directed evolution of enantioselective enzymes, see: (a) M. T. Reetz,
Tetrahedron 2002, 58, 6595; (b) M. T. Reetz, Proc. Natl. Acad. Sci. USA 2004, 101, 5716;
(b) M. T. Reetz In Methods in Enzymology, Vol. 388, D. E. Robertson, J. P. Noel (Eds.),
Elsevier: San Diego, 2004, 238. See also: (d) N. J. Turner, Trends Biotechnol. 2003, 21,
474.
15 A. Berkessel, H. Gröger (Eds.), D. MacMillan, Asymmetric Organocatalysis: From
Biomimetic Synthesis to Applications in Asymmetric Synthesis, Wiley-VCH: Weinheim,
2005.
16 E. N. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.), Comprehensive Asymmetric Catalysis, Vol.
1-3, Springer: Berlin, 1999.
17 (a) W. S. Knowles, Angew. Chem. Int. Ed. 2002, 41, 1998; (b) R. Noyori, Angew. Chem.
Int. Ed. 2002, 41, 2008;(c) K. B. Sharpless, Angew. Chem. Int. Ed. 2002, 41, 2024.
18 R. A. Sheldon, Chemtech, 1994, 38.
19 R. A. Sheldon, J. Chem. Technol. Biotechnol.1997, 68, 381.
20 a) G. Seoane, Curr. Org. Chem. 2000, 4, 283; b) K. Faber, Biotransformations in Organic
Chemistry, 5th edn., Springer, Berlin, Heidelberg, New York, 2004; c) J. Sukumaran, U.
Hanefeld, Chem. Soc. Rev. 2005, 34, 530; d) R. J. H. Gregory, Chem. Rev. 1999, 99, 3649;
e) J. Brussee, A. van der Gen, in Stereoselective Biocatalysis, P. N. Ramesh (Ed.), Marcel
Dekker, New York, 2000, pp. 289; f) M. North, Tetrahedron: Asymmetry 2003, 14, 147; j)
J.-M. Brunel, I. P. Holmes, Angew. Chem. Int. Ed. 2004, 43, 2752; h) M. Breuer, K.
Introduction: BioCatalysis and Chemocatalysis 29
Ditrich, T. Habicher, B. Hauer, M. Kesseler, R. Sturmer, T. Zelinski, Angew. Chem. Int.
Ed. 2004, 43, 788.
21 R. Weis, R. Gaisberger, W. Skranc, K. Gruber, A. Glieder, Angew. Chem. Int. Ed. 2005,
44, 4700.
22 R.N. Patel, A. Banerjee, B. Davis, J. Howell, C. McNamee, D. Brzozowaski, J. North, D.
Kronenthal, L. Szarka, Bioorg. Med. Chem. 1994, 2, 535.
23 A. Yajima, K. Naka, G. Yabuta, Tetrahedron Lett. 2004, 45, 4577.
24 D. Koszelewski, I. Lavandera, D. Clay, G. M. Guebitz, D. Rozzell, W. Kroutil, Angew.
Chem. Int. Ed. 2008, 47, 9337.
25 a) M . Suffness, M. E. Wall: Discovery and development of taxol. In Taxol: Science and
Application. Edited by Suffness M. New York: CRC press; 1995; b) R. Patel, Annu. Rev.
Microbiol. 1998, 52, 361; c) R. N. Patel, A. Banerjee, R. Y. Ko, J. M. Howell, W. S. Li, F.
T. Comezoglu, R. A. Partyka, L. J. Szarka: Biotechnol. Appl. Biochem. 1994, 20, 23.
26 a) M . Suffness, M. E. Wall: Discovery and development of taxol. In Taxol: Science and
Application. Edited by Suffness M. New York: CRC press; 1995. b) R. Patel, Annu. Rev.
Microbiol. 1998, 52, 361; c) R. N. Patel, A. Banerjee, R. Y. Ko, J. M. Howell, W. S. Li, F.
T. Comezoglu, R. A. Partyka, L. J. Szarka: Biotechnol. Appl. Biochem. 1994, 20, 23.
27 see review: (a) E. Brenna, C. Fuganti, S. Serra, Chem. Soc. Rev. 2008, 37, 2443; (b) E.
Brenna, C. Fuganti, S. Serra, P. Kraft, Eur. J.org. Chem. 2002, 967;(c) S. Serra, C. Fuganti,
E. Brenna. Trends in Biotechnology, 2005, 23, 193; (d) A. Abate, E. Brenna, C. Fuganti, F.
G. Gatti, T. Giovenzana, L. Malpezzi, S. Serra. J. Org. Chem. 2005, 70, 1281.
28 A. Miyashita, A. Yasuda, H. Takaya, K. Toriumi, T. Ito, T. Souchi, R. Noyori, J.Am.Chem.
Soc. 1980, 102, 7932.
29 T. Ohta, H. Takaya, R. Noyori, Inorg. Chem. 1988, 27, 566.
30 (a) T. Katsuki, K. B. Sharpless, J. Am. Chem. Soc. 1980, 102, 5974; (b) E. N. Jacobsen, I.
Marko, W. S. Mungall, G. Schröder, K.B. Sharpless, J. Am. Chem. Soc. 1988, 110, 1968.
31 Selected books for review: a) Handbook of Organopalladium Chemistry for Organic
Synthesis, Ed. E-i. Negishi, John Wiley & Sons, 2002; b) Palladium Reagents and
Catalysts-New Perspectives for the 21st Century, J. Tsuji, John Wiley & Sons, 2004.
32 Selected reviews: a) W. Cabri, I. Candiani, Acc. Chem. Res. 1995, 28, 2; b) G. T. Crisp,
Chem. Soc. Rev.1998, 27, 427. c) I. P. Beletskaya, A. V. Cheprakov, Chem. Rev. 2000,
100, 3009.
33 See, for review: a) Cross-Coupling Reaction-A Practical Guide, Ed. N. Miyaura, (Series:
Topics in Current Chemistry), Springer, Berlin, 2002; b) A. F. Littke, G. C. Fu, Angew.
Chem. Int. Ed. 2002, 41, 4176; c) R. R. Tykwinski, Angew. Chem. Int. Ed. 2003, 42, 1566;
30 Chapter 1
d) Metal-Catalyzed Cross-coupling Reactions, 2nd Edition, Ed. A. de Meijere, F.
Diederich, Wiley-VCH, Weinheim, 2004.
34 See, for review: a) M. Gauss, A. Seidel, P. Torrence, P. Heymanns, in Applied
Homogeneous Catalysis with Organometallic Compounds, Ed. B. Cornils, W. A.
Herrmann, VCH, Weinheim, 1996, pp. 104; b) J. Muzart, Tetrahedron 2005, 61, 9423.
35 See, for review: a) B. M. Trost, C. Lee, in Catalytic Asymmetric Synthesis, Ed. I. Ojima,
Wiley-VCH, New York, 2000, pp. 593; b) B. M. Trost, M. L. Crawley, Chem. Rev. 2003,
103, 2921.
36 See, for review: a) S. S. Stahl, Angew. Chem. Int. Ed. 2004, 43, 3400; b) M. S. Sigman, D.
R. Jensen, Acc. Chem. Res. 2006, 39, 221.
37 Selected examples: a) K. Mikami, K. Takahashi, T. Nakai, T. Uchimaru, J. Am. Chem. Soc.
1994, 116, 10948; b) E. Hagiwara, A. Fujii, M. Sodeoka, J. Am. Chem. Soc. 1998, 120,
2474; c) Y. Hamashima, D. Hotta, M. Sodeoka, J. Am. Chem. Soc. 2002, 124, 11240.
38 see, for review: B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103, 2921.
39 M. Sawamura, R. Kuwano Y. Ito, Angew. Chem. Int. Ed. Engl. 1994, 33, 111.
40 Y. Hashimoto, Y. Horie, M. Hayashi, K. Saigo, Tetrahedron: Asymmetry 2000, 11, 2205.
41 J. Dupont, C. S. Consorti, J. Spencer, Chem. Rev. 2005, 105, 2527.
42 S. Jautze, R. Peters, Angew. Chem. Int. Ed. 2008, 47, 9284.
43 Some recent examples: a) R. Takeuchi, S. Kezuka, Synthesis 2007, 3349; b) O. V. Singh,
H. Han, J. Am.Chem. Soc. 2007, 129, 774; c) C. Defieber, A. Ariger, P. Moriel, E. M.
Carreira, Angew. Chem. Int. Ed. 2007, 46, 3139; d) Y. Yamashita, A. Gopalarathnam, J. F.
Hartwig, J. Am. Chem. Soc. 2007, 5, 7508; e) S. Spiess, C. Berthold, R. Weihofen, G.
Helmchen, Org. Biomol. Chem. 2007, 5, 2357; f) G. Helmchen, A. Dahnz, P. Dübon, M.
Schelwies, R. Weihofen, Chem. Commun. 2007, 675; g) I. Dubovyk, I. D. G. Watson, A.
K. Yudin, J. Am. Chem. Soc. 2007, 129, 14172; h) M. J. Pouy, A. Leitner, D. J. Weix, S.
Ueno, J. F. Hartwig, Org. Lett. 2007, 9, 3949; i) C. Liang, F. Collet, F. Robert-Peillard, P.
Muller, R. H. Dodd, P. Dauban, J. Am. Chem. Soc. 2008, 130, 343; f) C. Welter, R. M.
Moreno, S. Streiff, G. Helmchen, Org. Biomol. Chem. 2005, 3, 3266.
44 a) J. R. Porter, G. Wirschun, K. W. Kuntz, M. L. Snapper, A. H. Hoveyda, J. Am. Chem.
Soc. 2000, 122, 2657;b) M.-Y. Ngai, A. Barchuk, M. J. Krische, J. Am. Chem. Soc. 2007,
129, 12644; c) N. Abermil, G. Masson, J. Zhu, J. Am. Chem. Soc. 2008, 130, 12596.
45 O. Mumm, F. Möller, Chem. Ber. 1937, 70, 2214.
46 a) L. E. Overman, J. Am. Chem. Soc. 1974, 96, 597; b) L. E. Overman, J. Am. Chem. Soc.
1976, 98, 2901.
47 A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180.
48 A. R. Chianese, S. J. Lee, M. R. Gagné, Angew. Chem. Int. Ed. 2007, 46, 4042.
Introduction: BioCatalysis and Chemocatalysis 31
49 P. Beak, J. Bonham, J. T. Lee, J. Am. Chem. Soc. 1968, 90, 1569.
50 a) L. E. Overman, Angew. Chem. Int. Ed. 1984, 23, 579; b) P. Watson, L. E. Overman, R.
G. Bergman, J. Am. Chem. Soc. 2007, 129, 5031.
51 See, for example: Y. Yamamoto, H. Shimoda, J. Oda, Y. Inouye, Bull. Chem. Soc. Jpn.
1976, 49, 3247.
52 M. E. Weiss, D. F. Fischer, Z.-q. Xin, S. Jautze, W. B. Schweizer, R. Peters, Angew.
Chem. Int. Ed. 2006, 45, 5694.
53 a) A. Fürstner, P. W. Davies, Angew. Chem. Int. Ed. 2007, 46, 3410; b) A. R. Chianese, S.
J. Lee, M. R. Gagné, Angew. Chem. Int. Ed. 2007, 46, 4042; c) selected very recent
asymmetric application: C. A. Mullen, A. N. Campbell, M. R. Gagné, Angew. Chem. Int.
Ed. 2008, 47, 6011.
54 F. P. Fanizzi, F. P. Intini, L. Maresca, G. Natile, J. Chem. Soc.,Dalton Trans. 1992, 309.
55 H. Huang, R. Peters, Angew. Chem. Int. Ed. 2009, 48, 604.
56 see, e.g.: a) O. Pàmies, J-E. Bäckvall, Chem. Rev. 2003, 103, 3247. b) T. R. Ward, Chem.
Eur. J. 2005, 11, 3798.
57 M. T. Reetz, K. Schimossek, Chimia 1996, 50, 668.
Chapter 2
Chemoenzymatic Resolution of Cis and Trans -3,6-dihydroxy-α-ionone. Synthesis of the Enantiomeric Forms of Dehydrovomifoliol and 8,9-Dehydrotheaspirone.1
2.1 Introduction. This chapter describes the synthesis of both enantiomers of cis- and trans-3-acetoxy-6-
hydroxy-α-ionone. The title compounds are prepared by resolution of the
diastereoisomerically pure racemic 3,6-dihydroxy-α-ionone isomers. These building blocks
were used for the synthesis of both enantiomeric forms of the natural norterpenoids
dehydrovomifoliol 1 and 8,9-dehydrotheaspirone 2.
2.1.1 General Introduction and Motivation. Numerous methods are available for the syntheses of 3,6-dihydroxy-α-ionone isomers. In the
preceding chapter a straightforward synthesis of all isomeric forms of the 3-acetoxy-6-hydroxy-α-
ionone were developed.
2.2 Literature Overview.
2.2.1 Known Ionone Isomers.
Ionone isomers and their hydroxylated derivatives are important starting materials for the synthesis
of several natural products. Since many of the latter compounds show biological activity, which is
strictly related to their absolute configuration, their synthesis requires optically active starting
materials.2 Therefore the enantioselective preparation of these chiral building blocks has become an
important research topic. Ionone isomers and their hydroxylated derivatives are potential building
bloks for the stereospecific synthesis of compounds of the general structure 82 (Figure 2.1).
34 Chapter 2
R'OH
O
R
O
12
3 4 5
6
7
89
10
OO
OH
O
OH
OCOOH
R= OH, H or OR'= carotenoids or
apocarotenoid chain
O
( carotenoidnumbering )
82
83 1
284
Fig 2.1.
Carotenoids and apocarotenoids of type 82 have been isolated3 from different natural sources and
the most known is (+)-abscisic acid 83 that is well established as an important growth regulator in
most plants.4 Also (+)-dehydrovomifoliol 98 occurs in nature5, but its relevance is due to its use as
penultimate precursor in the well established synthesis of 83.6 Moreover, spiroderivatives 84 and 2
are important flavors. Theaspirone 84 is a component of thea scent7 whereas the less known
dehydrotheaspirone 2 has received increasing attention after its isolation from tobacco,8 Riesling
wine,9 nectarines,10 honey,5c and Reseda odorata flowers.11 All the above mentioned compounds
share the same difficult accessibility by chemical synthesis, particularly in their enantiomerically
pure forms. On this topic the known procedures are based essentially on three approaches: the
resolution of the enantiomers, the asymmetric synthesis and the use of two easily available C-9
chiral building blocks. The first method10,12 proved to be unsuitable for preparative purposes and
was applied in few analytical studies dedicated to the evaluation of the physical12a-b or
organoleptic10,12c properties of compounds 84 and 2, respectively. Concerning the second
pathway,13 some leading methods exploited Sharpless epoxidation13a and chiral bicyclic lactams13b
or ketals13c alkylation procedure as a key step in the formation of the quaternary asymmetric centre.
The obtained chiral intermediates were then manipulated in order to obtain derivatives 1 and 2. On
the other hand, the third pathway is based on the use of (4R,6R) and (4R,6S) isomers of 4-hydroxy-
2,2,6-trimethylcyclohexanone2,14 that are in turn obtained in high optical purity by microbial
reduction of oxoisophorone and by fractional crystallization of its diastereoisomeric esters,
respectively. The latter two compounds were used as starting materials in a number of
carotenoids syntheses involving the preparation of compounds of type 1, 82, 83.
Synthesis of the enantiomeric forms of dehydrovomifoliol and 8,9-dehydrotheaspirone 35
Fuganti et al. have been working on the enantioselective synthesis of different norterpenoid
compounds such as ionone,15 irone,16 damascone17 and 7,11-epoxymegastigma-5(6)-en-9-
one18 isomers.
In 1998, Fuganti et al.19 reported a successful combination of simple chemical and enzymic
methods allowed to prepare extremely valuable (R)- and (S)- α-ionone using inexpensive racemic
α-ionone 85 as a starting material (scheme 2.1). Two different approaches have been devised by
interchanging the application of traditional techniques of fractional crystallisation and enzyme-
mediated reactions. Fractional crystallisations, from hexane, of 4-nitrobenzoate derivatives of α-
ionol were successfully used in both synthetic paths to achieve diastereoisomeric purity, while
optical activation was assured by enantioselective enzyme-mediated acetylation of α-ionol and
hydrolysis of α-ionol acetate.
O O O
(±)-85 (S)-86, 97%ee (R)-86, 97%ee
+
Scheme 2.1. Chemoenzymatic approach for synthesis enantiopure of (R)- and (S)- α-ionone.
In 2005, the same group also reported the synthesis of the isomers of the natural C-13
norterpenoids derivatives 7,11-epoxymegastigma-5(6)-en- 9-one and 7,11-epoxymegastigma-5(6)-
en-9-ols. The racemic compounds were resolved for the first time by mean of lipase-mediated
acetylation. All isomers were obtained in very good yield and high enantiomeric purity (scheme
2.2).18
O
(±)-85 (±)- 87 (−)-88 (+)-88
O
O
O
OH
O
OH
Scheme 2.2. Chemo-enzymatic approach for the synthesis of 7,11-epoxymegastigma-5(6)-en-9-one and 7,11-epoxymegastigma-5(6)-en-9-ol.
Recently, fuganti et al.17 reported a new chemio-enzymatic approach to all the isomeric forms of
the norterpenoid flavor damascone (scheme 2.3). The synthetic pathway is divergent, compact, and
operationally simple and does not require demanding reaction conditions or reagents. The starting
material is a racemic α-ionone that is inexpensive and commercially available. The procedure
described gives access to the title compounds in high regio- and enantiomeric purity and compares
3.4.4 Determination of the Absolute Configuration of γ-Iralia Isomers. The absolute configuration of the enantiomeric forms of 106 and 109 was unknown. In order to
associate odour descriptions with the configuration of γ-ionone isomers, it was necessary to assign
these data. Since the absolute configuration of the enantiomers of α isomers 104 and 107 was
determined unambiguously,6f we decided to correlate the enantiomeric forms of 106 and 109 with
the above mentioned α isomers. Indeed, it is known6c that treatment of γ-ionone isomers with
concentrated phosphoric acid give isomerization of the exocyclic double bond without any
racemization. Therefore, a sample of compound (−)-106 and of compound (−)-109 were treated
with H3PO4 (Scheme 3.6). By this mean a complete isomerization of the starting γ-isomers to α and
β isomers were achieved. 8-methyl γ-ionone (−)-106 afforded a mixture of (S)-(−) 8-methyl α-
ionone 104 and 8-methyl β-ionone 105 whereas 10-methyl γ-ionone (−)-108 afforded a mixture of
(R)-(+) 10-methyl α-ionone 107 and 10-methyl β-ionone 108. In conclusion, the absolute
configuration of (−)-106 and (−)-109 were assign unambiguously as (S) and (R), respectively.
52 Chapter 3
O
(−)-109
O
(−)-106
i
71%
O
(S)-(−)-104
i
O
(R)-(+)-10765%
+ 105
+ 108
α/ β 83:17
α/ β 78:22
Scheme 3.6. Chemical correlation of enantioenriched γ-iralia isomers 106 and 109 with enantioenriched α-iralia isomers 104 and 107. Reagents and conditions: (i) 85% H3PO4.
3.4.5 Olfactory Evaluation of the Iralia Isomers. The regioisomers of β-iralia and the enantiomerically enriched forms of γ-iralia were evaluated by
qualified perfumers (Givaudan Schweiz AG, Fragrance Research). The following results were
obtained:
8-Methyl β-ionone 105 - Floral-woody and powdery violet note with a more pronounced woody,
powdery cedarwood character and fatty-buttery aspects. Weaker than 108 and beta-ionone on the
blotter, less dry than beta-ionone. Dry down weak powdery-woody, and less substantive than 108.
10-Methyl β-ionone 108 - Strong and typical floral-woody beta-ionone note with a more
pronounced floral violet side, less woody-powdery and stronger than 105 on blotter. Dry down
floral-woody, typical beta-ionone like, more substantive than 105.
(S)-(−) 8-Methyl γ-ionone 106 - Woody-ambery mix odor between methyl ionone and Iso E Super
of dry character.
(R)-(+) 8-Methyl γ-ionone 106 - Rich and interesting woody-ambery leather odor with fruity-floral
facets in the direction or irone and methyl ionone and additional green accents.
(S)-(+) 10-Methyl γ-ionone 109 - Woody-floral odor in the direction of methyl ionone, with a
fruity-floral violet inclination and facets of orris, but also an oily background
(R)-(−) 10-Methyl γ-ionone 109 - Woody odor in the direction of methyl ionone with
additional dry, leathery aspects.
Synthesis of the enantiomeric forms of the Iralia® isomers 53
3.5 Conclusion. A number of results have been achieved. New regioselective syntheses of the methyl ionones
isomers 104-109 were reported. The enantiomers of the γ isomers 106 and 109 are prepared by a
chemo-enzymatic approach and their absolute configuration is determined by chemical correlation
with the known α isomers. Finally, the odor properties of all the above mentioned compounds were
evaluated by professional perfumers. In a previous works, Fuganti et al. reported the odour
descriptions of the enantiomers of α isomers 104 and 107. Therefore, a complete description of
each component of the commercial odorants Iralia® were achieved. The following considerations
are noteworthy:
a) All the isomeric forms show distinct olfactory features.
b) For the methyl ionone isomers, the difference between α isomers and γ isomers, although
evident, are less pronounced than those reported for ionone series.6a
c) The difference between enantiomers of γ-methyl ionone isomers are much less pronounced than
those reported for ionone series.
d) Overall, these data show that any structural modification to the ionone framework (methyl group
introduction and position, double bond position absolute configuration) gives a definite and
unpredictable modification of the odour.
3.6 References.
1 A. Barakat, E. Brenna, C. Fuganti, S. Serra, Tetrahedron: Asymmetry 2008, 19, 2316.
2 (a) G. Ohloff, Scent and Fragrances: The Fascination of Fragrances and their Chemical
Perspectives; Springer-Verlag: Berlin, 1994; (b) P. Kraft, J.A. Bajgrowicz, C. Denis, G.
11 (a) E.T. Theimer, W.T. Somerville, B. Mitzner, S. Lemberg, J. Org. Chem. 1962, 27, 635;
(b) E.T. Theimer, W.T. Somerville, B. Mitzner, S. Lemberg, J. Org. Chem. 1962, 27, 2934.
12 S. Serra, C. Fuganti, E. Brenna, Flavour Fragr. J. 2007, 22, 505.
Chapter 4
The Asymmetric Aza-Claisen Rearrangement: Develop- ment of Widely Applicable Pentaphenylferrocenyl Palla- dacycle Catalysts.1
4.1 Introduction.
This chapter describes the synthesis of pentaphenyl ferrocenyl oxazolines and their
diastereoselective ortho-metallation with Pd(II) to the corresponding pentaphenylferrocenyl
oxazoline palladacycles (PPFOP).
The synthesis of pentaphenylferrocenyl oxazoline 11, based on valinol, and a route to its
palladacycle 4 (preliminary study, improvement of catalyst preparation, characterisation and
application) were conducted in the Peters group (ETH Zurich, Switzerland) by the author. New
aza-Claisen substrates (not known in the literature) used in this chapter were prepared and
characterised by Daniel F. Fischer (former Ph.D. student, ETHZ) except for 211 (N-cyclohexyl),
while literature known substrates were prepared by the author.
4.1.1 General Introduction and Motivation. The preparation of pentaphenyl ferrocenyl oxazoline palladacycles was investigated to study if the
high catalytic activity and selectivity of pentaphenyl ferrocenyl imidazoline palladacycle 77 (FIP-
X) is mainly due to the N-sulfonylated imidazoline- or due to the pentaphenylferrocenyl moiety.
4.1.2 Literature Overview. Despite the impressive progress achieved in asymmetric catalysis during the last decade, an
increasing number of new catalysts, ligands, and applications are reported every year to satisfy the
need to embrace a wider range of reactions and to improve the efficiency of existing processes.
Because of their availability, unique stereochemical aspects, and a wide variety of coordination
modes and possibilities for the fine-tuning of steric and electronic properties, ferrocene-based
56 Chapter 4
ligands constitute one of the most versatile ligand architectures in the current scenario of
asymmetric catalysis. Over the last few years ferrocene catalysts have been successfully applied in
an amazing variety of enantioselective processes. This short survey documents these recent
advances, with special emphasis on the most innovative asymmetric processes and the development
of novel and efficient types of ferrocene ligands.
4.1.2.1 Structural Variety of Chiral Ferrocenyl Oxazoline Ligands. In recent years an amazing number and variety of chiral ferrocenyl oxazoline ligands have been
used in asymmetric catalysis. The asymmetric hydrogenation of heteroaromatic compounds is a
challenging field that is receiving increasing attention. In a recent study, Zhou and co-workers2
have shown the usefulness of ferrocenyloxazolinylphosphines (Fc-Phox, 131) as P,N ligands in the
Ir-catalyzed asymmetric hydrogenation of 2-substituted and 2,6-disubstituted quinolines. The
hydrogenation of 2-methylquinoline was chosen as a model reaction to assess the optimization of
the ligand structure revealing that the tert-butyl-substituted ligand 131 was the most efficient (90%
ee, >95% conversion; scheme 4.1).
N
O
Fe t-BuPPh2N
[{Ir(COD)Cl}2]/131/I2
toluene, H2(600psi), RT NH
S/C: 100; conv [%]: >95; ee [%]: 90 Fc-Phox-131129 130
Scheme 4.1. Fc-Phox/Ir-catalyzed asymmetric hydrogenation of 2-methylquinoline.
Regarding the hydrogenation of the challenging class of simple ketones, in a very recent study at
Solvias it was demonstrated that complexes prepared in situ from [RuCl2(PPh3)3] and the readily
available ferrocenyl phosphine oxazoline ligands (Fc-Phox, 134) are extremely effective and
reactive catalysts for the hydrogenation of aryl alkyl ketones with remarkable enantioselectivities
(up to 99% ee) and excellent S/C ratios (up to 10000–50000)3 (scheme 4.2).
N
O
Fe i -PrPPh2
R = H, 98.5% ee Fc-Phox- 134R = Cl, 96% eeR = F, 96% eeS/C 10000 to 50000
R
O
R
OHRuCl2(PPh3)3/134H2 (20−80 bar)
toluene, 1M NaOH, RT132 133
Scheme 4.2. Fc-Phox/Ru-catalyzed hydrogenation of aryl ketones.
Asymmetric Aza-Claisen Rearrangement & PPFOPCl 57
Moyano and co-workers4 found that the Phox ligand 139, analogous to 138 but with a geminal
dimethyl group at the C5 position of the oxazoline ring, led to a significant enantioselectivity in the
asymmetric allylic alkylation reaction of dimethyl malonate 136 with 2-cyclohexenyl acetate 135
(58% ee; Table 4.1, entry 2), while ligand 138 provided the product in only 11% ee. The authors
hypothesized that the geminal dimethyl group in ligand 139 restricts the conformational mobility of
the ligand, the ferrocene moiety becoming oriented towards the π-allylpalladium moiety. A
sterically highly demanding class of planar chiral Phox ligands, possessing a pentamethylferrocene
backbone, have been recently developed by Helmchen and co-workers.5 In particular, ligand 140
with matched central and planar chirality has provided excellent yields and enantioselectivities
(94% ee) in the Pd-catalyzed asymmetric allylic alkylation6 of cycloalkenyl acetates with dimethyl
sodiomalonate (Table 4.1, entries 3) using 1 mol% of catalyst.
Table 4.1: Ferrocene ligands in the asymmetric allylic alkylation of cyclic substrates.
Chiral ferrocenyl oxazoline ligands have widely emerged for the catalytic asymmetric Heck
reaction,7,8 asymmetric Diels–Alder reactions,9,10 addition of diethylzinc to aldehydes,11,12,13 and
[3+2] cycloadditions.14 More recently the catalytic asymmetric intramolecular version of the
Kinugasa reaction has been developed.15 The new family of phosphaferrocene–oxazoline ligands
143 provided excellent results in terms of reactivity and stereoselectivity (Scheme 4.3). A range of
tricyclic β-lactams 142 containing a 6,4 or a 7,4 ring system were obtained with very good
58 Chapter 4
enantiocontrol under catalysis with the combination CuBr/143 (5 mol%). The i-Pr-substituted
ligand 143a was typically found to be the ligand of choice for the generation of a β-lactam fused to
a six-membered ring (86–90% ee), whereas for seven-membered rings the t-Bu-substituted
analogue 143 gave superior results (85–91% ee).
PFe
N
O
RPhX
NArO
n
X
NH H
O Ar
nCuBr/143 (5.0 mol%),Cy2NMe (0.5 equiv.),CH3CN, 0 °C
R = i-Pr, 143aR = t-Bu,143b
141 142
X n L* yield[%] ee[%]
CH2 1 143a 74 88
O 2 143b 68 91
Scheme 4.3. Catalytic enantioselective synthesis of polycyclic β-lactams through intramolecular Kinugasa reaction.
4.1.2.2 Chiral Ferrocenyl Oxazoline Ligands and Palladacycles. Over the past decade or so, there has been a great deal of interest in the application of palladacycles
as catalysts for organic synthesis.
Based on the synthesis of enantiopure 2-ferrocenyl oxazolines 144 and their diastereoselective
ortho-lithiation which was independently reported by Uemura, Sammakia and Richards in 1995,17
some years later, Overman published the first synthesis of 2-ferrocenyl oxazoline palladacycles
(FOP 146, see Scheme 4.4 a).18 Since the desired relative configuration with respect to planar
chirality was opposite to the outcome of a simple one-step lithiation protocol, a multi-step
procedure had to be used with first blocking the undesired ortho-position and subsequent
introduction of an iodo-substituent, followed by oxidative addition with Pd(0). The indirection via
iodination and oxidative addition of Pd(0) had to be used since Overman reported the oxidative
decomposition of the ligand by Pd(II).18b Very recently, however, the direct cyclopalladation of
such ferrocenyl oxazolines 147 with Pd(II) acetate to 148 was reported (Scheme 4.4 b).19
Asymmetric Aza-Claisen Rearrangement & PPFOPCl 59
N
O
Fe
1. s-BuLi, then TMS-Cl2. t-BuLi, then ICH2CH2I
Fe
ON
TMS
I
Fe
NO
TMS
PdI2
Pd2(dba)3
a)
b)
N
O
Fe
Pd(OAc)2, DCMΔ
N
O
Fe Pd
AcO2
144 145 146
147 148
Scheme 4.4. Two routes to 2-ferrocenyl oxazoline palladacycles.
Concerning the field of pentamethyl/pentaphenyl ferrocenes, only very few oxazolines are known.
Richards et al. prepared a 2-pentaphenylferrocenyl oxazoline derived from (L)-serine and modified
the ester functionality to obtain bidentate ligands 149 (Scheme 4.5). A palladacycle with a C-Pd σ-
bond has not been reported, though. In 2006, Helmchen et al.5 reported the synthesis and ortho-
lithiation of 2-pentamethylferrocenyl oxazolines 151 to prepare planar chiral
pentamethylferrocenyl oxazolines 151, but again, those complexes were only used to prepare
palladacycles.
In addition, there is Richards’ COP-X 150 which was published in 1999 and since 2003 used for
the aza-Claisen rearrangement.20
O
Ni -PrPdX
2
Co PhPh
Ph Ph
Fe
PPh2O
Nt-BuPhFe
PhPhPh
PhN
O
R
R = OH, OMe, OPPh2, PPh2R' = H, Me, Ph
R'R'
149151 150
Scheme 4.5. Metal sandwich complex oxazolines with a spectator ligand other than Cp.
4.1.2.3 Direct Enantioselective and Diastereoselective Cyclopalladations The first direct diastereoselective cyclopalladation via C-H activation was reported by Sokolov in
1977 (Scheme 4.6).21 Treatment of Ugi’s amine with Na2PdCl4 in MeOH in the presence of NaOAc
generated palladacycle 153 in 84% yield with a dr of 85:15. Later, Lόpez repeated this reaction and
was able to improve the diastereoselectivity.22
60 Chapter 4
FeNMe2
Pd Cl2
FeNMe2
Na2PdCl4,NaOAc, MeOH
84%,dr = 85:15
Fe
PdNMe2
Cl2
disfavored
+
152 153 Scheme 4.6. First diastereoselective cyclopalladation. Richards and co-workers studied the cyclopalladation of the cobalt sandwich complex derived
imidazoles 154 (Scheme 4.7).23 The rotamer 154 is more favored than 154b due to the fact that
former one minimizes interactions of either the cyclohexyl or tert-butyl substituent with the
tetraphenylcyclobutadienyl floor. The bottom face of the imidazole is blocked by the bulky floor.
The palladation occurred exclusively via the preferred rotamer 154a. The imidazole can thus be
regarded as being in an environment of virtual planar chirality. The palladacycles 155 were
afforded in good yields with high diastereoselectivities, i.e., only the major diastereomer was found
by NMR spectroscopy.
Pd(OAc)2,AcOH
Co
Pd NN
AcO
2
Ph Ph
PhPh
Co
NN
Ph Ph
PhPh
R = t-Bu, 75%R = Cy, 76%
RMeH R
MeH
155154a
Co
N
NPh Ph
PhPh
Me
H R
154b Scheme 4.7. Cyclopalladation of the cobalt sandwich complex derived imidazoles.
Richards also reported the highly diastereoselective cyclopalladation of a cobalt sandwich complex
derived oxazoline 156 (Scheme 4.8).20a Only a single cyclopalladated diastereoisomer 150 (X =
OAc) was formed in 72% yield (R = i-Pr). A severe repulsion between the phenyl rings of the
cyclobutadiene ligand and the oxazoline connected i-Pr group results in a preferred conformation
displaying effective planar chirality. Therefore, the cyclopalladation proceeds with high
diastereoselectivity. In contrast and surprisingly, if R is a t-Bu group, the opposite
Asymmetric Aza-Claisen Rearrangement & PPFOPCl 61
diastereoselectivity was observed in palladacycle 159. This effect was explained with the steric
repulsion between the attacking Pd and t-Bu group, which is predominant over the repulsion
between the cyclobutadiene substituent and the t-Bu group.24
Pd(OAc)2,AcOH
Co
Pd NO
i-PrX
2
Ph Ph
PhPh
Co
N
O
R
Ph Ph
PhPh
Co
PdN
O
t-BuOAc
2
PhPh
Ph Ph
R = i-Pr
Pd(OAc)2,AcOH
R = t-Bu
150 (X = OAc)
Co
NO
Ph Ph
PhPh
HMe
[Pd]
Co
N
O
Ph Ph
PhPh
MeMe
[Pd] Me
Me
vs. vs.
H
H
Co
ON
Ph Ph
Ph
MeMe
[Pd]
H
Co
ON
Ph Ph
Ph
MeMe
[Pd]
H
Me
159
156
Scheme 4.8. Diastereoselective cyclopalladation of a cobalt sandwich complex derived oxazoline.
The first diastereoselective syntheses of planar chiral metallocene bispalladacycles was reported by
Kang et al. in 2002. A variety of optically active bispalladacycles were prepared via
diastereoselective bis-ortho-lithiation followed by iodination and cyclopalladation by oxidative
addition (Scheme 4.9).25
62 Chapter 4
NMe2
NMe2
Fe
Et
Et
NMe2
NMe2
Fe
Et
Et
II
NPd
Et N
I
NPd
Et
IFe
N
NO
NO
FeN
O
NO
Fe II
NPd
O YR
I
NPd
O
IFe
YR
YR = SMe, OMe or Oi-Pr
1. n-BuLi, RT2. I2, −78 oC to RT
1. MeI, acetone, 0 oC2. MeNH(CH2)2NMe2,
CH3CN, 50 oC3. Pd2(dba)3, PhH, RT
1. sec-BuLi, −78 oC2. I(CH2)2I, −78 oC to RT
160 161162
163 164
165
Scheme 4.9. Diastereoselective syntheses of planar chiral metallocene bispalladacycles.
Richards and co-workers26 recently reported the formation of planar chiral phosphapalladacycles
167 via a highly enantioselective transcyclopalladation in high yields (Scheme 4.10). The complex
150 (X = OAc) (see Scheme 4.8) was used as the palladium source. The driving force of this
reaction is the formation of a more stable palladacycle with a more favorable P-Pd bond instead of
8b E n-Pr 92 92 16b Z i-Bu 58 90 a 150(X = OTFA), 20 mol% H.B., 30 h. b 150(X = Cl), 60 h.
In 2007, Richards and Nomura observed that the enantioselectivity of the rearrangement catalyzed
by 150 (X = Cl) was still useful over a temperature range of 50 to 80 oC with acetonitrile as the
solvent, at least for certain substrates.28 The optimum yield was obtained at 70 oC with a catalyst
loading of only 0.25 mol% with and a reaction time of 48 h. These conditions were successfully
applied to few (E)-configured trichloroacetimidates to give the product amides in moderate to good
yields and good to high enantioselectivities (84-94% ee) (Table 4.6, Entries 1-5). However, the
barrier of low yields and low enantioselectivities for (Z)-configured (Entry 7) or 3-aryl (Entry 6)
substituted imidates still remained.
68 Chapter 4
Table 4.6. Enantioselective aza-Claisen rearrangement of allylic trichloroacetimidates by Richards
et al in 2007:
ON
i -PrPdX
2
Co PhPh
Ph Ph150 (X = Cl)
OHN
CCl3
R
OHN
CCl3
R*
150 (X = Cl),MeCN, 70 oC
70 71
# R E/Z 150 (X = Cl)
[mol%]
Time
[h]
Yield
[%]
ee
[%]
1 Me E 0.25 48 82 89
2 CH2Ph E 0.25 48 68 90
3 n-Pr E 0.25 48 79 92
4a CH2CH=CH2 E 0.75 72 68 84
5 CH2OTBDMS E 0.25 48 72 94
6b Ph E 1.0 96 31 0
7 n-Pr Z 0.25 72 21 67 a Additional 150 (X = Cl) (0.5 mol%) added after 48 h and the reaction maintained for a further 24 h. b 0.5 mol% 150 (X = Cl), plus additional 0.5 mol% after 48 h and the reaction maintained for a
further 48 h.
Peters and coworkers reported the synthesis of the first ferrocenyl imidazoline palladacycles
(Scheme 4.13).29 N-Alkyl substituted pentamethylferrocene imidazolines 176 could not be
diastereoselectively cyclopalladated directly because of either low diastereoselectivities (with
Na2PdCl4, MeOH) or oxidative decomposition (Pd(OAc)2, AcOH). Therefore the palladacycles 177
were obtained via ortho-lithiation, iodination and oxidative addition of Pd2(dba)3. In contrast, the
N-alkyl substituted pentaphenylferrocene imidazoline palladacycles 179 could not be obtained via a
lithiation approach but via direct cyclopalladation with high diastereoselectivity (16:1). Later these
results were extended to N-sulfonyl ferrocene imidazolines 178 enabling also the direct
cyclopalladation of pentamethylferrocenes.30
Asymmetric Aza-Claisen Rearrangement & PPFOPCl 69
FeN
NPh
I
FeN
NPh
Pd I
2
Pd2(dba)3benzene
FePh PhPhPh
Ph
N
N
R2
R1
R1Na2PdCl4, NaOAcMeOH, Benzene
FePh PhPhPh
Ph
N
N
R2
R1
R1Pd Cl
2
176 177
178 179 Scheme 4.13. Diastereoselective synthesis of ferrocene imidazoline palladacycles. In an effort to overcome the previous limitations for the synthetically useful trifluoroacetimidate
substrates 174 (i.e. catalyst loadings ≥ 10 mol%, difficult access to catalysts and limited structural
variation of the catalyst), Peters et al.29,30 designed a new palladacycle system FIP based on
ferrocene imidazoline as C,N-ligand for Pd(II) (Figure 4.1). The design of the catalyst allows the
independent variation of five different modules (Figure 4.1). The Cp-spectator ligand (the Cp ring
at the bottom, dark red can, e.g., be Cp (R4 = H), Cp* (R4 = Me) or CpФ (R4 = Ph) allowing for a
steric and electronic tuning. With the electron withdrawing effect of 5 Ph groups in CpФ the
electron density on the Pd(II)-centre decreases and the catalyst becomes more active due to an
enhanced Lewis acidity. Additionally, the enhanced bulk led to an improvement of the
enantioselectivity. The iron atom of the ferrocene core (red) can either be Fe(II) or the less electron
rich Fe(III). A ferrocenium Fe(III) species formed during the catalyst activation via oxidation with
a silver salt, is probably one major reason for the enhanced catalytic activity as compared to the
COP catalyst. The influence of the residues R1 in the imidazoline backbone (green) is not as
significant as the product yields obtained using different imidazoline derivatives for the
rearrangement vary only slightly, while the enantioselectivity remains almost unchanged for
different imidazoline substituents R1. Owing to its better accessibility the imidazoline backbone
Scheme 4.14. Synthesis of bispalladacycle 186, the best catalyst for the rearrangement of (Z)-
configured imidates 187.
4.2 Results and Discussion.
4.2.1 Synthesis of Oxazoline Palladacycles.
2-Pentaphenylferrocenyl oxazolines 11 (R1 = i-Pr, R2 = H) and 191 (R1 = R2 = Ph) were prepared
in 86% and 66% yield, respectively, in a simple and scalable two-step procedure via formation of
the secondary amide 189, 190 (Scheme 4.15) from pentaphenyl ferrocene carboxylic acid 10 and
(S)-valinol 192 or (1R,2S)-1,2-diphenylethanolamine 193, followed by tosylation of the free OH-
group to induce ring formation (Scheme 4.15).
Fe
PhPh
Ph
Ph Ph Fe
PhPh
Ph
Ph PhNH Fe
PhPh
Ph
Ph Ph
NOHO
O O
HO
R1
R2
a, b c
10 189/190 11/191
H2N OH
H2N OH
192
193
R1
R2
Asymmetric Aza-Claisen Rearrangement & PPFOPCl 75
Scheme 4.15. Oxazoline formation. a) (COCl)2, DCM, cat. DMF, b) (S)-valinol, NEt3, DCM, 0 °C to RT, 91% (189) / (1R,2S)-2-amino-1,2-diphenylethanol, DCE, pyridine, 80 °C, 83% (190); c) TsCl, NEt3, cat. DMAP, DCM, 91% (11) / 79% (191).
While formation of the amide of valinol (192, R1 = i-Pr, R2 = H) proceeded between 0 °C and RT,
preparation of the corresponding amide of 1,2-diphenyl-ethanolamine (193, R1 = R2 = Ph) required
heating to 80 °C. Treatment of those amides with p-tosylchloride then led to smooth ring closure to
the diastereomerically pure oxazolines, even though in the case of 191, a benzylic tosylate is
formed as intermediate which, however, fortunately does not epimerise.
Upon heating oxazolines 11 and 191 with palladium(II) acetate in acetic acid, palladacycles 194
and 195 precipitated in diastereomerically pure form and could be isolated by filtration, while by-
products and possibly the other diastereomer stayed in solution (see Scheme 4.16). Further
purification was carried out by preparative crystallisation allowing pentane to diffuse into a
solution of the crude complex in DCE, a method which was found to be superior to recrystallisation
from AcOH or cyclohexane as well as column chromatography and which still allows a preparation
on a multi-gram scale, delivering 194 and 195 in 93% and 72% yield, respectively.
Fe
PhPh
Ph
Ph PhO
NR1
R2
Fe
PhPh
Ph
Ph Ph
Pd OAcO
NR1
R2
2Pd(OAc)2,HOAc,95 °C
93/72%
11/191 194/195 Scheme 4.16. Cyclopalladation with palladium(II) acetate in acetic acid. 194: 93%, 195: 72%.
Other conditions for cyclopalladation than Pd(OAc)2 in acetic acid, notably Na2PdCl4 in
combination with NaOAc in methanol/benzene or DCM, as well as Pd(OAc)2 in DCM or benzene
failed to give any cyclopalladated product, though a change in the 1H-NMR-spectrum was observed
within minutes after mixing, being evidence for a coordination of Pd(II) to the oxazoline. Instead of
cyclopalladation, a complete decomposition was found to take place within less than 30 min. This
decomposition also occurred when the mixture of palladium(II) acetate in acetic acid with
oxazoline 11, leading to a dark red solution, was diluted with water and extracted with DCM
without prior heating. These results suggest that while Pd(II) in principle destroys the ligand, acetic
acid prevents this decomposition and allows at elevated temperature to form a carbon-Pd-σ-bond in
the initially formed Pd-oxazoline complex.
Conversion of the acetate bridged palladacycles 194 and 195 to the chloride bridged complexes 4
and 196 took place in 95% and 93% yield, respectively, by simply stirring a suspension of 194 or
76 Chapter 4
195 and LiCl in methanol/benzene. While the acetate bridged dimers exist as a single diastereomer
relative to the Pd-acetate square plane (see Figure 6.2), the chloride bridged complexes were found
as a ca. 2:1 mixture of diastereomers (geometrical isomers around the Pd-Cl-square plane).
Fe
PhPh
Ph
Ph Ph
Pd OAcO
NR1
R2
2
Fe
PhPh
Ph
Ph Ph
Pd ClO
NR1
R2
2
LiCl, PhH,MeOH, RT
95/93%
4/196194/195 Scheme 4.17. Exchange of the bridging ligand acetate with chloride. 4: 95%, 196: 93%.
4.2.2 Determination of the Absolute Configuration.
The absolute configuration of palladacycle 194 was determined by X-ray crystal structure analysis
(see Figure 4.2). In contrast to 194 (X = OAc), the iso-propyl group is pointing towards the
sandwich core.
Fig 4.2. Crystal structure of 194. The unit cell consists of 4 asymmetric units, with each asymmetric
unit consisting of two molecules which differ in the sense of orientation of the CpΦ phenyl groups (only one rotamer is shown for clarity); one molecule of solvent (DCE) is also incorporated per asymmetric unit. Concerning the distance between the two Pd-atoms, a metal-metal bond seems likely. CCDC-number: 703503.
The chloride bridged complexes, 4 and 196, were readily distained by treatment of the acetate
bridged palladacycles with LiCl in methanol/benzene. While the acetate bridged dimers exists as
single geometrical isomer around the Pd-acetate square plane (Figure 4.3, left side), the chloride
Asymmetric Aza-Claisen Rearrangement & PPFOPCl 77
bridged complexes were found to be a ca. 2:1 mixture of geometrical isomers (Figure 4.3, right
side).
PdN Cl
ClPd
N
PdN Cl
ClPd
Cl bridged cis-isomer
Cl bridged tr ans-isomer
N
PdN O
O
PdO
ON
acetate bridged dimer Fig 4.3.
The absolute configuration of palladacycle 195 was indirectly assigned through the known absolute
configuration of the catalysis outcome of the aza-Claisen rearrangement of imidate and confirmed
by 1H-NOESY experiments.
Fe
PhPh
Ph Ph
Pd
2
NO
OAcPhH
HPh
Fig 4.4. 1H-NOESY for Palladacycle 195.
4.2.3 Catalysis with Known Substrates.
4.2.3.1 Substrate Synthesis. All imidates bearing no base-sensitive functional groups were prepared in THF in high yields by
reaction of imidochloride 6 with the corresponding allylic alcohol 5 which was deprotonated with
either NaH or LHMDS (see Scheme 4.21b). The latter base, available as 1 M solution in THF, gave
identical results. Its advantage compared to solid NaH is the generally more convenient handling of
a solution under inert atmosphere. In addition, it reacts almost immediately with the allylic alcohol,
while NaH reacts significantly slower due to poor solubility.
78 Chapter 4
The formation of imidoyl chlorides 6 was achieved by using a primary amine, triphenylphosphine
and carbon tetrachloride in the presence of trifluoroacetic acid and triethylamine. This is a multiple
step reaction carried out in one-pot.31 All of the reagents are mixed and heated to reflux to furnish
the required imidoyl chloride 6 in good yield. During the reaction an amide is formed and reacts in
situ with excess triphenylphosphine and carbon tetrachloride to generate the corresponding imidoyl
chloride.
R NH2
PPh3, CCl4, NEt3,TFA, Δ
N Cl
CF3
R
6 Scheme 4.18. Methods for the formation of imidoyl chlorides 6.
PPh3
CCl4Ph3P Cl CCl3
CF3CO2H
OPh3P
O
CF3Cl
−CHCl3
R NH2
NH
O
CF3R
Ph3P Cl CCl3
NR
O
CF3PPh3 Cl
N Cl
CF3R
−Ph3PO
−Ph3PO−CHCl36
Scheme 4.20. Mechanism of the formation of imidoyl chlorides.
Allylic alcohols 5 without functional groups in the residue R are either commercially available
(trans- or cis-2-hexenol (E/Z)-197, trans-cinnamol (E)-199) or were prepared from the
corresponding α,β-unsaturated esters 198 by reduction with DIBAL (see Scheme 4.21, a). The
standard method to obtain these esters is the trans-selective Horner-Wadsworth-Emmons32 (HWE)
reaction (for (E)-configuration) or the Still-Gennari33 modification of this method (for (Z)-
configuration). Compounds bearing Ph(CH2)2, i-Pr, c-hex, or t-Bu as residue were prepared
according to this way following literature procedures (see experimental part in Chapter 7).
Asymmetric Aza-Claisen Rearrangement & PPFOPCl 79
R O
PO
OMe
O
OMeOMe
BuLi, THFR O
OMe
2.7 equiv. DIBALTHF, −78 °C to RT
R OH
PO
OMe
O
OCH2CF3
OCH2CF3
KHMDS,18-C-6 (5 equiv.)
R OMeO
2.7 equiv. DIBALTHF, −78 °C to RT
R
OH
R OH
R O CF3
N
OMe
NaH or LHMDS, then 6
a)
b)
~60-99%
(Z)-198 (E )-198
(Z)-199 (E)-199
5 7
Scheme 4.21. a) Synthetic routes to (E)- and (Z)-configured allylic alcohols 199 via Horner-Emmons (right) and Still-Gennari (left) reaction; b) formation of N-PMP-trifluoroacetimidates 7. 18-C-6: 1,4,7,10,13,16-Hexaoxacyclooctadecane.
Selectivity of the HWE reaction is usually fair to poor (in some cases, a 1:1 mixture was obtained)
requiring a separation of isomers by preparative column chromatography; highest (E)-selectivities
are generally obtained when working in 1,2-dimethoxyethane at RT, while in THF at –78 °C
mainly the (Z)-isomer is formed. Also the Still-Gennari modification only provides good
selectivities if the aldehyde moiety is α,β-unsaturated or aromatic. It is, however, of highest
importance to use diastereomerically pure allylic alcohols since the minor diastereomer is almost
exclusively converted to the minor enantiomer. Only 0.5% of the minor diastereomer will thus
lower the highest possible ee by 1.0% in the case of full conversion.
An alternative method to prepare α,β-unsaturated esters 198 is the Cu(I)-mediated 1,4-addition of
alkyl-lithium or Grignard reagents to methyl- or ethylpropiolate 200 (Scheme 4.22). In this
reaction, it is often possible to obtain almost absolute diastereoselectivity (minor isomer below
detection limit in NMR) or at least to produce only few percent of the undesired isomer hence
facilitating purification.34 The reaction is also possible, though limited in utility, in the introduction
of an iso-propyl group which proceeded with complete diastereoselectivity, but with a
comparatively low yield of only 26%, since a competitive reduction of Cu(I) by iso-propyl
magnesium halide takes place.
80 Chapter 4
R O
OMe 2.7 equiv. DIBALTHF, −78 °C to RT
R OHH CO2Me
CuI, RLi, THF, −40 °C to −78 °CorCuI, RMgHal, TMEDA, THF,−40 °C to −78 °C
4.2.4.1 Primary Investigation of the Aza-Claisen Rearrangement Using a Model Substrate.
Utilizing the optimized conditions for activating imidazoline catalyst FIP-Cl 77, that is 3.75 equiv
of AgTFA per precatalyst dimer,30 oxazoline PPFOP-Cl 4 (0.5 mol%) rearranged the 3-
monosubstituted model substrate 201 with only 44% yield and 90% ee (Table 4.10, entry 1) at 40
°C for 24 h (83% conversion after 72 h), whereas FIP-Cl 77 gave practically full conversion and
95% ee with 1/10 of the catalyst amount. As the nature of the Ag salt has a large impact on the
reaction rate and selectivity, further Ag salts were examined. It was found that AgNO3 generates a
highly active and selective catalyst (Table 4.10, entry 2), whereas AgOTs allows high activity
(Table 4.10, entry 3) but considerably lower enantioselectivity. Further studies were thus carried
out with AgNO3.
By using 2 equiv of AgNO3 per Cl-bridged dimer PPFOP-Cl 4, full conversion and 96% ee were
obtained with 0.5 mol% precatalyst, whereas 0.2 mol% led to only 45% conversion (Table 4.10,
entries 4, 5). Part of this catalytic activity might be explained by oxidation of 4 to the
corresponding active ferrocenium system on the surface of precipitated AgCl.
However, nonactivated 194 also has some, yet low, catalytic activity (6% conversion with 1 mol%
catalyst at 40 °C for 24 h; Table 4.10, entry 6). Complete oxidation to the corresponding
ferrocenium species is accomplished with 4 equiv of AgNO3 per Cl-bridged dimer resulting in the
best reactivity.
In addition to i-Pr-substituted complex 4, the 4,5-diphenyl-substituted oxazoline palladacycle 196
was examined. While there is practically no difference in enantioselectivity, the catalytic activity
slightly decreases (Table 4.10, entries 7–10). Whereas 0.1 mol% 4 completely converted the test
substrate within 24 h at RT (Table 4.10, entry 10), the same amount of 196 at 40 °C resulted in
only 70% yield due to incomplete conversion (Table 4.10, entry 9). Since complex 196 was
prepared in lower yields and from a more expensive amino alcohol than 4, all further investigations
were carried out with 4.
Asymmetric Aza-Claisen Rearrangement & PPFOPCl 81
A screening of the catalyst amount was performed for both the E- and the Z-configured test
substrates (E)-/(Z)-201. As for the imidazoline palladacycle FIP-Cl 77, the E-configured substrate
not only reacts considerably faster than its Z-configured counterpart, but it also provides
significantly higher ee values. Although (E)-201 reacts completely within 1 d at 40 °C using only
0.05 mol% precatalyst (Table 4.10, entry 11), full conversion for (Z)-201 requires 2 mol% (Table
4.10, entry 12). Ferrocenyl bisimidazoline bispalladacycle complexes thus remain the catalysts of
choice for Z-configured substrates.40
The enantioselectivity obtained for (E)-201 did not significantly change within the investigated
temperature range. Catalyst loadings below 0.05 mol% were studied as well, but the results were
not reliable, which is most probably explained by a partial catalyst deactivation by trace impurities
of the substrate. A certain threshold of catalyst is thus necessary on laboratory scale. The same was
found with FIP-Cl 77, in which catalyst loadings below 0.05 mol% had resulted in low
conversions even at prolonged reaction times.
82 Chapter 4
Table 4.10. Optimization of the rearrangement of model substrates E-/Z-201 catalyzed by 4, 196:
Pr
NPMP
CF3
O
Pr
NPMP
CF3
O
(Y mol%) Cat*, AgX,(4Y mol%) P.S., DCM
*
201 202
Fe
PhPh
Ph
Ph Ph
Pd ClO
Ni-Pr 2
Fe
PhPh
Ph
Ph Ph
Pd ClO
NPh
Ph
2
4196
# E/Z
201
Cat* Cat*
loading
[mol%]
AgX
/ Y
Temp. /
Time
[°C]/ [h]
Yield
[%]a
ee
[%]b
[config.]
1 E 4 0.5 AgTFA / 3.75 40 / 24 44 90 (R)
2 E 4 0.5 AgNO3 / 3.75 40 / 24 >99 97 (R)
3 E 4 0.5 AgOTs / 3.75 40 / 24 98 77 (R)
4 E 4 0.5 AgNO3 / 1.0 40 / 24 99 96 (R)
5 E 4 0.2 AgNO3 / 0.4 40 / 24 45 N.D.
6c E 4 1.0 --- 40 / 24 6 N.D.
7 E 4 0.2 AgNO3 / 3.75 RT / 24 >99 97 (R)
8 E 196 0.2 AgNO3 / 3.75 RT / 24 >99 97 (R)
9 E 196 0.1 AgNO3 / 3.75 40 / 24 70 N.D.
10 E 4 0.1 AgNO3 / 3.75 RT / 24 99 97 (R)
11 E 4 0.05 AgNO3 / 3.75 40 / 24 99 97 (R)
12 Z 4 2.0 AgNO3 / 3.75 40 / 24 97 88 (S)
13 Z 4 1.0 AgNO3 / 3.75 40 / 24 87 88 (S) a determined by 19F-NMR spectroscopy. b determined by HPLC after hydrolysis to the amine.
Asymmetric Aza-Claisen Rearrangement & PPFOPCl 83
4.2.4.2 Aza-Claisen Rearrangement of Previous Substrates Catalyzed by 4. Oxazoline 4 activated by AgNO3 is in general more reactive than imidazoline FIP-Cl 77 (Table
4.11, entries 2–15). For instance, with the (E)-3-Ph-substituted substrate 26h, a temperature of 40
°C was necessary using FIP-Cl 77, whereas 4 is effective already at RT (Table 4.9, entry 2). Also,
the 3,3-disubstituted substrate 210 (R’= (CH2)3OTIPS, R=CH2OBn), which required 4 mol% FIP-
Cl 77 and a reaction time of 3.5 d to give a yield of 51%, reacted within 2 d in a nearly quantitative
yield (or within 3 d with 2 mol% catalyst; Table 4.11, entries 12, 13).
Like with FIP-Cl 77, N-substituted quaternary stereocenters can be generated with almost perfect
stereocontrol (Table 4.11, entries 8–13).
Due to the enhanced catalytic activity, the substrates that could not be processed with FIP-Cl 77 or
any other reported chiral catalyst were investigated: whereas allylic trifluoroacetimdates bearing a
tBu or a Bn moiety as R1 still did not react at useful rates (Table 4.11, entries 6, 7) although mono-
α-branched aliphatic residues R1 such as i-Pr or c-Hex are well tolerated (Table 4.11, entries 4, 5),
this catalyst is for the first time able to rearrange substrates bearing branched aliphatic N-
18 213 (CH2)2Ph H H CCl3 225 0.5 24 50 85 97[c] a ee determined by chiral stationary phase HPLC after hydrolysis to the amine. b ee determined by chiral stationary phase HPLC. c ee determined by chiral stationary phase HPLC after cleavage of
TIPS with TBAF.
86 Chapter 4
4.2.5 Challenging New Substrates.
4.2.5.1 Synthesis of Substrates. Trifluoroacetimidates 234 with 3-aryl prop-2-enyl residues were prepared starting from the
corresponding cinnamic acid/aldehyde derivatives 232, which are commercially available in
diastereomerically pure form. 4-Trifluoromethyl (232a), 4-methyl (232c) and 4-chloro- (232b)
cinnamic acid were converted to the corresponding methyl ester with MeI/K2CO3 in DMF and then
reduced with DIBAL. 4-Methoxy cinnamic aldehyde (236) was reduced with NaBH4 in ethanol.
Cinnamoyl alcohol 232d itself is commercially available.
Synthesis and purification of the corresponding imidates 234 proceeded smoothly except for
imidate 234d bearing the electron rich 4-methoxy-phenyl substituent: this compound rearranged
partially during synthesis and could not be isolated in absolutely pure form via column
chromatography, even if solvents were removed at RT. However, trituration with pentane gave
sufficiently pure material, which was then stored at –18 °C.
Trichloroacetimidates 243 and 213 were prepared via NaH-catalysed addition of the corresponding
alcohols onto trichloroacetonitrile,37 O-Hex-2-enyl thiocarbamate 245 was obtained via
condensation of hex-2-enol with N,N-dimethyl thiocarbamoyl chloride.38
HN
CCl3
O
Ph
HN
CCl3
O S
NMe2
O
243 213 245 Fig 4.6. Other substrates.
4.2.5.2 Catalysis with New Substrates.
Substrates were investigated which could previously not be rearranged in an asymmetric fashion
because they already react in the absence of a transition metal simply via a thermal rearrangement
to a considerable degree:
Allylic trifluoroacetimidates tend to undergo a thermal rearrangement at ambient temperature if the
bond O-C(1) is weak, i.e. if a carbocation 246 would be comparatively stabilised.
NPMP
CF3
ONPMP
CF3
O NPMP
CF3
OC1
202 215246
Scheme 4.26. If the bond C1-O is weakened and the transition state structure has some carbocation type character, a fast thermal rearrangement results.
88 Chapter 4
Though allylic imidates can always result in an allylic carbocation, the resonance stabilisation
through a further aromatic substituent considerably favours the stabilisation of this carbocation. As
a consequence, imidate 234 reacted with COP-X 150 in 72% yield and only 81% ee (5 mol%) due
to a competing thermal rearrangement at 40 °C (and decomposition via the carbocation),24 while
FIP-X 77 was able to rise these values to 99% yield and 88% ee, which is however still far below
the ee-values obtained for substrates bearing aliphatic residues. Better results would not be
achieved without heavily raised catalyst loadings since a temperature of 40 °C had been necessary
to obtain reasonable conversions.
PPFOP-Cl 4, on the other hand, could convert 215 at RT and was thus able to produce an ee-value
of 98% (see Table 4.12.a), entry 5). To extend the use of aza-Claisen rearrangements, we prepared
a series of aryl-substituted imidates 234 with different substituents, ranging from the rather electron
poor 4-trifluoromethyl-phenyl to the electron rich 4-methoxy-phenyl as well as a diene substrate
bearing two conjugated double bonds.
Substrates bearing a weakly electron donating or even withdrawing substituent have an intrinsic
thermal rearrangement rate constant, low enough to allow for a successful asymmetrically
catalysed reaction at RT, while 234d, bearing a 4-methoxy-phenyl group, reacts simply too “fast”,
even in the fridge (Table 4.12, entry 8).
The same problem occurs with 240, bearing two conjugated double bonds, though this compound
reacts faster in the metal-catalysed rearrangement due to its α-unbranched residue, allowing to
20 20a) A. M. Stevens, C. J. Richards, Organometallics 1999, 18, 1346. b) L. E. Overman, C.
E. Oven, M. M. Pavan, C. J. Richards, Org. Lett. 2003, 5, 1809.
21 V. I. Sokolov, L. L. Troitskaya, O. A. Reutov, J. Organomet. Chem. 1977, 133, C28.
22 C. Lόpez, R. Bosque, X. Solans, M. Font-Bardia, Tetrahedron: Asymmetry 1996, 7, 2527.
96 Chapter 4
23 G. Jones, C. J. Richards, Organometallics 2001, 20, 1251.
24 R. S. Prasad, C. E. Anderson, C. J. Richards, L. E. Overman, Organometallics 2005, 24,
77.
25 J. Kang, K. H. Yew, T. H. Kim, D. H. Choi, Tetrahedron Lett. 2002, 43, 9509.
26 F. X. Roca, M. Motevalli, C. J. Richards, J. Am. Chem. Soc. 2005, 127, 2388.
27 J. Kang, T. H. Kim, K. H. Yew, W. K. Lee, Tetrahedron: Asymmetry 2003, 14, 415.
28 H. Nomura, C. J. Richards, Chem. Eur. J. 2007, 13, 10216.
29 R. Peters, Z.-q. Xin, D. F. Fischer, W. B. Schweizer, Organometallics 2006, 25, 2917.
30 M. E. Weiss, D. F. Fischer, Z.-q. Xin, S. Jautze, W. B. Schweizer, R. Peters, Angew. Chem.
Int. Ed. 2006, 45, 5694.
31 K. Tamura, H. Mizukami, K. Maeda, H. Watanabe, K. Uneyama, J. Org. Chem. 1993, 58,
32.
32 S. K. Thompson, C. H. Heathcock, J. Org. Chem. 1990, 55, 3386.
33 W. C. Still, C. Gennari, Tetrahedron Lett. 1983, 24, 4405.
34 This reaction is in principal known, see for an early example a) D. Michelot, G.
Linstrumelle, Tetrahedron Lett. 1976, 17, 275. For an investigation about the scope of
carbon-nucleophiles (methylbutynoate-addition), see also b) R. J. Anderson, V. L. Corbin,
G. Cotterrell, G. R. Cox, C. A. Henrick, F. Schaub, J. B. Siddall, J. Am. Chem. Soc. 1975,
97, 1197.
35 Prepared in analogy to: K. Tamura, H. Mizukami, K. Maeda, H. Watanabe, K. Uneyama, J.
Org. Chem. 1993, 58, 32.
36 Prepared from pivaloyl aldehyde via HWE and reduction with DIBAL, see: S. K.
Thompson, C. H. Heathcock, J. Org. Chem. 1990, 55, 3386.
37 L. E. Overman, J. Am. Chem. Soc. 1974, 96, 597.
38 L. E. Overman, S. W. Roberts, H. F. Sneddon, Org. Lett. 2008, 10, 1485.
39 P. Watson, L. E. Overman, R. G. Bergman, J. Am. Chem. Soc. 2007, 129, 5031.
40 S. Jautze, P. Seiler, R. Peters, Angew. Chem. Int. Ed. 2007, 46, 1260.
41 M. E. Güunay, C. J. Richards, Organometallics 2009, 28, 5833.
42 D. F. Fischer, Z.-q. Xin, R. Peters, Angew. Chem. Int. Ed. 2007, 46, 7704.
43 Z.-q. Xin, D. F. Fischer, R. Peters, Synlett 2008, 1495.
Chapter 5
Intramolecular Hydroamination of Unactivated Olefins using a Highly Strained Planar Chiral Platinacycle.
5.1 Introduction. This chapter describes Pt(II) complexes 12 which catalyze the intramolecular oxidative amination
of unactivated olefins1 with alkyl amines, amides, and sulphonamides.
Pt(II) complexes 12 were prepared in two steps starting from a ferrocene bisimidazoline 185 by
diastereoselective cycloplatination.2
This research project was carried out by the author in the Peters group (University of Stuttgart,
Stuttgart, Germany).
5.1.1 General Introduction and Motivation. Functionalized nitrogen heterocycles are the components of a wide range of naturally occurring and
biologically active molecules. This, coupled with the limitations associated with traditional
methods for C-N bond formation, has stimulated considerable interest in the development of new
and more efficient methods for the synthesis of nitrogen heterocycles. The intramolecular addition
of the N-H bond of an amine across an unactivated C=C bond (hydroamination) represents an atom
economical and potentially expedient approach to the synthesis of nitrogen heterocycles. However,
despite considerable effort in this area, the intramolecular hydroamination of unactivated C=C
bonds with alkylamines remains problematic. For example, rare earth,3 alkali,4 alkaline earth,5 and
group 46 metal complexes catalyze the intramolecular hydroamination of unactivated C=C bonds
with alkyl amines, but the synthetic utility of these protocols is compromised by the poor functional
group compatibility and extreme moisture-sensitivity of the catalysts. Alkyl 4-pentenyl amines
undergo intramolecular hydroamination in the presence of Brønsted acids, but forcing conditions
are required.7 Conversely, late transition metal-catalyzed systems for the intramolecular
hydroamination of unactivated C=C bonds with alkylamines have typically been restricted to vinyl
arenes and conjugated dienes.
98 Chapter 5
In response to the limitations associated with the hydroamination of unactivated C=C bonds, an
effective Pt-catalyzed protocol for the intramolecular hydroamination of amino alkenes has been
applied.
5.1.2 Literature Overview. Nitrogen-containing saturated heterocyclic systems are important core structures in organic
chemistry because of their presence in many natural products. For this reason, simple procedures
for the formation of pyrrolidines and piperidines are highly desirable. One of the most appealing
approaches to these heterocycles is hydroamination, in which the nitrogen carbon bond is formed
by the addition of an amine to an olefin.
The development of efficient methodologies for the synthesis of nitrogen heterocycles is of high
importance in the context of an economical and environmentally benign preparation of
sophisticated targets with biological activities. An intermolecular catalytic asymmetric
hydroamination might face this challenge by efficient cyclisation of functionalised substrates. Until
now, various amino–alkene, amino–diene and amino–allene derivatives were successfully
enantioselectively transformed into the corresponding heterocycles.
Different researchers have worked in this field and the most important recent examples will be
discussed here.
R. A. Widenhoefer and coworker8 have reported effective Pt(II)-catalyzed protocols for the
addition of carbon,9 nitrogen,10 and oxygen11 nucleophiles to unactivated olefins.12 The platinum-
catalyzed hydroamination of γ-amino olefins tolerated substitution at the allylic and internal
olefinic carbon atoms and tolerated both primary and secondary N-bound alkyl groups. Heating a
concentrated dioxane solution of γ-amino olefin 287 (0.5 M) with a catalytic mixture of
[PtCl2(H2C=CH2)]2 (2.5 mol %) and PPh3 (5 mol %) at 120 °C for 16 h led to the isolation of
pyrrolidine 288 in 75% yield (scheme 5.1).
NHBnBnN
PhPh
Ph
Ph
[PtCl2(H2C=CH2)]2 (2.5 mol%)PPh3 (5 mol%)
dioxane, 120 °C, 16h75%287 288
Scheme 5.1. Hydroamination of amino olefins catalyzed by a mixture of Pt(II) and Ph3P.
It was reported that gem-dialkyl substitution at the β-position of the γ-amino olefin facilitated
hydroamination, but was not essential. Platinum-catalyzed hydroamination tolerated a range of
functionality including bromo, nitro, and cyano groups, carboxylic esters, acetals, and benzyl and
silyl ethers.
Intramolecular Hydroamination of Unactivated Olefins 99
The reaction mechanism proceeds via formation of a platinum amine complex and subsequent C-N
bond formation and presumably occurs via intramolecular ligand exchange followed by outer-
sphere attack.
In 2008, R. A. Widenhoefer and coworker13 have reported that mixtures of PtCl2 and sterically
hindered o-biphenyl phosphines catalyze the intramolecular hydroamination of amino alkenes at
60°–80 °C displaying improved scope and generality relative to the catalyst generated from Zeise’s
dimer and PPh3 protocols,8 as a supporting ligand for platinum-catalyzed hydroamination (scheme
5.2).
NHBn BnN(5 mol%)PtCl2,
(5 mol%) 291,
diglyme, 60 °C, 10h86%
P
Me2N
t -But-Bu
289 290 291
Scheme 5.2. Hydroamination of amino olefins catalyzed by a mixture of PtCl2 and ligand 291.
Subsequently, J. Uenishi and coworkers14 illustrated the Pd(II)-catalyzed intramolecular cyclization
of N-protected δ-amino allylic alcohols 292 and the stereospecific synthesis of 2-substituted and
2,6- disubstituted piperidines 294 (scheme 5.3). The reaction gives a syn SN2′ product majorly
through syn-coordination of the Pd(II)-catalyst to the allylic alcohol followed by syn-azapalladation
and syn-elimination of PdCl(OH), leading to the product. Although the syn-azapalladation is found
to be more favored, the formation of a minor isomer suggests that the anti-azapalladation is also
possible and the reaction pathway depends upon the substrate and solvent. The advantages of this
method are: (i) No oxidant such as CuCl2 is required, because the Pd(II)-catalyst is regenerated
during the reaction. This is how it differs from other oxidative cyclizations to an alkene15 by
Wacker-type reactions. (ii) The reaction proceeds smoothly at 0 °C with excellent selectivities.
NHPG
OHPdCl2(CH3CN)2
(20 mo%)CH2Cl2 or THF
NPG
NH HCli. Pd(OH)2/C, MeOH
H2, 24hii. HCl gas, Et2O
PG = Cbz, Boc292 293 294
Scheme 5.3. Pd(II)-catalyzed cyclizations of nitrogen nucleophile to chiral allylic alcohols. The development of chiral catalysts for the asymmetric hydroamination of alkenes (AHA) has
remained challenging.
100 Chapter 5
The first chiral rare earth metal based hydroamination catalysts were reported by Marks and co-
workers in 1992.16a-b Although enantioselectivities of up to 74% ee were achieved, the application
of these C1-symmetric chiral ansa-lanthanocenes was limited due to a facile epimerization process
via reversible protolytic cleavage of the metal cyclopentadienyl bond under the reaction conditions
of catalytic hydroamination.16b-c
K. C. Hultzsch et al.17 had developed rare earth metal complexes with sterically demanding tris-
(aryl)silyl-substituted binaphtholate ligands which are efficient catalysts for the asymmetric
hydroamination/cyclization of aminoalkenes and the kinetic resolution of R-substituted
aminopentenes (scheme 5.4). Catalytic activities are comparable to those of lanthanocene catalyst
systems, while enantioselectivities of up to 95% ee were attained in the cyclization of achiral
aminopentenes. The hydroamination mechanism for the binaphtholate catalyst system is similar to
that proposed for lanthanocene catalysts, based on the rate dependencies on substrate and catalyst
concentrations and the observed activation parameters.
R4 NH2
R3
R2R1
n
SiAr3
OO
SiAr3
Ln = Sc, Y, La, Lu
∗HN
R1
R2
R3
R4
n
R1, R2, R3 = H, alkyl,arylR4 = H, Aryln = 1, 2
ee = up to 95%
Ln X
297
295 296
Scheme 5.4. Catalytic hydroamination/cyclization of aminoalkenes by using a binaphtholate
catalyst.
A new chiral tetradentate ligand has been prepared by Xiang et al.18 These organolanthanide
amides have displayed moderate to good catalytic activity for the asymmetric
hydroamination/cyclization of representative aminoalkenes, although enantioselectivities have
remained low (up to 24% ee) ( scheme 5.5).
Intramolecular Hydroamination of Unactivated Olefins 101
NH2Ln = Sm, Y, Yb
∗HN
ee = up to 24%
N
N
N
N
Lnthf
N(SiMe3)2
300
298 299
Scheme 5.5. Catalytic hydroamination/cyclization of aminoalkenes using organlanthanide amides. S. R. Chemler and coworkers19 reported that copper(II) promoted the diastereoselective synthesis
of disubstituted pyrrolidines via an intramolecular aminooxygenation of alkenes. He investigated
the aminooxygenation reaction of 4-pentenyl sulfonamide 305 using catalytic amounts of
copper(II) salts. The use of a bisoxazoline ligand [(R,R)-Ph-box 308] gave better conversion than
the 2,2′-dipyridyl ligand 307 under catalytic conditions using O2 (1 atm) (scheme 5.6).
R1
NHR2
NR1O N
R2
Cu(EH)2 (1.5 equiv)Cs2CO3, TEMPO (3 equiv.)xylenes, 130 °C, 24h
76-97%
R1 = i -Pr, CH2OTBDPS, Bu, 3-Butenyl dr = > 20: 1R2 = Ts, PMBS, NsEH = 2-ethylhexanoate
301 302
NO N
Cu(EH)2 (1.5 equiv)Cs2CO3, TEMPO (1.5 equiv.)xylenes, 130 °C, 24h
Scheme 5.10. Rhodium catalyzed intramolecular hydroamination of aminoalkenes. In 2009, M. Stradiotto et al.25 reported that [Ir(COD)Cl]2 is an effective precatalyst for the
hydroamination of unactivated alkenes with pendant secondary alkyl- or arylamines, at relatively
low loadings (typically 0.25-5 mol % Ir) and without the need for added ligands or cocatalysts
(scheme 5.11).
104 Chapter 5
NHRRN
R'R'
R'
R'
cat. [Ir(COD)Cl]2
1,4-dioxane
R = Bn, R' = Ph, yield up to 89%318 319
Scheme 5. 11. Intramolecular hydroamination of unactivated alkenes by secondary alkylamines
employing [Ir(COD)Cl]2 as a pre-catalyst.
Specifically, the development of hydroamination protocols using an inexpensive and
environmentally benign metal catalyst is greatly anticipated. To date, most of the investigations on
the intramolecular hydroamination of alkenes catalyzed by late transition metals have focused on
the use of amides or carbamates bearing electron-withdrawing N-substituents such as Ts, Cbz, Boc,
or Ac groups instead of free amines.26 M. Sawamura and coworkers27 introduced a Cu-Xantphos
system [Cu(O-t-Bu)-Xantphos, 10-15 mol %] that catalyzes the intramolecular hydroamination of
unactivated terminal alkenes bearing an unprotected aminoalkyl substituent in alcoholic solvents,
giving pyrrolidine and piperidine derivatives in excellent yields (scheme 5.12).
NHR1 N
R2
R2
R2
R2
cat. Cu(O-t-Bu)-Xantphos
alcoholic solventhigh yield
R1 = H, alkyl, COR R2 = alkyl, Ph,n = 1,2
n n
FGH2C
FG = OMe, F, CN, CO2Me
O
Me Me
PPh2 PPh2
Xantphos 324
R1
322 323
Scheme 5.12. Cu(I)-catalyzed hydroamination of unactivated alkenes bearing secondary amino or
amido groups. The intramolecular addition of the N-H bond of an amine across an unactivated C=C bond
(hydroamination) represents an atom economical and potentially expedient approach to the
synthesis of nitrogen heterocycles. However, despite considerable efforts in this area, the
intramolecular hydroamination of unactivated C=C bonds with alkylamines remains problematic. A
Pt(II)-catalyzed protocol for the intramolecular hydroamination of amino alkenes has been applied.
Intramolecular Hydroamination of Unactivated Olefins 105
5.2 Results and Discussion.
5.2.1 Synthesis of a Bisimidazoline Platinacycle 12.
A bisimidazoline platinacycle 12 was prepared according to R. Peters et al.2 with an overall 40%
yield in two steps. Bisimidazoline 185 was treated with Zeise’s salt giving a mixture of a monomer
and a Cl-bridged dimer. Treatment of the reaction mixture with Na(acac) completely converts both
the monomer and dimer to the same monomeric acac-complex, which provides the
diastereomerically pure monomer 325 after treatment with LiCl and HCl (scheme 5.13).
Fe
N
Pt
N
PhPh
O
Ts
N
N Ph
Ts Ph
Fe
N
N Ph
Ts Ph
K[(H2C=CH2)PtCl3],NaOAc, MeOH, benzene,RT, then Na(acac), RT
185 Pt-Bis-Imi-acac 325
N
N Ph
Ts Ph
O LiCl, HCl,MeOH, benzene
Fe
N
Pt
N
PhPh
Cl
Ts
N
N Ph
Ts Ph12
90%dr > 50 :1
Scheme 5.13. Formation of the strained complex 12 by diastereoselective cycloplatination.
5.2.2 Synthesis of Amino Olefin.
5.2.2.1 General Procedure for the Synthesis of 4-Mono-substituted Amino Olefins.
Mono-substituted amino olefins were prepared by applying a methodology which has been reported
by R. A. Widenhoefer et al,8 starting from commercially available diphenylacetonitrile in three
steps with moderate to very good yields as shown in (scheme 5.14).
Scheme 5.14. General scheme for the synthesis of monosubstituted amino olefins.
N-Benzyl-2,2-diphenylpent-4-en-1-amine 287, which is a model substrate for catalysis
experiments, was prepared with an overall yield of 58%. N-(3-Chlorobenzyl)-2,2-diphenylpent-4-
en-1-amine 327 and N-phenethyl-2,2-diphenylpent-4-en-1-amine 328 were prepared by Markus
Bischoff (research student) in overall yields of 37% and 19%, respectively.
N-(2,2-Diphenylpent-4-enyl)-4-methylbenzenesulfonamide 330 was prepared starting from 2,2-
diphenylpent-4-en-1-amine 326 with TsCl in the presence of Et3N in 71% yield. N-(2,2-
Diphenylpent-4-enyl)acetamide 329 was prepared starting from 2,2-diphenylpent-4-en-1-amine
326 with AcCl in the presence of pyridine in 98% yield (scheme 5.15).
NH2
Ph
Ph
Ph
Ph NH
TsTsCl, Et3N,DCM, RT
71%98%
Ph
Ph NH
CH3COCl, Py,DCM, 0 °C, RT
O
329 326 330 Scheme 5.15. Protection of amino olefin 326 with TsCl or AcCl.
5.2.2.2 4,5-Di-substituted Amino Olefins.
(Z)-N-Benzyl-2,2-diphenylhept-4-en-1-amine 333 was prepared according to the same method used
for the preparation of mono-substituted olefins8 with an overall 49% yield as shown below
(scheme 5.16).
Intramolecular Hydroamination of Unactivated Olefins 107
NH2
Ph
Ph
Ph
Ph NH
Ph
CNPh
Ph
i. PhCHO, MeOHii. NaBH4
i. LAH, Et2Oii. NaOH, H2OCNPh
Ph
i. NaH, DMFii. allyl bromide
84% 94%
Et
EtEt 331 332
62%
333
Scheme 5.16. Synthesis of di-substituted Amino olefin.
(Z)-Benzyl 2,2-diphenylhept-4-enylcarbamate 334 was prepared starting from (Z)-2,2-
diphenylhept-4-en-1-amine 332 with benzyl chloroformate in the presence of NaHCO3 in 90%
yield (scheme 5.17).
NH2
Et Et
CbzCl, NaHCO3EtOH/H2O (3:2)
90%
Ph
Ph
Ph
Ph NH
Cbz
332 334
Scheme 5.17. Protection of di-substituted amino olefin with Cbz.
The same methodology was applied in order to prepare (Z)-benzyl 2,2-diphenyloct-5-
enylcarbamate, but without success. Introducing a modification in the first step by using
homoallylic iodide and LHMDS instead of homoallylic bromide and NaH provided the target
product with an overall yield of 68% as shwon in (scheme 5.18).
108 Chapter 5
Ph
Ph CN I LHMDS, THF-78 °C, RT
CNPhPh
Et
PhPh
Et
PhPh
Et
i. LAH, Et2Oii. NaOH, H2O
CbzCl, NaHCO3EtOH/H2O (3:2)
95% 79%NH2
NHCbz
335 336
91%
337
Scheme 5.18. Synthesis of 5,6-di-substituted amino olefin protected with Cbz group.
5.2.3 Results and Discussion
5.2.3.1 Catalysis.
Initial screening experiments were performed by using 1 equiv. of Ag-salt per precatalyst (5 mol%)
12 in three different solvents (benzene, dioxane, and toluene) thus exchanging Cl− by a more labile
binding counterion. Heating for 20 h at 110 °C led to >99% conversion in case of the entry 1,2 with
12% and 22% ee, respectively (Table 5.1), while in the case of the entry 3, 73% conversion with 14
% ee (Table 5.1) was observed.
Table 5.1. Pt (II)-Catalyzed intramolecular hydroamination of aminoalkene:
NHBnBnN
PhPh
Ph
Ph
(5 mol%)12,(5 mol%) AgOOCC3F7,Y, 110 °C, 20h
287 288 # Y yielda/[%] eeb/[%]
1 Benzene >99 12
2 Dioxane >99 22
3 Toluene 73 14 a determined by H-NMR by comparing the integrals of product and starting material, followed by
multiplication with the mass balance.b determined by HPLC.
Intramolecular Hydroamination of Unactivated Olefins 109
From these initial results, it can be seen that there is catalytic activity of Pt(II) towards
hydroamination of the unactivated olefins. The solvent was found to have no great influence on the
reaction outcome, and the reaction rate shows a slight decrease in the case of toluene being used as
a solvent.
5.2.3.2 Investigation of the Influence of the Silver Salt.
Utilizing 1 equiv. of different Ag-salts per precatalyst (5 mol%) 12 in dioxane and heating up for
48h at 70 °C gave >99% conversion in case of the entry 1, 3 and 5 with 15%, 16%, and 15% ee
respectively (Table 5.2), while in case of the entry 2 and 4 conversion values of 79 and 56% with
9% and 7% ee, respectively (Table 5.2) were observed. In the entry 6 no silver salt was involved,
and the reaction did not occur.
Table 5.2. Screening of silver salts with model substrate:
NHBnBnN
PhPh
Ph
Ph
(5 mol%) 12,(5 mol%) Y,dioxane, 70 °C, 48h
287 288
# Y yielda/[%] eeb/[%]
1 A >99 15.5 2 B 79 9.4 3 C >99 16.4 4 D 56 7 5 E >99 15.5
6 - -c - a determined by H-NMR by comparing the integrals of product, and starting material followed by
multiplication with the mass balance.b determined by HPLC.c No reaction.
OSO
AgO
OSO
AgOO
SO
AgO
OSO
AgO
O
O OO
SO
AgO
A B C D E
Very good catalytic activity was obtained with different Ag-salt as an activating agent, and the
reaction rate was still quite high when the temperature was decreased. The counter ion was found
to have no significant influence on the reaction outcome. The enantioselectivities still show no
great variations.
110 Chapter 5
5.2.3.3 Investigation of the Influence of the Amino Protecting Group. The effect of different amino protecting groups was tested for the intramolecular hydroamination of
unactivated olefins. Different amino protecting groups such as aryl units, amides, carbonate esters,
and sulphonamides were examined, in order to see the influence of the protecting group on the
reaction outcome. The amide, and sulphonamide substrates were studied under the following
reaction conditions utilizing (5 mol%) 12 precatalyst in dioxane and heating at 70 °C for 48h
(Table 5.3 entry 1,2). m-Chlorobenzyl amine was tested using 1.0 equiv. of AgOOCC3F7 per
precatalyst (5 mol%) in dioxane and heating at 110 °C for 20h (Table 5.3, entry 3). A carbamate of
a di- substituted olefin was also examined under the following reaction conditions: (i) (5 mol %) 12
precatalyst in dioxane and heating at 90 °C for 48h; (ii) 1 equiv. of AgOSO2CF3 precatalyst (5
mol%) 12 in dioxane and heating at 100 °C for 48h. In addition aryl substituted and free amines
were also examined using 1 equiv. of AgOOCC3F7 per precatalyst (5 mol%) 12 in dioxane and
heating at 110 °C for 20h (Table 5.3, entry 8, 9).
Table 5.3. Screening of different protecting groups.
NHRRN
PhPh
Ph
Ph
(5.0 mol%) 12,Y-(5.0 mol%),
dioxane, T (°C), t (h)R1
R1
n n397 a-e
# R R1 N Amino
olefin
Y-Ag-salt T[°C]
/t[h]
yielda/
Product 397
eeb/[%]
1 Ac H 1 329 - 70 /48 NR 2 Ts H 1 330 - 70 /48 NR 3 mClPhCH2 H 1 327 AgOOCC3F7 110 /20 >99 12
4 Cbz Et 1 334 - 90/48 25% isomerization
5 Cbz Et 1 334 AgOSO2CF3 100/48 Isomerization 6 Cbz Et 2 337 - 90/48 Decomposed 7 Cbz Et 2 337 AgOSO2CF3 100/48 Isomerization 8 Bn Et 1 233 AgOOCC3F7 110/20 33 c
9 H H 1 326 AgOOCC3F7 110/20 Decomposed a determined by 1H-NMR by comparing the integrals of product, and starting material, followed by
multiplication with the mass balance. b determined by HPLC. c No success for determination ee.
From the results reported in Table 5.3 we observed no influence on the reaction outcome changing
from an aryl protecting group to an amide, sulfone amide or carbonate ester. In case of the entry 1
and 2, there was no reaction at all. In case of the entry 3, the product was formed with > 99%
conversion and with 12% ee. In case of the entry 4, 5, and 7, an isomerized olefin was obtained
Intramolecular Hydroamination of Unactivated Olefins 111
while in case of the entry 7 the aminoalkene decomposed. In the case of the disbstituted amino
olefin (entry 8), the product was formed in 33 % conversion. For ee determination different HPLC
methods, chiral GC, and the formation of the corresponding Mosher amide were examined but all
attempts were not successful. The primary amines (entry 9) were found to be decomposing.
5.2.3.4 Investigation of the Influence of Additives. Utilizing 1 equiv. of Ag-salt per precatalyst (5 mol%) in dioxane in the presence of of pyridine or
acetonitrile and heating for 48h at 70 °C gave no conversion in case of (entry 1), and 73%
conversion in case of the entry 2 (Table 5.4).
Table 5.4: screening of additives with model substrate 287.
NHBnBnN
PhPh
Ph
Ph
(5 mol%) 12,(5 mol%) AgOOCC3F7,Y, 70 °C, 48h
287 288
# Y [20.0 mol%] yielda/[%] eeb/[%]
1 Pyridine NR - 2 CH3CN 73 19
a determined by 1H-NMR by comparing the integrals of product, and SM, followed by multiplication with the mass balance. b determined by HPLC.
It was observed from these two runs that pyridine inactivated the catalyst while the less Lewis basic
acetonitrile had no influence on the reaction outcome, but still enantioselectivity was low with 19%
ee.
After investigation of the effects of solvent, silver salts, protecting groups and additives on the
reaction outcome it is likely that the reaction pathway has two potential mechanisms which have to
be considered (Scheme 5.19) and which have been discussed for alternative Pt-catalyzed additions
to alkenes. 1b Coordination of a C=C bond to an electrophilic Pt center activates the alkene toward
outer sphere attack by a protic nucleophile NuH. The newly formed Pt-C bond is then cleaved by
protonolysis (see below) to regenerate the catalyst.
Scheme 5.20 shows an alternate inner-sphere mechanism, in which the nucleophile first coordinates
to Pt by deprotonation of NH and ligand exchange. The key step is a 1,2-migratory insertion of a
bound olefin into the Pt-N bond. Again, the newly formed Pt-C bond is cleaved by protonolysis.
112 Chapter 5
Fe PtN
NTs
Ph
Ph
N
N
Ts
Ph
Ph
A
Fe PtN
NTs
Ph
Ph
N
N
Ts
Ph
Ph
ANHBn
Fe PtN
NTs
Ph
Ph
N
N
Ts
Ph
Ph
A
BnNPh
Ph
NHBnPh
Ph
outer-spherenucleophilic attack
Protonolysis
A = O2CC3F7
Ph
Ph
BnHN
Ph Ph
Scheme 5.19. Possible route to the product distribution observed when N-Benzyl-2,2-diphenylpent-4-en-1-amine 287 is Reacted with Pt(II) -12.
Intramolecular Hydroamination of Unactivated Olefins 113
Fe PtN
NTs
Ph
Ph
N
N
Ts
Ph
Ph
Fe PtN
NTs
Ph
Ph
N
N
Ts
Ph
Ph
A
BnNPh
Ph
NHBnPh
Ph
1,2-migratoryinseration
Protonolysis
A = O2CC3F7
A HNBn Ph
Ph
Fe PtN
NTs
Ph
Ph
N
N
Ts
Ph
Ph HNBn Ph
Ph
A .
A
Fe PtN
NTs
Ph
Ph
N
N
Ts
Ph
PhHN
Bn Ph
Ph
Scheme 5.20. Possible route to the product distribution observed when N-Benzyl-2,2-diphenylpent-
4-en-1-amine 287 is reacted with Pt(II)-12.
5.3 Attempts to the Development of an Improved Catalyst. Platinacycle 12 catalyzed the intramolecular hydroamination with high reactivity yet with low
enantioselectivity as a result of a competing inner- and outer-sphere attack. By introducing strongly
binding anionic ligands like for instance Ph or C6F5 the inner-sphere attack should be largely
impeded, leaving only one site for coordination free. Several attempts were tested.
Fe
N
Pt
N
PhPh
Ts
N
N Ph
Ts Ph
ClFe
N
Pt
N
PhPh
Ts
N
N Ph
Ts Ph
R
R = Ph, Me, C6F5
12 338
Scheme 5.21. General approach for the development of a suitable catalyst.
114 Chapter 5
Reaction conditions have been applied which are described in literature for other Pt-complexes.
Several attempts were made by testing for instance MeMgBr, Et2O: PhH / RT);28 PhMgBr, THF/
5.4.2 Screening Different Conditions for Cycloplatination. In a first attempt to evaluate the potential metallation abilities of the ferrocenyl ligands with a
platinum(II) source, their reactivity with the platinum(II) complexes [PtCl2(L)2] (L = dmso, CH3CN
or Cl,) or Zeise salt was studied under different experimental conditions.
Ligand 11 was examined under different reaction conditions (Table 5.5, Entry 1, 2, 3): (i) 1 equiv.
of cis-[PtCl2(dmso)2], 2 equiv. of AcONa in (MeOH: PhH 4:1), and heating at 70 °C for 2 h; (ii) 2
equiv. of K[(H2C=CH2)PtCl3], 4 equiv. of NaOAc , and stirring overnight at RT, then heating at 60
°C for 30 min; (iii) 2 equiv. K2PtCl4 in AcOH, 110 °C, 24h. The 1H NMR spectra of the crude
reaction mixtures showed that in case of conditions (i) and (ii) Pt(II) binds to N. After addition of
Ph3P, ligand 11 is released again demonstrating that C-Pt bond formation did not take place, while
in case of using reaction conditions (iii) ring opening of the oxazoline moity is noticed.
Ligand 149 was examined under the following reaction conditions (Table 5.5, Entry 4-9): (i) 2
equiv. K2PtCl4, in AcOH, 110°C, 12h. (ii) 2 equiv. K2PtCl4, AcONa in (MeOH: PhH 4:1), 110 °C,
15h. (iii) 1 equiv. of cis-[PtCl2(dmso)2] in (MeOH: PhH 4:1), 110 °C, 15h. (iv) 1 equiv. of
PtCl2(CH3CN)2 in PhMe, 110 °C, 1h. (v) K[(H2C=CH2)PtCl3](1.equiv.),NaOAc (2.equiv.), (MeOH:
PhMe 4:1), 110 °C, 15h. The 1H NMR spectra of the crude reaction mixtures showed that in case of
(i) ring opening of the oxazoline moity occurs. In case of (ii) no product formation has occurred. In
contrast, in case of (iii) and (v) the starting material decomposed, while in case of (iv) the 1H-NMR
spectrum is too complex.
Ligand 348 was treated with 1 equiv. K[(H2C=CH2)PtCl3], 2 equiv. NaOAc in (MeOH: PhMe 4:1),
and stirred at RT for 15h (Table 5.5, entry 10). The 1H NMR spectrum of the crude reaction
mixture showed that the starting material decomposed.
Ligand 341 was treated with 2 equiv. K[(H2C=CH2)PtCl3], 4 equiv. NaOAc in (MeOH: PhMe 4:1),
and stirred at RT for 48h (Table 5.5, entry 11). The 1H NMR spectrum of the crude reaction
mixture showed that Pt(II) binds to N, but addition of Ph3P regenerates ligand 341.
Intramolecular Hydroamination of Unactivated Olefins 117
Ligand 344 was treated with 2 equiv. K[(H2C=CH2)PtCl3], 4 equiv. NaOAc in (DCE: tBuOH 4:1),
and stirred at RT−80 °C. The 1H NMR spectrum of the crude reaction mixture showed that the Me-
N bond was cleaved.
Ligand 345 was treated with 2 equiv. K[(H2C=CH2)PtCl3], 4 equiv. NaOAc in MeOH: PhH 4:1 and
stirred at RT for 70h. No product formation occurred. In case of ligand 346 the same conditions
were applied (Table 5.5, entry 14) giving a Pt(II) coordination to N, yet a C-Pt bond is not formed.
Ligand 347 was examined under the following reaction conditions (Table 5.5, Entry 15,16): (i) 1
equiv. of cis-[PtCl2(dmso)2] in (MeOH: PhH 4:1), RT, 15h; (ii) K[(H2C=CH2)PtCl3] (2.equiv.),
NaOAc (4.equiv.), (MeOH: PhMe 4:1), RT, 48h. A complex mixture was formed with (i), while in
case of (ii) decomposition was found. Table 5.5. Investigation of the cycloplatination of different ligands.
After screening different conditions for cycloplatination in order to get platinacycles, we have
noticed that some ligands are not stable for C-Pt formation, others give coordination to N, while in
118 Chapter 5
case of Ligand 11, and 149 entry 3, 4, Table 5.5, ring opening of the oxazoline36 was observed as
shown in the (scheme 5.24).
Fe
PhPh
Ph
Ph PhNHFe
PhPh
Ph
Ph Ph
NO
OH3CO2K2PtCl4, AcOH
reflux, 24h
11 343
Scheme 5.24. Ring opening of oxazoline.
5.5 Conclusion. In conclusion, a Pt(II)-catalyzed intramolecular hydroamination of unactivated olefins has been
developed giving pyrrolidine and piperidine derivatives. Enantioselectivity was low as a result of a
competing inner-sphere and outer-sphere mechanism. Further extensions of this chemistry towards
improved selectivity by developing other platinacycles can be envisioned, and are currently
explored in the Peters group.
5.6 References.
1 a) A. Fürstner, P. W. Davies, Angew. Chem. Int. Ed. 2007, 46, 3410; b) A. R. Chianese, S. J.
Lee, M. R. Gagné, Angew. Chem. Int. Ed. 2007, 46, 4042; c) selected very recent asymmetric
application: C. A. Mullen, A. N. Campbell, M. R. Gagné, Angew. Chem. Int. Ed. 2008, 47,
6011.
2 H. Huang, R. Peters, Angew. Chem. Int. Ed. 2009, 48, 604.
3 (a) S. Hong, T. J. Marks, Acc. Chem. Res. 2004, 37, 673; (b) D. Riegert, J. Collin, A. Meddour,
E. Schulz, A. Trifonov, J. Org. Chem. 2006, 71, 2514; (c) J. Y. Kim, T. Livinghouse, Org.
Lett. 2005, 7, 4391; (d) J. Y. Kim, T. Livinghouse, Org. Lett. 2005, 7, 1737; (e) D. V. Gribkov,
K. C. Hultzsch, F. Hampel, J. Am. Chem. Soc. 2006, 128, 3748; (f) G. A. Molander, E.
Dowdy, D. J. Org. Chem. 1999, 64, 6515; (g) Y. K. Kim, T. Livinghouse, Y. Horino, J. Am.
Chem. Soc. 2003, 125, 9560.
4 P. H. Martínez, K. C. Hultzsch, F. Hampel, Chem. Commun. 2006, 2221.
5 M. R. Crimmin, I. J. Casely, M. S. Hill, J. Am. Chem. Soc. 2005, 127, 2042.
6 S. Majumder, A. L. Odom, Organometallics 2008, 27, 1174.
7 L. Ackermann, L. T. Kaspar, A. Althammer, Org. Biomol. Chem. 2007, 5, 1975.
8 C. F. Bender, R. A. Widenhoefer, J. Am. Chem. Soc. 2005, 127, 1070.
Intramolecular Hydroamination of Unactivated Olefins 119
9 (a) C. Liu, X. Han, X. Wang, R. A. Widenhoefer, J. Am. Chem. Soc. 2004, 126, 3700; (b) X.
Wang, R. A. Widenhoefer, Chem. Commun. 2004, 660.
10 X. Wang, R. A. Widenhoefer, Organometallics 2004, 23, 1649.
11 H. Qian, X. Han, R. A. Widenhoefer, J. Am. Chem. Soc. 2004, 126, 9536.
12 For recent examples of Pt-catalyzed olefin coupling see: (a) C. Hahn, M. E. Cucciolito, A.
Vitagliano, J. Am. Chem. Soc. 2002, 124, 9038; (b) W. D. Kerber, J. H. Koh, M. R. Gagné,
Org. Lett. 2004, 6, 3013.
13 C. F. Bender, W. B. Hudson, R. A. Widenhoefer, Organometallics 2008, 27, 2356.
14 S.M. Hande, N. Kawai, J. Uenishi, J. Org. Chem. 2009, 74, 244.
15 (a) Z. Zhang, C. Pan, Z. Wang, Chem. Commun. 2007, 4686; (b) R. M. Trend, Y. K. Ramtohul,
B. M. Stoltz, J. Am. Chem. Soc. 2005, 127, 17778.
16 (a) M. R. Gagné, L. Brard, V. P. Conticello, M. A. Giardello, T. J. Marks, C. L. Stern,
Organometallics 1992, 11, 2003; (b) M. A. Giardello, V. P. Conticello, L. Brard, M. R. Gagné,
T. J. Marks, J. Am. Chem. Soc. 1994, 116, 10241; (c) J.-S. Ryu, T. J. Marks, F. E. McDonald,
J. Org. Chem. 2004, 69, 1038.
17 D. V. Gribkov, K. C. Hultzsch, F. Hampel, J. Am. Chem. Soc. 2006, 128, 3748.
18 L. Xiang, Q. Wang, H. Song, G. Zi, Organometallics 2007, 26, 5323.
19 M. C. Paderes, S. R. Chemler, Org. Lett. 2009, 11, 1915.
20 J. A. Bexrud, J. D. Beard, D. C. Leitch, L. L. Schafer, Org. Lett. 2005, 7, 1959.
21 R.K. Thomson, J. A. Bexrud, L. L. Schafer, Organometallics 2006, 25, 4069.
22 M. C. Wood, D. C. Leitch, C. S. Yeung, J. A. Kozak, L. L. Schafer, Angew. Chem. Int. Ed.
2007, 46, 354.
23 E. B. Bauer, G. T. S. Andavan, T. K. Hollis, R. J. Rubio, J. Cho, G. R. Kuchenbeiser, T. R.
Helgert, C. S. Letko, F. S. Tham, Org. Lett. 2008, 10, 1175.
24 Z. Liu, J. F. Hartwig, J. Am. Chem. Soc. 2008, 130, 1570.
25 K. D. Hesp, M. Stradiotto, Org. Lett. 2009, 11, 1449.
26 (a) F. E. Michael, B. M. Cochran, J. Am. Chem. Soc. 2006, 128, 4246; For Au, see: (b) J.
Zhang, C.-G. Yang, C. Chuan, J. Am. Chem. Soc. 2006, 128, 1798.
27 H. Ohmiya, T. Moriya, M. Sawamura, Org. Lett. 2009, 11, 2145.
28 B. L. Madison, S. B. Thyme, S. Keene, B. S. Williams, J. Am. Chem. Soc. 2007, 129, 9538.
29 J. B. Seneclauze, P. Retailleau, R. Ziessel, New J. Chem. 2007, 31, 1412.
30 S. Diring, P. Retailleau, R. Ziessel, J. Org. Chem. 2007, 72, 10181.
31 S. Diring, P. Retailleau, R. Ziessel, Synlett 2007, 3027.
32 L. Schwartsburd, R. Cohen, L. Konstantinovski, D. Milstein, Angew. Chem. Int. Ed. 2008, 47,
3603.
33 G. Jones, C. J. Richards, Tetrahedron: Asymmetry 2004, 15, 653.
120 Chapter 5
34 R. Peters, Z.-q. Xin, D. F. Fischer, W. B. Schweizer, Organometallics, 2006, 25, 2917.
35 R. Peters, D. F. Fischer, Org. Lett. 2005, 7, 4137.
36 J. S. Fossey, C. J. Richards, Organometallics 2004, 23, 367.
37 R. W. Wason, K. McGrouther, P. R. R. Ranatunge-Bandarage, B. H. Robinson, J. Simpson,
Appl. Organomet. Chem. 1999, 13, 163.
Chapter 6
Miscellaneous.
This chapter describes projects which were not completed due to one of these reasons: results were
not useful, they were of moderate attractiveness or were completely different from those originally
targeted.
6.1 Synthesis of a Methoxy-Substituted Pentaphenyl Ferrocen- yl Imidazoline Palladacycle.
6.1.1 Literature Overview.
In 2002, Kang et al. published a study with several ferrocen-1,1’-diyl bispalladacycles 165 as
catalysts for the rearrangement of N-aryl benzimidates 171 (see Chapter 4.1.2.4).1 Complex 165,
bearing an isopropyl ether as third donor tooth is a remarkably active and still selective catalyst for
the rearrangement of benzimidate 171. (5 mol%) of 165 converted 172 in only 30 min at RT in
DCM in 91% yield and with 92% ee.
Fe
O
N
Pd
PdOI
N
O
OI
O
n-Pr
Ph
NPMP
O
n-Pr
Ph
NPMP
(5 mol%) 165,(10 mol%) AgOTFADCM, RT, 30 min
y: 91%, ee: 92%
171 172 165
Scheme 6.1. Tridentate bispalladacycles as catalysts for the aza-Claisen rearrangement.
One reason for the high activity seems to be the ether donor acting as a highly labile ligand for
Pd(II), which readily liberates a free coordination site. This enhances the rate of substrate
coordination.
We were thus interested to see if a similar rate enhancement could be achieved for pentaphenyl
ferrocenyl imidazoline palladacycles FIP-Cl by installation of a hemilabile ether donor.
122 Chapter 6
6.1.2 Results and Discussion.
Enantiopure 1,2-diphenyl ethylenediamines bearing substituents on the phenyl groups have become
commercially available only very recently. A short route to diamine 342 was published only after
most of this work had been done; compound 342 was thus prepared via a rather lengthy synthesis
starting from ortho-anisaldehyde 349 (see Scheme 6.2, a):2 Aluminium in basic methanol leads to
formation of a benzoin derivative which is oxidised by a “Swern” like reaction to the benzil
derivative 350. All further steps are in analogy to the synthesis of unsubstituted diamine 342.
O
OMe
1. Al, KOH, MeOH2. HBr, DMSO, Δ
OOMe
OMeO N
OMeN
MeO
NH4OAc,cyclohexanone,AcOH, Δ
1. Li, liquid NH3, THF−78 °C, then EtOH2. HCl aq.
NH2OMe
H2NMeO tartaric acid,
EtOH
NH2OMe
H2NMeO
a)
b)
NH2OH
H2NHO
O
OMe
DMSO, 70 °C
NOH
NHO
OMeMeON
OHN
HO
OMeMeO
352
349 350
342
349
353 354
351
Scheme 6.2. Synthesis of diamine 342. a) Route used in this project: b) Alternative route. For a) and b), literature yields are given which could not be reproduced in a single run.
The alternative route starts with commercially available (though rather expensive) ortho-OH
diamine 352, which forms a diimine 353 with various substituted benzaldehyde derivatives. This
diimine undergoes in situ a [3,3] sigmatropic rearrangement. The equilibrium lies stongly on the
product side due to more favourable hydrogen bonds (Scheme 6.2, b). The reaction has been found
to proceed with practically full transfer of chirality.
Miscellaneous 123
The compound prepared by the original route a) was found to be rather sensitive and was thus
stored as a frozen solution in benzene. Attempts to acylate the two amino functionalities (for ee-
determination by chiral column HPLC) with Ac2O and triethylamine in DCM at 0 °C failed since
the compound mainly decomposed, probably via an elimination pathway.
Gratifyingly, such an elimination was not observed neither in the formation of ferrocenyl
imidazoline 355 nor in the subsequent tosylation, allowing the preparation of imidazoline ligand
356 in 62% overall yield (Scheme 6.3).
Fe
PhPh
Ph
Ph Ph
NN
MeO-Ph
MeO-Ph
TsFe
PhPh
Ph
Ph Ph
NNH
Fe
PhPh
Ph
Ph PhHBF4
.HN
EtOdiamine 342,DCE, 80 °C, 7 h
OMe
OMe
TsCl, DMAP,NEt3, DCM
Na2PdCl4, NaOAc, MeOH, PhH Palladacycle 357a-c356
356yield: 62%over 2 steps
87%
355
Scheme 6.3. Formation of ortho-OMe imidazoline, tosylation and cyclopalladation.
Cyclopalladation took place under the identical conditions as used before, but as in the case of
unsubstituted FIP-Cl, only moderate conversion was obtained by overnight reaction, while
allowing the reaction mixture to stand for several weeks led to nearly complete conversion to 357.
The constitution of palladacycle 357 could be assigned only via X-ray crystal structure analysis. A
standard 1H-NMR had given reason to believe that Pd(II) was not bound to any carbon atom of the
upper Cp-ring (357a); on the other hand, a MALDI-MS measurement as well as NMR-experiments
with the addition of dppe had given unambiguous prove that there was a Pd-C σ-bond present, so
that initially, a structure where Pd was bound to a phenyl group of the pentaphenyl-Cp ligand was
assumed (357a).
124 Chapter 6
Fe
PhPh
Ph
Ph Ph
Pd
2
NNMeO-Ph
Ts
Cl
OMe
Fe
PhPh
Ph
Ph Ph
PdN
NMeO-Ph
Ts
OCl
PhFe
PhPh
PhN
NPh-OMe
OPdCl
Ts
357a 357b 357c
Figure 6.1. Possible structures of palladacycle. Left: Constitution assumed after 1H-NMR analysis. Middle: Originally anticipated and targeted constitution. Right: constitution determined by X-ray crystallography.
The crystal structure analysis could be solved only partially: The CpΦ-part seems to have an
inherent disorder, while the upper Cp-ring, including the palladium–chloride square plane and the
imidazoline, could be solved, showing unambiguously that structure 357c is correct. Contrary to
the expectations, this complex is also found as a chloride bridged dimer and not as a monomer with
OMe acting as a ligand as depicted in 357b (Figure 6.1). Though structure 357c is thus correct, in
solution, there still is probably a certain amount of monomeric structure 357b present, since some
minor signals in 1H-NMR disappear when at least 1 equiv. of a dppe is added.
The position of a monodentate phosphine coordinating to Pd is not as clear as with other
palladycycles described in previous chapters, where usually shortly after mixing only one isomer
was detected with P always found trans to the coordinating N. Even after 2 d in solution, there are
still two signals in 31P-NMR with relative intensities of ca. 6:1 at 17 ppm and −2 ppm respectively,
while the ratio after one hour is ca. 1:2. By correlating chemical shifts, the signal at 17 ppm (minor
signal after 1 h, major after 2 d) is assigned to a phosphine coordinated trans to N.
As a result of the lower preference for one coordination site, lower enantioselectivity is expected
for the aza-Claisen rearrangement which is based upon the premise that the olefin moiety is
coordinating trans to N.
Miscellaneous 125
6.2 Synthesis of a Pentaphenyl Ferrocenyl Oxazoline Pallada-
cycle with a Pd(III) Center.
6.2.1 Literature Overview. Palladium is a common transition metal for catalysis, and the fundamental organometallic
reactivity of palladium in its 0, I, II and IV oxidation states is well established. The potential role of
Pd(III) in catalysis has not been investigated because organometallic reactions that involve Pd(III)
have not been reported previously.
Recently in 2009, Ritter et al.4 have identified a previously unappreciated pathway for carbon–
heteroatom bond formation from Pd(III) and have evaluated its relevance to catalysis. Carbon–
chlorine (Scheme 6.4), carbon–bromine and carbon–oxygen reductive eliminations from discrete
bimetallic Pd(III) complexes were presented. This report discloses the first recognized
organometallic reactions from Pd(III) and implicates bimetallic Pd(III) catalysis as a mechanistic
alternative to monometallic Pd(II)–Pd(IV) redox cycles.
N N
(5.0 mol%) 360NCS, MeCN,100 °C, 50h
N
N
Pd
Pd
OO
OO
Cl
Cl
Cl
360
90% yield
358 361
N
Pd(OAc)2
−AcOHN
Pd
AcO
2
PhICl2CH2Cl2, –30 °C
358 359
Scheme 6.4. Chlorination of 358 with NCS is catalysed by 360. We were interested to see if a similar reaction could be achieved for pentaphenyl ferrocenyl
oxazoline palladacycles PPFOP-X 4, as both Pd(II) centers are already in close contact for a metal-
metal interaction as X-ray crystal structure analysis has revealed (se chapter 4.2.2).
6.2.2 Results and Discussion. Initial attempts investigated the addition of one equivalent of PhICl2 to PPFOP-Cl 4 in CH2Cl2 at
−50 °C resulting in an immediate colour change from red to dark brown. After the reaction mixture
126 Chapter 6
was stirred at −50 °C for 10 min the organic byproduct was removed from the crude reaction
mixture by trituration with diethyl ether. The crude solid was analyzed by 1H-NMR but the targeted
product could not be detected and only decomposition was observed (scheme 6.5).
Fe
PhPh
Ph
Ph Ph
Pd
2
NO
Cl
PhICl2DCM, −50 °C Fe
PhPh
Ph
Ph Ph
Pd
2
NO
ClCl
4 362
Scheme 6.5. Oxidation of PPFOP-Cl with PhICl2. After these first attempts were unsuccessful, palladium acetate dimer 195 was examined utilizing 1
equiv. of PhICl2 in CH2Cl2 at −70 °C. The reaction mixture was stirred at −70 °C for 10 min and
then solvent was removed by flushing N2 at the same temperature. The crude solid was triturated
with diethyl ether and was subsequently checked by 1H-NMR. The spectra were found to be more
promising than in the first attempt. The product could be purified by cholumn chromatography
using DCM:Et2O (2:1) as eluent.
PhICl2, DCM, −70 °C
Fe
PhPh
Ph
Ph Ph
NO
Pd OAc2
Fe
PhPh
Ph
Ph Ph
NO
Pd OAc2Cl
57%PhPh
Ph Ph
195 363
Scheme 6.6. Oxidation of PPFOP-Ac with PhICl2.
The product which might be the Pd(III) species 363 was obtained in 57% yield after purification.
The preliminary 1H-NMR spectra are completely different from starting material as the H3CCO
singlet of the CpΦ signals are shifted. Subsequently, for structure confirmation the mass spectra for
PPFOP-Cl 4, PPFOP-OAc 195, and the new product were obtained. By comparison the three
spectra were completely different from each other but the structure of 363 could not be
unambiguously confirmed so far. A possibility to determine the structure would be X-ray crystal
structure analysis. Several attempts were made to obtain suitable crystal for X-Ray measurements
but were not successful.
Miscellaneous 127
6.3 Intramolecular Hydroalkoxylation of Unactivated Olefins.
6.3.1 Literature Overview. The prevalence of saturated oxygen heterocycles in both naturally occurring and biologically active
molecules5 including the acetogenins and polyether antibiotics has fueled interest in the
development of new and efficient methods for the synthesis of cyclic ethers. Inter- or
intramolecular hydroalkoxylation, the formal addition of alcohols to carbon–carbon multiple bonds,
is a direct and efficient procedure for the synthesis of various ethers and oxygen-containing
heterocycles.6 The nucleophilic addition of alcohols under basic conditions has been studied
widely7 but the use of transition metal catalysts is more favorable for the hydroalkoxylation than
the use of bases, primarily due to their effectiveness and the milder conditions.8 In general, the
intermolecular addition of alcohols is more difficult than the intramolecular process.9 It has been
considered that the use of soft Lewis acidic transition metal catalysts is needed for intramolecular
hydroalkoxylation.
In 2004, Widenhoefer et al.8a have developed a mild and efficient platinum-catalyzed protocol for
the intramolecular hydroalkoxylation of unactivated γ- and δ-hydroxy olefins to form cyclic ether
Scheme 6.12. Chemoselective and regioselective synthesis of 3,4-didehydroionone isomers.
We were thus interested to see if a possibility to synthesize of 4,5-didehydroionone isomers and see
if the double bond in the position of 4,5 has impact factor on the fragrances properties.
Miscellaneous 137
6.5.2 Results and Discussion.
6.5.2.1 Synthesis of 4,5-Didehydro-α-Ionone 379. While aldol condensation of readily aldehyde with acetone in the presence of base and Wittig
reaction with phosphonate were not successful to reach the target compound because isomeric
products that are inseparable by the usual methodologies. It was found that the readily alcohol 380
is good starting material for the synthesis. Tosylation of the free OH-group, followed by addition of
phenyl thiol whereas deprotonated by NaH afforded the sulphide 381 in 95% yield. Oxidation of
the later compound with a mixture of (NH4)6.Mo7O24 and H2O2 gives the sulphone 382 in moderate
yield where the disulfide was occurred as byproduct. Deprotonation of sulphone 382 using n-BuLi
at −78 °C and epoxide in DMP were added then BF3.OEt2 added to the reaction mixture. The
reaction mixuter stirred for further 5h at −78 °C and leave overnight to warm at RT to give 383 in
38% yield that was oxidized by Dess Martin to give the corresponding ketone in quantitative yield.
Removal of PhSO2 group by DBU regenerates the target compound 379 in good yield (scheme
6.13).
OH
OH
i. TsCl, DCMii. PhSH, NaH,DMF, 50 °C
95%
SPh (NH4)6.Mo7O24,H2O2, MeOH, RT
40%
SO2Ph
i. nBuLi, THF, −78 °C
iii. BF3.OEt2
Oii. ,DMP
SO2Ph
i. Dess Marten, DCMii. DBU, DCM, RT
O
380 381 382
379 383 Scheme 6.13. Synthesis of 4,5-didehydro-α-ionone 379.
6.5.2.2 Synthesis of 4,5-Didehydro β and γ-Ionone 384 and 385. Several attempts were done to prepare 4,5-didehydro-β and γ-ionone but were not successful due to
isomeric products that are inseparable by the usual methodologies. The most routes were promising
but it comes at certen point and stops. For istance, synthesis of 4,5-didehydro-β-ionone starts form
3-oxo-β-ionone readily available by synthetic way. The later compound was reduced specifically
by NaBH4 and subsequently protected by Ac group using Ac2O/Py. Unsaturated double bond at the
position 4,5 388 was done by DDQ in refluxing benzene for 10h. Thioketal 389 formation and
reductive elimination by rany nickel was failed, also stereo specific reduction and then reductive
138 Chapter 6
elimination using Pd couldnot help (Scheme 6.14a). Pathway b which starts from readily alcohols
380 where oxidized using Dess Marten regenerates aldehyde where the double bond at 2,3 can
isomerized easly by DBU into 1,2 position. The later aldehyde reacts with bromoacetate ester in the
presence of Zn in THF to regenerate mixture of α and β isomers where not separated (Scheme
6.14b).
OH
O
O
i. NaBH4, MeOH,0 °C −>10 °C, 10 minii. Ac2O/Py, RT, 1.5h
OAc
O
OAc
O
DDQ, Benzene,reflux, 10h
SH
SHBF3.(Et2O)2,CHCl3, 0 °C
OAc
S S
Raney Nickel,EtOH, RT
OAcO
Oi. Dess Martin, DCMii. DBU, DCM
OEt
OOH
OEtBr
O
Zn, THF, 1h
a)
b)
386 387 388
389384 391
380 391 384/385
Scheme 6.14. Different approaches for synthesis of 4,5-didehydero- β-ionone.
In case of 4,5-didehydero- γ-ionone 393 it starts the synthesis from 5-hydroxy- γ-ionone 392.
Different condition was examined for dehydration such as protection of OH group by (e.g., Ms, Ts,
Ac) and base catalyzed reductive elimination (e.g., t-BuOK, DBU). Wolf kischner also was tested
but no one of these conditions afford the product (scheme 6.15).
OHO
O
392 393 Scheme 6.15. Approache for the synthesis of 4,5-didehydero- γ-ionone.
Miscellaneous 139
6.6 Conclusion. In a summary, these projects were carried out by the author either in the Fuganti or Peters research
laboratory. Further extensions of this chemistry are still in the progress.
6.7 References.
1 J. Kang, K. H. Yew, T. H. Kim, D. H. Choi, Tetrahedron Lett. 2002, 43, 9509.
2 Y. Liu, C. A. Sandoval, Y. Yamaguchi, X. Zhang, Z. Wang, K. Kato, K. Ding, J. Am.
Chem. Soc. 2006, 128, 14213.
3 a) H. Kim, Y. Nguyen, C. P.-H. Yen, L. Chagal, A. J. Lough, B. M. Kim, J. Chin, J. Am.
Chem. Soc. 2008, 130, 12184. In an older report, the high diastereoselectivity of this
reaction has been described already: b) F. Vögtle, E. Goldschmitt, Chem. Ber. 1976, 109,
1.
4 D. C. Powers, T. Ritter, Nature Chem. 2009, 1, 302.
5 (a) M. C. Elliot, J. Chem. Soc., Perkins Trans 1 2000, 1291; (b) M. C. Elliot, E. Williams,
J. Chem. Soc., Perkins Trans 1 2001, 2303; (c) F. Q. Alali, X. X. Liu, J. L. McLaughlin, J.
Nat. Prod. 1999, 62, 504.
6 For recent reviews of catalytic hydroalkoxylation, see: (a) K. Tani, Y. Kataoka, In
Catalytic Heterofunctionalization; A. Togni, H. Grützmacher, Eds.; Wiley-VCH:
Weinheim, 2001; pp 171–216; (b) F. Alonso, I. P. Beletskaya, M. Yus, Chem. Rev. 2004,
104, 3079.
7 D. Tzalis, C. Koradin, P. Knochel, Tetrahedron Lett. 1999, 40, 6193.
8 For recent examples of Lewis acidic transition metal catalyzed hydroalkoxylation, see: (a)
H. Qian, X. Han, R. A. Widenhoefer, J. Am. Chem. Soc. 2004, 126, 9536; (b) N. T. Patil,
N. K. Pahadi, Y. Yamamoto, Can. J. Chem. 2005, 83, 569; (c) Y. Oe, T. Ohta, Y. Ito,
Synlett 2005, 179; (d) Y. Matsukawa, J. Mizukado, H. Quan, M. Tamura, A. Sekiya,
Angew. Chem. Int. Ed. 2005, 44, 1128; (e) L. Coulombel, I. Favier, E. Duñach, Chem.
Commun. 2005, 2286; (f) T. Hirabayashi, Y. Okimoto, A. Saito, M. Morita, S. Sakaguchi,
Y. Ishii, Tetrahedron 2006, 62, 2231; (g) K. M. Gligorich, M. J. Schultz, M. S. Sigman, J.
Am. Chem. Soc. 2006, 128, 2794; (h) L. Coulombel, M. Rajzmann, J.-M. Pons, S. Olivero,
E. Duñach, Chem. Eur. J. 2006, 12, 6356; (i) X. Yu, S. Y. Seo, T. J. Marks, J. Am. Chem.
Soc. 2007, 129, 7244; (j) P. Lemechko, F. Grau, S. Antoniotti, E. Duñach, Tetrahedron
Lett. 2007, 48, 5731.
9 For recent examples of gold-catalyzed intramolecular hydroalkoxylation, see: (a) A.
Hoffmann-Röder, N. Krause, Org. Lett. 2001, 3, 2537; (b) Y. Liu, F. Song, Z. Song, M.
Liu, B. Yan, Org. Lett. 2005, 7, 5409; (c) A. S. K. Hashmi, M. C. Blanco, D. Fischer, J. W.
140 Chapter 6
Bats, Eur. J. Org. Chem. 2006, 1387; (d) V. Belting, N. Krause, Org. Lett. 2006, 8, 4489;
(e) B.; Liu, J. K. De Brabander, Org. Lett. 2006, 8, 4907; (f) Z. Zhang, C. Liu, R. E.
Kinder, X. Han, H. Qian, R. A. Widenhoefer, J. Am. Chem. Soc. 2006, 128, 9066; (g) Z.
Zhang, R. A. Widenhoefer, Angew. Chem. Int. Ed. 2007, 46, 283; (h) B. Alcaide, P.
Almendros, T. M. del Campo, Angew. Chem. Int. Ed. 2007, 46, 6684; (i) C. Deutsch, B.
Gockel, A. Hoffmann-Röder, N. Krause, Synlett 2007, 1790; (j) F. Volz, N. Krause, Org.
Biomol. Chem. 2007, 5, 1519; (k) G. L. Hamilton, E. J. Kang, M. Mba, F. D. Toste,
Science 2007, 317, 496; (l) J. Erdsack, N. Krause, Synthesis 2007, 3741.
10 (a) C. H. Heathcock, S. L. Graham, M. C. Pirrung, W. Plavac, C. T. White, In The Total
Synthesis of Natural Products; Apsimon, J. W., Ed.; Wiley: New York, 1983; Vol. 5, p
333; (b) J. H. Rigby, In Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.;
Elsevier Science Publishers B. V.: Amsterdam, 1988; Vol. 12, p 233; (c) B. M. Fraga, Nat.
g/dL, CHCl3). IR, 1H-NMR, MS: in accordance with that of (−)-96.
Resolution of (3SR,6SR)-3,6-dihydroxy-α-ionone ((±)-95). According to general procedure GP1 (±)-95 was converted in the acetate (+)-97 and diol (−)-95.
The latter compound was acetylated to give (−)-95 and both esters were submitted to the fractional
crystallisation procedure to afford enantiopure (+)-97 (2.1 g, 12% yield after 3 crystallizations) and
(−)-97 (1.75 g, 10% yield after 4 cristallizations) showing the following spectral data: