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University of Groningen
Novel asymmetric copper-catalysed transformationsBos, Pieter
Harm
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Novel Asymmetric Copper-Catalyzed Transformations
Pieter Harm Bos
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The work described in this thesis was carried out at the
Stratingh Institute for Chemistry, University of Groningen, The
Netherlands. The work was financially supported by: The Netherlands
Organization for Scientific Research (NWO-CW). Printed by: Ipskamp
Drukkers, Enschede, The Netherlands Cover: The Great Wave Off
Kanagawa by Katsushika Hokusai, 1829-32 Cover design: Pieter
Bos
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Rijksuniversiteit Groningen
Novel Asymmetric Copper-Catalyzed Transformations
Proefschrift
ter verkrijging van het doctoraat in de Wiskunde en
Natuurwetenschappen aan de Rijksuniversiteit Groningen
op gezag van de Rector Magnificus, dr. E. Sterken, in het
openbaar te verdedigen op
maandag 19 maart 2012 om 14.30 uur
door
Pieter Harm Bos
geboren op 3 juni 1983 te Hefshuizen
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Promotor: Prof. dr. B. L. Feringa Copromotor: Dr. S. R.
Harutyunyan Beoordelingscommissie: Prof. dr. V. Gouverneur Prof.
dr. ir. A. J. Minnaard Prof. dr. J. G. de Vries ISBN:
978-90-367-5379-1 (print) 978-90-367-5378-4 (digital)
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A-Tableofcontents.docx
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A-Tableofcontents.docx
TableofContentsChapter 1 Introduction 1 1.1 Methodology
development in organic chemistry 2
1.2 Transition metal catalysis 2
1.3 Asymmetric C-C bond forming reactions 4
1.3.1 Asymmetric conjugate addition 4
1.3.2 Asymmetric allylic substitution 6
1.4 Aim and outline of this thesis 7
1.5 References 8
Chapter 2 Catalytic Asymmetric Conjugate Addition of Grignard
Reagents to α,β-Unsaturated Sulfones 11 2.1 Introduction
12
2.1.1 The use of sulfones in organic chemistry 12
2.1.2 Conjugate addition of organometallic reagents to
,-unsaturated sulfones 13
2.1.3 Catalytic asymmetric conjugate reduction of
,-disubstituted ,-unsaturated sulfones 15
2.1.4 Rhodium-catalyzed asymmetric conjugate addition of
organoboronic acids to ,-unsaturated sulfones 17
2.1.5 Catalytic asymmetric conjugate addition of diorganozinc
reagents to ,-unsaturated sulfones 18
2.2 Goal 19
2.3 Results and Discussion 19
2.3.1 Catalyst screening 19
2.3.2 Solvent screening 20
2.3.3 Optimization of the copper salt 21
2.3.4 Optimization of copper/ligand ratio 22
2.3.5 Scope of Grignard reagents 23
2.3.6 Scope of ,-unsaturated sulfones 23
2.3.7 The influence of the 2-pyridyl group and limitations of
the system 24
2.4 Conclusion 25
2.5 Experimental section 26
2.6 References 36
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A-Tableofcontents.docx
Chapter 3 Catalytic Asymmetric Conjugate Addition of Dialkylzinc
Reagents to α,β-Unsaturated Sulfones 39 3.1 Introduction
40
3.1.1 The use of sulfones in organic chemistry 40
3.1.2 Asymmetric copper-catalyzed conjugate addition of
diorganozinc reagents to ,-unsaturated compounds 40
3.1.3 Conjugate addition of organometallic reagents to
,-unsaturated sulfones 42
3.2 Goal 42
3.3 Results and Discussion 43
3.3.1 Optimization of solvent and temperature 43
3.3.2 Influence of the copper salt 44
3.3.3 Optimization of copper/ligand ratio 44
3.3.4 Scope of diorganozinc reagents 45
3.3.5 Scope of ,-unsaturated sulfones 46
3.4 Conclusion 47
3.5 Experimental Section 47
3.6 References 57
Chapter 4 Catalytic Asymmetric Conjugate Addition/Oxidative
Dearomatization Towards Multifunctional Spirocyclic Compounds
59 4.1 Introduction 60
4.1.1 Asymmetric copper-catalyzed conjugate addition of Grignard
reagents 60
4.1.2 Sequential transformations based on copper-catalyzed
asymmetric conjugate addition of organometallic reagents
60
4.1.3 Oxidative dearomatization 62
4.1.4 Intra- and intermolecular oxidative enolate heterocoupling
64
4.2 Goal 65
4.3 Results and Discussion 66
4.3.1 Strategy 66
4.3.2 Synthesis of naphthol-based substrates 67
4.3.3 Optimization of the enantioselective Cu-catalyzed
conjugate addition 69
4.3.4 One-pot conjugate addition/oxidative cyclization
70
4.3.5 Determination of the absolute configuration of the
spirocyclic product 74
4.3.6 Synthesis of phenol-based substrates 75
4.3.7 Conjugate addition of EtMgBr to phenol-based substrates
77
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A-Tableofcontents.docx
4.3.8 Attempted oxidative cyclization 78
4.3.9 Synthesis of pyrrole-based substrate 80
4.3.10 Asymmetric conjugate addition of EtMgBr to pyrrole-based
substrate 81
4.3.11 Oxidative cyclization of pyrrole-based substrate 109
81 4.4 Conclusion and future prospects 82
4.5 Experimental Section 83
4.6 References 109
Chapter 5 Catalytic Asymmetric Carbon-Carbon Bond Formation via
Allylic Alkylations with Organolithium Compounds 113 5.1
Introduction 114
5.1.1 Organolithium compounds in asymmetric C-C bond formation
114
5.1.2 Properties of organolithium compounds 119
5.1.3 Copper-catalyzed asymmetric allylic alkylation
121
5.2 Goal 123
5.3 Results and Discussion 123
5.3.1 Strategy and challenges 123
5.3.2 Optimization of solvent 124
5.3.3 Optimization of the chiral ligand 126
5.3.4 Optimization of the copper salt 128
5.3.5 Scope of the asymmetric allylic alkylation with
organolithium reagents 128
5.3.6 Mechanistic studies 131
5.4 Conclusions 134
5.5 Experimental Section 135
5.6 References 147
Chapter 6 Copper-Catalyzed Asymmetric Ring Opening of
Oxabicyclic Alkenes with Organolithium Reagents 151 6.1
Introduction 152
6.1.1 Stoichiometric ring opening of oxabicyclic alkenes
152
6.1.2 Palladium and Rhodium-catalyzed asymmetric ring opening
153
6.1.3 Copper-catalyzed asymmetric ring opening 155
6.1.4 Catalytic asymmetric ring opening using organolithium
reagents 156
6.2 Goal 157
6.3 Results and Discussion 157
6.3.1 Screening of ligands and conditions 157
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A-Tableofcontents.docx
6.3.2 Copper-catalyzed ring opening with organolithium reagents
159
6.3.3 System limitations 160
6.4 Conclusion and Future Prospects 162
6.5 Experimental Section 163
6.6 References 170
Chapter 7 Asymmetric Autocatalysis in Organic Reactions: A
Spectroscopic Study 173 7.1 Introduction 174
7.1.1 Asymmetric autoinduction 174
7.1.2 Asymmetric autocatalysis: The Soai system. 175
7.1.3 Evidence for autocatalysis in organocatalytic reactions
177
7.2 Goal 179
7.3 Results and Discussion 179
7.3.1 Synthesis of the products and product stability
179
7.3.2 Reaction monitoring by Raman spectroscopy 180
7.3.3 Influence of work-up procedure on the purity of product 13
185 7.3.4 Monitoring the reaction in time using 1H-NMR
spectroscopy 186
7.4 Conclusion 191
7.5 Experimental Section 192
7.6 References 197
Summary 199 Nederlandse Samenvatting 205 Acknowledgement 211
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A-Tableofcontents.docx
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Chapter 1 Introduction
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Chapter1-final-nocode.docx
Chapter 1
1.1 Methodology development in organic chemistry As a
consequence of the increased complexity of target molecules in
industry and academic research, the development of new methodology
remains an important aspect of organic chemistry both in current
time as well as for the future. Across the entire field of
chemistry, from material science to pharmaceutical chemistry,
efficient synthetic methods are crucial and of increasing
importance, especially in the context of sustainable chemistry for
the future.1-3 A key concept for methodology development in organic
chemistry is synthetic efficiency, which was defined by Barry M.
Trost as ‘the ability to convert readily available building blocks
into the target molecule in relatively few synthetic operations
that require minimal quantities of raw materials and produce
minimal waste’.2, 4 This concept of efficiency can be divided
further into two major components: selectivity and atom economy.
Selectivity can be categorized according to chemical reactivity
(chemoselectivity), orientation (regioselectivity), and spatial
arrangement (diastereo- and enantioselectivity). The development of
novel methodology that is able to achieve both selectivity as well
as atom economy must remain to be a prime goal in synthetic organic
chemistry.1
1.2 Transition metal catalysis Transition metal catalysis plays
an important role in the continuing quest for novel reactivity.1, 5
Besides opening up routes to novel products, transition metal
catalysis also has the ability to solve the important issues of
selectivity and atom economy in chemical reactions indicated in the
first paragraph of this chapter. Due to the seemingly limitless
combinations of transition metals and (chiral) ligands, transition
metal catalysis can be utilized for a broad range of reactions
including: hydrogenation,6-12 isomerization,13 oxidation,14-16
hydrosilylation17-20 and carbon-carbon bond forming reactions.1, 5,
21 Some selected pioneering examples are presented in Scheme 1.
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Chapter1-final-nocode.docx
Introduction
Scheme 1 Selected examples of transition metal catalyzed
transformations. As a result of its wide applicability the field of
transition metal catalysis has been recognized by the 2001 Nobel
prize, for the development of ‘Chirally catalyzed hydrogenation and
oxidation reactions’;8, 22, 23 the 2005 Nobel prize, for the
development of ‘The metathesis method in organic synthesis’;24-26
and the 2010 Nobel prize, for the development of
‘Palladium-catalyzed cross couplings in organic synthesis’.27,
28
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Chapter1-final-nocode.docx
Chapter 1
1.3 Asymmetric C-C bond forming reactions Carbon-carbon bond
formation covers a wide spectrum of reactions and because the
formation of new carbon-carbon bonds is arguably the most important
process in organic synthesis its development and application is one
of the most widely explored fields.1, 5 A whole range of
carbon-carbon bond forming reactions has been developed including:
carbonylation,29-31 hydroformylation,32-34 hydrocyanation,35
(cross-)metathesis36-40 and a plethora of cross-coupling reactions
(Suzuki,41-43 Negishi,27, 44-46 Heck,47-51 Hiyama,52, 53 and many
more). A fascinating aspect of many C-C bond forming reactions is
the possibility to synthesize chiral molecules. Chirality and
efforts towards the control of chirality have intrigued the
chemical community since the introduction of the tetrahedral model
of the carbon atom by Van ‘t Hoff 54-57 and Le Bel58 138 years ago.
New standards and regulations in the chemical industry have led to
an increasing demand for enantiopure molecules for the synthesis of
pharmaceuticals, agrochemicals, flavors, fragrances and many other
compounds.1, 5, 59-62 In response to this demand, the field of
asymmetric carbon-carbon bond forming reactions grew explosively in
the past few decades resulting in major breakthroughs.5 An
important factor in the success of transition metal catalyzed
asymmetric transformations has been the design of chiral ligands.
By employing these chiral ligands, chemists are able to fine-tune
the environment of the transition metal center, ideally leading to
the desired reaction in high overall yield with exceptional levels
of regio- and stereocontrol.
1.3.1 Asymmetric conjugate addition One of the most versatile
methods for enantioselective carbon-carbon bond formation is the
asymmetric conjugate addition.63, 64 This transformation is used as
a key step in the synthesis of numerous natural products and
biologically active compounds and has been the subject of intensive
research over the past decades.65-77 In particular the
copper-catalyzed asymmetric conjugate addition of organometallic
reagents has proven to be successful in the synthesis of a wide
range of enantiopure building blocks starting from a large variety
of α,β-unsaturated substrates (see also Chapters 2, 3 and 4).75-77
In the asymmetric conjugate addition, the nucleophile is
transferred to the β-position of α,β-unsaturated substrate 1. This
process results in the formation of stabilized carbanion 2.
Subsequent protonation leads to the isolation of the desired
β-chiral product 3 (Scheme 2). Trapping with an electrophile leads
to the formation of product 4 bearing two stereocenters (Scheme
2).
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5
Chapter1-final-nocode.docx
Introduction
REWG Nu
-
REWG
Nu* R
EWGNu
*
H+
REWG
Nu*
1 2
3
E+
REWG
Nu*
4 E*
Scheme 2 Conjugate addition. EWG = electron withdrawing group;
Nu- = carbon nucleophile;
E+ = electrophile. A major challenge in the asymmetric conjugate
addition reaction is the control of the regioselectivity. Addition
of a soft nucleophile generally takes place at the β-position of
the unsaturated system, whereas 1,2-addition is favored in the case
of hard nucleophiles like organometallic reagents. In the case of
copper-catalyzed asymmetric conjugate addition reactions, careful
tuning of the catalytic system can prevent the direct 1,2-addition
of hard organometallic reagents to the electron withdrawing group
and afford the desired β-chiral product with excellent enantiomeric
excess. An additional benefit of the copper-catalyzed asymmetric
conjugate addition is the possibility for sequential
transformations, i.e. trapping of the carbanion with an
electrophile (Scheme 2), leading to the introduction of multiple
stereocenters in a one-pot procedure with excellent enantio- and
diastereoselectivity (see Chapter 4 for a more detailed
discussion).72, 77-84 The use of asymmetric tandem transformations
is a very powerful approach in organic synthesis. Tandem
transformations based on the asymmetric conjugate addition of
organometallic reagents generally take advantage of the high
enantioselectivities obtained in the conjugate addition reaction.
The enolate formed in the asymmetric conjugate addition lends
itself towards the development of sequential processes, in which
trapping of the enolate leads to the formation of two or more
stereocenters in a one-pot procedure (see Scheme 3).
Scheme 3 Tandem transformation triggered by asymmetric conjugate
addition. E = electrophile;
R = alkyl/aryl group; M = metal; L = chiral ligand; * =
stereogenic center.
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Chapter1-final-nocode.docx
Chapter 1
In the past three decades considerable efforts have been
directed towards the development of efficient catalytic systems and
for this reason the copper-catalyzed asymmetric conjugate addition
has been reviewed extensively.66, 73-77
1.3.2 Asymmetric allylic substitution Together with the
asymmetric conjugate addition, asymmetric allylic alkylations are
among the most powerful asymmetric carbon-carbon bond forming
reactions known to date and have therefore received widespread
attention over recent decades.75, 76, 85, 86 The asymmetric allylic
substitution reaction provides access to optically active building
blocks that are frequently employed in the synthesis of complex
natural products and pharmaceuticals. During the past two decades
significant progress was achieved in this field and numerous
catalytic systems were developed suitable for a range of substrates
bearing different leaving groups and with different organometallic
based nucleophiles, i.e. R2Zn, R3Al, RMgX, RLi and RBY2.75, 76
Scheme 4 Asymmetric allylic substitution. LG = leaving group.
The allylic substitution can proceed via two distinct pathways
(Scheme 4). Depending on the catalytic system and the nucleophile,
different ratios of SN2 versus SN2’ product are obtained. The
palladium-catalyzed allylic substitution87-91 proceeds either via
addition of a ‘soft’ nucleophile, such as malonates, directly to
π-allyl intermediate 9a or, in the case of ‘hard’ nucleophiles, is
proposed to proceed via a transmetallation to palladium to form
π-allyl complex 9b followed by carbon-carbon bond formation. For
the palladium-catalyzed allylic substitution different nucleophiles
give a different ratio of SN2 (10) versus SN2’ (11) product. The
copper-catalyzed version generally yields the chiral branched SN2’
product 11 via transmetallation of the nucleophile to copper and
formation of a σ-alkyl intermediate followed by reductive
elimination.85 A more detailed overview of the copper-catalyzed
allylic alkylation with organometallic reagents is presented in
Chapter 5.
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Chapter1-final-nocode.docx
Introduction
A significant advantage of both the copper-catalyzed asymmetric
conjugate addition as well as the copper-catalyzed asymmetric
allylic alkylation using organometallic reagents are the high
compatibility with many functional groups, the low cost of the
copper-salts used to form the active catalyst compared to e.g.
palladium (Pd(OAc2): 10 g, €482 vs CuBr2: 10 g, €40),92 and their
excellent results with respect to regio- and
enantioselectivity.
1.4 Aim and outline of this thesis The aim of this thesis was to
develop novel asymmetric copper-catalyzed transformations providing
enantiopure building blocks. In Chapter 2, a highly efficient
method for the asymmetric copper-catalyzed conjugate addition of
Grignard reagents to α,β-unsaturated 2-pyridylsulfones is
described. Using a Cu/TolBinap complex, excellent
enantioselectivities and high yields are obtained for a wide
variety of aliphatic substrates. A complementary approach, the
asymmetric copper-catalyzed conjugate addition of dialkylzinc
reagents to α,β-unsaturated 2-pyridylsulfones using a monodentate
phosphoramidite ligand, is described in Chapter 3. In Chapter 4, a
sequential asymmetric copper-catalyzed conjugate addition/oxidative
cyclization protocol is reported. This methodology allows for the
synthesis of highly functionalized benzofused spirocyclic compounds
and a high degree of molecular complexity is achieved in a one-pot
transformation. Chapter 5 describes the development of a
copper-based chiral catalytic system that allows carbon-carbon bond
formation via allylic alkylation with organolithium reagents with
extremely high enantioselectivities and is able to tolerate several
functional groups. The most critical factors in achieving
successful asymmetric catalysis with organolithium reagents were
determined to be the solvent used and the structure of the active
chiral catalyst. The active form of the catalyst was identified
through spectroscopic studies as a diphosphine copper monoalkyl
species. Chapter 6 extends the utility of the use of organolithium
reagents in asymmetric catalysis with the development of a highly
efficient method for the asymmetric ring opening of oxabicyclic
alkenes. Using a copper/chiral phosphoramidite complex together
with a Lewis acid (BF3•OEt2), full selectivity for the anti isomer,
high yields and excellent enantioselectivities were obtained for
the multifunctional ring opened products. The final chapter of this
thesis, Chapter 7, describes the spectroscopic study of an
asymmetric Mannich reaction, reported in 2007 by Mauksch and
Tsogoeva, which was reported to be autocatalytic. The combined
spectroscopic data indicate that this Mannich reaction is not
catalyzed by the product. Several control experiments were
performed, demonstrating that addition of the product does not
accelerate product formation.
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Chapter1-final-nocode.docx
Chapter 1
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Chapter 1
(73) López, F.; Minnaard, A. J.; Feringa, B. L. Acc. Chem. Res.
2007, 40, 179. (74) Lopéz, F.; Minnaard, A. J.; Feringa, B. L. In
The Chemistry of Organomagnesium Compounds; Rappoport, Z.; Marek,
I. Eds.; Wiley: Chicester, U. K. 2008; Part 2, Chapter 17 (75)
Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Minnaard, A. J.;
Feringa, B. L. Chem. Rev. 2008, 108, 2824. (76) Alexakis, A.;
Bäckvall, J. E.; Krause, N.; Pàmies, O.; Diéguez, M. Chem. Rev.
2008, 108, 2796. (77) Jerphagnon, T.; Pizzuti, M. G.; Minnaard, A.
J.; Feringa, B. L. Chem. Soc. Rev. 2009, 38, 1039. (78) Teichert,
J. F.; Feringa, B. L. Angew. Chem. Int. Ed. 2010, 49, 2486. (79)
Stolz, D.; Kazmaier, U. Metal Enolates As Synthons in Organic
Chemistry; In Chemistry of Metal Enolates; Wiley: Chichester, U. K.
2009, 355. (80) Howell, G. P.; Fletcher, S. P.; Geurts, K.; Ter
Horst, B.; Feringa, B. L. J. Am. Chem. Soc. 2006,
128, 14977. (81) Guo, S.; Xie, Y.; Hu, X.; Xia, C.; Huang, H.
Angew. Chem. Int. Ed. 2010, 49, 2728. (82) Welker, M.; Woodward,
S.; Alexakis, A. Org. Lett. 2010, 12, 576. (83) Feringa, B. L.;
Pineschi, M.; Arnold, L. A.; Imbos, R.; De Vries, A. H. M. Angew.
Chem. Int. Ed. Engl. 1997, 36, 2620. (84) Arnold, L. A.; Naasz, R.;
Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2001, 123, 5841.
(85) Geurts, K.; Fletcher, S. P.; Van Zijl, A. W.; Minnaard, A. J.;
Feringa, B. L. Pure and Applied
Chemistry 2008, 80, 1025. (86) Lu, Z.; Ma, S. Angew. Chem. Int.
Ed. 2008, 47, 258. (87) Trost, B. M.; Van Vranken, D. L. Chem. Rev.
1996, 96, 395. (88) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003,
103, 2921. (89) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1. (90)
Trost, B. M. J. Org. Chem. 2004, 69, 5813. (91) Tsuji, J. Palladium
Reagents and Catalysts, Innovations in Organic Synthesis; Wiley:
Chichester, U. K. 1995. (92) Source: www.sigma-aldrich.com, January
2012.
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Chapter 2 Catalytic Asymmetric Conjugate Addition of Grignard
Reagents to α,β-Unsaturated Sulfones
In this chapter a highly efficient method is reported for the
asymmetric conjugate addition of Grignard reagents to ,-unsaturated
2-pyridylsulfones. Using a Cu/TolBinap complex, excellent
enantioselectivities and high yields are obtained for a wide
variety of aliphatic substrates.*
* Parts of this chapter have been published: Bos, P. H.;
Minnaard, A. J.; Feringa, B.L. Org. Lett. 2008, 10, 4219.
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Chapter 2
2.1 Introduction As already described in the introductory
chapter of this thesis, the conjugate addition of organometallic
reagents to ,-unsaturated compounds is one of the most versatile
methods for the formation of C-C bonds.1, 2 This transformation is
used as a key step in the synthesis of numerous natural products
and biologically active compounds and has been the subject of
intensive research over the past decades.3-12 The development of a
catalytic method for the enantioselective conjugate addition
reaction of organometallic reagents to ,-unsaturated sulfones is an
important goal in extending the current methodology.
2.1.1 The use of sulfones in organic chemistry The utility of
sulfones for organic synthesis was recognized in the late 1970’s13
and because of their duality of functioning both as nucleophiles in
basic media and electrophiles in Lewis acidic media they have been
dubbed “chemical cameleons”.14 Sulfonyl-containing intermediates
have frequently been used in the total synthesis of a large number
of biologically active natural compounds.15 As a result, methods
for their synthesis have been well developed.13, 16, 17 Sulfones
bearing a stereocenter at the -position are highly versatile
intermediates in organic chemistry due to the ease of
derivatization and by providing access to a wide range of building
blocks, including aldehydes and ketones, alkynes, alkenes, alkanes,
and haloalkanes.15, 18 This versatility was nicely demonstrated by
Carretero et al. in an article describing the catalytic asymmetric
conjugate reduction of ,-disubstituted ,-unsaturated sulfones (see
also section 2.1.3).19 The resulting -substituted highly
enantioenriched sulfones were converted into four differently
functionalized chiral compounds without compromising the
enantiomeric excess (see Scheme 1).
-
13
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Catalytic Asymmetric Conjugate Addition of Grignard Reagents to
α,β-Unsaturated Sulfones
Me
PhSO2Py
(S)-1 (94% ee)originating from
conjugate reduction
Me
Ph
Me
Ph
Me
Ph
Ph
Ph
OEt
O
Me
Ph
Ph
O
KHMDS, DME-78 oC
then PhCHO(R)-5, 87%
1. n-BuLi, then BnBr2. Na(Hg), Na2HPO4, MeOH
(R)-2, 75%
1. n-BuLi, then ClCO2Et
2. Zn, aq. NH4Cl(R)-3, 80%
1. n-BuLi, then ClCOPh2. Zn, aq. NH4Cl
(R)-4, 69% Scheme 1 Examples of synthetic applications of chiral
enantioenriched 2-pyridylsulfones. HMDS: hexamethyldisilazide; DME:
1,2-dimethoxyethane.19 The first three transformations (Scheme 1,
compounds (R)-2, (R)-3 and (R)-4) are based on the generation of
the highly nucleophilic sulfonyl carbanion followed by
carbon-carbon bond formation by reaction with an appropriate carbon
electrophile (benzyl bromide, ethyl chloroformate, or benzoyl
chloride respectively). After subsequent desulfonylation the
products were isolated in good yields without compromising the
enantiomeric excess. In the last example, Julia-Kocienski
olefination of (S)-1 with benzaldehyde afforded alkene (R)-5
directly in 87% yield, with complete selectivity for the E isomer
and no loss of enantiomeric excess was observed. The
Julia-Kocienski olefination occurs without racemization at the
allylic stereogenic center.20
2.1.2 Conjugate addition of organometallic reagents to
,-unsaturated sulfones A vast number of diastereoselective
conjugate addition reactions to ,-unsaturated sulfones have been
reported.21, 22 Groundbreaking work of Fuchs et al. is especially
noteworthy.21 Using ,-unsaturated sulfones as substrates together
with either organolithium reagents or organocuprates interesting
molecular structures were synthesized. In the first example a
number of functionalized cyclooctane structures were built up using
the addition of organometallic reagents to cyclooctenyl phenyl
sulfone 6
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14
Chapter2-Final-nocode.docx
Chapter 2
(Scheme 2). In this case simple organolithium reagents gave the
best results giving predominantly the syn diastereomers (ratio
7a:7b, up to 100:0) with yields up to 93%.23
Scheme 2 Conjugate addition (6) and allylic alkylation (8) of
organometallic reagents.23 Allylic alkylation of methyllithium to
epoxy cyclooctenyl phenyl sulfone 8 gave the product (9) in 90%
isolated yield. Unfortunately, the authors could not determine the
syn:anti ratio in this case. The total synthesis of (+)-carbacyclin
is another example in which the utility of the ,-unsaturated
sulfone group is demonstrated elegantly.24 In this case the
presence of the ,-unsaturated sulfone group allows for the regio-
and stereoselective introduction of carbon substituents onto a
preformed ring (Scheme 3).
Scheme 3 Total synthesis of (+)-carbacyclin 15.24
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15
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Catalytic Asymmetric Conjugate Addition of Grignard Reagents to
α,β-Unsaturated Sulfones
Reaction of bromocuprate 11 with optically active 10 afforded
the allylic alkylation product. This compound was subsequently
converted into 12 in two steps. Conjugate addition of chiral
vinyllithium reagent 13 to 12 and subsequent intramolecular
trapping of the resulting carbanion followed by desilylation with
TBAF provided 14. Treatment with lithium in liquid ammonia afforded
the desulfonylated, debenzylated product and completion of the
synthesis was achieved by selective oxidation of the primary
alcohol to give (+)-carbacyclin 15.24 Another method reported in
literature is based on a stereoselective conjugate addition of
methyllithium to enantiomerically pure γ-alkoxy-,-unsaturated
phenyl sulfone 16 for the stereoselective construction of
polypropionate chains using an iterative approach (Scheme 4).25
Scheme 4 Iterative construction of polypropionate chains.25
After the conjugate addition the syn isomer 17 was isolated
exclusively. By a three step protocol, ,-unsaturated phenyl sulfone
18 can be generated, which could be employed as a substrate in a
subsequent conjugate addition reaction with methyllithium. In this
way polypropionate segments with up to four consecutive
stereocenters were constructed.
2.1.3 Catalytic asymmetric conjugate reduction of
,-disubstituted ,-unsaturated sulfones A complementary approach to
the catalytic asymmetric conjugate addition is the catalytic
asymmetric conjugate reduction of ,-disubstituted Michael
acceptors. This method is a useful and practical alternative for
the preparation of enantioenriched carbonyl compounds and related
systems bearing a stereocenter at the -position. Pioneering work on
the copper hydride catalyzed asymmetric conjugate reduction of
,-disubstituted ,-unsaturated esters by Buchwald et al. led to the
development of a vast number of conjugate reduction procedures
using various Michael acceptors.26-36 Remarkably, despite the great
chemical versatility of sulfones in synthesis37, the catalytic
asymmetric conjugate reduction of ,-disubstituted ,-unsaturated
sulfones was only developed recently. In 2007, the group of
Carretero et al. reported the catalytic asymmetric conjugate
reduction of ,-unsaturated 2-pyridylsulfones using PhSiH3 as the
hydride source and CuCl/t-BuONa/(R)-Binap as the chiral catalytic
system (see Scheme 5).19 This methodology has quite a broad scope
with regard to the substitution of the vinyl
-
16
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Chapter 2
Scheme 5 Enantioselective conjugate reduction developed by
Carretero et al.19 sulfone 19 and the resulting -substituted
2-pyridylsulfones were obtained with high enantiomeric excess and
in excellent isolated yields. The authors noted that the use of the
2-pyridylsulfonyl group in the substrate was absolutely necessary
in order to get satisfactory results. If an ordinary phenylsulfonyl
group was used no conjugate reduction was observed under the
reaction conditions. This effect was also noted for the
rhodium-catalyzed conjugate addition of boronic acids to
,-unsaturated sulfones (see section 2.1.4) and it is believed that
the possible coordination between copper and the 2-pyridylsulfone
group can result in a strong rate acceleration in the conjugate
reduction reaction.38, 39 In the same year an extension to this
methodology was published by Charette et al. circumventing the
necessity of the 2-pyridylsulfonyl group.40 In their paper a
general procedure is reported for the enantioselective reduction of
simple vinyl phenyl sulfones catalyzed by a copper-phosphine
complex (see Scheme 6).
Scheme 6 Enantioselective conjugate reduction developed by
Charette et al.40 Absolutely crucial to the success of this
procedure is the use of the hemilabile bidentate ligand Me-DuPhos
monoxide L1. The addition of aqueous sodium hydroxide was necessary
to obtain reproducible conversions. With the optimized procedure in
hand a variety of vinyl phenyl sulfones were shown to give the
desired product 22 with excellent yield and enantiomeric excess. It
must be noted that when using an aliphatic acyclic substrate a
bulkier ligand had to be used in order to reach a satisfactory
enantiomeric excess.
-
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Catalytic Asymmetric Conjugate Addition of Grignard Reagents to
α,β-Unsaturated Sulfones
2.1.4 Rhodium-catalyzed asymmetric conjugate addition of
organoboronic acids to ,-unsaturated sulfones In 2004, Carretero et
al. developed a general method for the catalytic asymmetric
conjugate addition of arylboronic acids to acyclic ,-unsaturated
sulfones.41 As a model reaction the behavior of a variety of
propenyl sulfones 23, with a different substitution pattern at the
sulfur atom, were evaluated using the standard conditions described
for the rhodium-catalyzed conjugate addition of phenylboronic acids
to enones (Table 1).42 Table 1 Influence of sulfone substitution on
the Rhodium-catalyzed conjugate addition.41
23 R Conversion (%)a 23a-e
, , , ,
98 (74%)
23g
>98 (98%)
23h N
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Chapter2-Final-nocode.docx
Chapter 2
After establishing the crucial role of the 2-pyridyl sulfone
group different chiral ligands were screened for the
enantioselective addition of arylboronic acids to 23g. Using
Chiraphos as the chiral ligand, the desired products could be
isolated in excellent yields (up to 98%) with good to excellent
enantiomeric excess (77-92%) (see Scheme 7). The major drawback of
this method is that it is limited to the introduction of aryl
groups.
Scheme 7 Catalytic asymmetric conjugate addition of arylboronic
acids.41 The same catalytic system was also used for the formation
of all-carbon quaternary centers upon addition of alkenylboronic
acids to ,-disubstituted ,-unsaturated sulfones (Scheme 8).44
Although lower conversions were achieved compared to the conjugate
addition using arylboronic acids, the products were obtained with
excellent enantiomeric excess (88-99%).
Scheme 8 Catalytic asymmetric conjugate addition of
alkenylboronic acids.44
2.1.5 Catalytic asymmetric conjugate addition of diorganozinc
reagents to ,-unsaturated sulfones An alternative to the
rhodium-catalyzed conjugate addition and the copper-catalyzed
conjugate reduction described earlier in this chapter was reported
by Charette et al.45 Shortly before our results on this topic were
published (vide infra) a method was reported for the catalytic
asymmetric conjugate addition of diorganozinc reagents to vinyl
sulfones (Scheme 9).
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Catalytic Asymmetric Conjugate Addition of Grignard Reagents to
α,β-Unsaturated Sulfones
Scheme 9 Catalytic asymmetric conjugate addition of diorganozinc
reagents.45 Using a copper/(R)-Binap complex, optically active
sulfones 31 were obtained with enantiomeric excess up to 98%.
Several diorganozinc reagents were reported, but the system is
limited to primary diorganozinc reagents and yields are modest to
excellent (52-93%). Again, the 2-pyridyl sulfone group was
essential in order to get satisfactory results.
2.2 Goal The aim of this research project was to develop
methodology for the catalytic asymmetric conjugate addition of
Grignard reagents to ,-unsaturated sulfones. The resulting
optically active sulfones with a stereocenter at the -position have
been shown to be highly versatile intermediates in organic
chemistry due to the ease of derivatization and provide access to a
wide range of building blocks. These products are not accessible
via the rhodium-catalyzed conjugate addition of boronic acids,
since this methodology is limited to the introduction of
arylboronic acids. Major advantage of the conjugate addition of
Grignard reagents, compared to the related conjugate reduction, is
that this approach is more modular and thus circumvents the
necessity to introduce the substituents at the stereogenic center
in the early stages of the synthesis.
2.3 Results and Discussion
2.3.1 Catalyst screening Initially, we studied the addition of
ethylmagnesium bromide to ,-unsaturated sulfone 32a using bidentate
phosphine ligands (L2-L5) (Table 2). All reactions gave full
conversion overnight, but the best results were obtained using
binaphthyl-type phosphine ligands L2 and L5, whereas
ferrocenyl-type ligands L3 and L4 gave negligible
enantioselectivity. Tol-Binap L2 provided a slightly higher
enantiomeric excess compared to Binap (L5) and was used for further
screening.
-
20
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Chapter 2
Table 2 Copper/ligand catalyzed addition of EtMgBr to
,-unsaturated sulfone 32a.a, b
Entry Ligand eec,d (%)
1 (R)-Tol-Binap (L2) 47 (R) 2 (R,SFc)-Josiphos (L3) 6 (S) 3
(R,RFc)-Taniaphos (L4) 3 (S) 4 (R)-Binap (L5) 46 (R)
a Conditions: 32a (1 eq., 0.1 mmol in DCM) was added to a
solution of EtMgBr (1.2 eq.), CuI (with L2/L5) or CuBr·Me2S (with
L3/L4) (5 mol %) and L2-L5 (5 mol %) in t-BuOMe at 40 oC, 16 h. b
Full conversion after 16 h, determined by GC-MS. c Enantiomeric
excess determined by chiral HPLC (see Experimental Section). d
Determined by comparison with literature data based on the sign of
the optical rotation.
2.3.2 Solvent screening We observed that the use of an alkyl
substituted substrate gave higher ee. Therefore, we switched to
aliphatic substrates and applying the Cu/Tol-Binap catalytic
system, the addition to ,-unsaturated sulfone 34a in several
solvents was examined (Table 3). In all cases full conversion was
obtained overnight at 40 oC. Running the reaction in DCM or t-BuOMe
resulted in similar enantioselectivities (Table 3, entries 1 and
3). Using toluene, Et2O or CPME as a solvent provided a slightly
lower ee. However, slow addition of the substrate over five hours
to the reaction mixture in t-BuOMe increased the enantiomeric
excess significantly (Table 3, entry 4). Notably, the use of THF
resulted in a very low enantiomeric excess, probably due to
coordination with the copper-catalyst or a shift in the Schlenk
equilibrium to monomeric EtMgBr species. This dependence is in
contrast to that reported by Charette et al. for the conjugate
addition of organozinc reagents in which an
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Catalytic Asymmetric Conjugate Addition of Grignard Reagents to
α,β-Unsaturated Sulfones
increase in enantioselectivity was observed with THF as the
solvent using a different catalytic system.45
Table 3 Solvent dependence in the addition of EtMgBr to sulfone
34a.a, b
Entry Solvent eec,d (%)
1 DCM 87 (+) 2 Toluene 80 (+) 3 t-BuOMe 88 (+) 4 t-BuOMee 92 (+)
5 THF 8 (−) 6 Et2O 76 (+) 7 CPMEf 68 (+)
a Conditions: 34a (1 eq., 0.1 mmol) was added to EtMgBr (1.2
eq.), CuI (5 mol %), L2 (6 mol %) in solvent at 40 oC, 16 h.b Full
conversion after 16 h, determined by GC-MS. c Determined by chiral
HPLC (see Experimental Section).d The absolute configuration of the
product is not known. e Slow addition of the substrate solution
over 5 h. f CPME = cyclopentyl methyl ether.
2.3.3 Optimization of the copper salt With the exception of
copper(I)cyanide, which gave a lower enantiomeric excess, all
copper(I)- and copper(II)-salts tested provided similar results in
the conjugate addition reaction of EtMgBr to sulfone 34a (Table 4).
In all cases full conversion was obtained after 16 h and no
significant effect of the change in counterion (except for CN) was
observed. Slow addition of the substrate solution to the reaction
mixture increased the enantioselectivity in the case of CuI (Table
4, entries 4 and 5) while copper(I)chloride gave rise to
quantitative conversion and excellent enantiomeric excess (93% ee)
even with faster addition times (Table 4, entries 6 and 7).
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Chapter 2
Table 4 Influence of the copper salt on the addition of EtMgBr
to sulfone 34a.a, b
Entry Copper salt eec,d (%)
1 CuCN 69 (+) 2 CuBr·Me2S 89 (+) 3 Cu(OTf)2 87 (+) 4 CuI 88 (+)
5 CuIe 92 (+) 6 CuCl 93 (+) 7 CuCle 93 (+)
a Conditions: 34a (1 eq., 0.1 mmol in t-BuOMe) added directly to
EtMgBr (1.2 eq.), Cu salt (5 mol %), L2 (6 mol %) in t-BuOMe at 40
oC, 16 h.b Full conversion after 16 h, determined by GC-MS. c
Determined by chiral HPLC (see Experimental Section).d The absolute
configuration of the product is not known. e Slow addition of
substrate over 5 h.
2.3.4 Optimization of copper/ligand ratio Increasing the metal
to ligand ratio from 1:1 to 2:1 results in a decrease in
enantioselectivity (Table 5). We attribute this to the fact that
not all of the copper is bound to the ligand, giving rise to a
significant amount of ligand-free copper mediated reaction. It was
found that a small excess of ligand with respect to the copper gave
the best result (Table 5, entry 4). Increasing the ligand to metal
ratio further (Table 5, entry 3) did not improve the
enantioselectivity. Table 5 Influence of the copper to ligand ratio
on the addition of EtMgBr to sulfone 34a.a, b
Entry CuCl (mol%) L2 (mol%) [Cu]:L2 eec,d (%)
1 5 5 1:1 83 (+) 2 10 5 2:1 62 (+) 3 5 10 1:2 85 (+) 4 5 6 1:1.2
93 (+)
a Conditions: 34a (1 eq., 0.1 mmol in t-BuOMe) was added
directly to EtMgBr (1.2 eq.), CuCl and L2 in t-BuOMe at 40 oC, 16
h.b Full conversion after 16 h, determined by GC-MS. c Determined
by chiral HPLC (see Experimental Section).d The absolute
stereochemistry of the product is not known.
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Catalytic Asymmetric Conjugate Addition of Grignard Reagents to
α,β-Unsaturated Sulfones
2.3.5 Scope of Grignard reagents Several Grignard reagents were
examined using the conditions optimized for EtMgBr (Table 6). In
all cases full conversion was observed after 16 h and high isolated
yields were obtained. Excellent ee’s were obtained for alkyl
Grignard reagents (Table 6, entries 1-5). With MeMgBr a slightly
lower enantiomeric excess and yield were attained. Both n-BuMgBr
and C6H5C2H4MgBr gave similar enantioselectivities and a slightly
lower yield (Table 6, entries 3 and 4). Furthermore, the use of
but-3-enylmagnesium bromide also resulted in excellent yield and
enantioselectivity (Table 6, entry 5). This functionalized Grignard
reagent provides an additional handle for further
functionalization.46 Notably, the reaction using PhMgBr did not
proceed in an enantioselective manner (Table 6, entry 6). Table 6
Asymmetric conjugate addition of various Grignard reagents to
sulfone 34a.a, b
Entry R Product Yieldc (%) eed, e (%)
1 Et 35a 97 93 (+) 2 Me 35b 80 89 (−) 3 n-Bu 35c 88 93 (+) 4
C6H5C2H4 35d 87 87 (−) 5 But-3-enyl 35e 95 94 (+) 6 Ph 35f 80 0
a Conditions: 34a (1 eq., 0.4 M in t-BuOMe) added over 5 h to
RMgBr (1.2 eq.), CuCl (5 mol%), L2 (6 mol%) in t-BuOMe at 40 oC, 16
h.b Full conversion after 16 h, determined by GC-MS. c Isolated
yields. d Determined by chiral HPLC (see Experimental Section).e
The absolute configuration of the product is not known.
2.3.6 Scope of ,-unsaturated sulfones The synthetic
applicability of this highly enantioselective procedure was
extended using a set of ,-unsaturated substrates under the
optimized conditions (Table 7). All sulfones provided the desired
products in excellent yields (88-97%) and excellent
enantioselectivities (88-94%). Substitution of the ,-unsaturated
sulfone at the - or -position did not influence the
enantioselectivities or yields (Table 7, entry 1 to 5) and the
reactions proceed with both excellent yields and enantiomeric
excesses. The presence of a protected alcohol group (Table 7, entry
6) or phenyl group at the -position in the substrate (Table 7,
entry 7) did not affect this enantioselective transformation either
and the reactions
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24
Chapter2-Final-nocode.docx
Chapter 2
resulted in high isolated yields of optically active
-disubstituted sulfones with excellent ee’s. Table 7 Asymmetric
conjugate addition of EtMgBr to ,-unsaturated sulfones.a, b
Entry 34 R Product Yieldc (%) eed, e (%)
1 34a n-Pent 35a 97 93 (+) 2 34b n-Oct 36 90 92 (+) 3 34c i-Bu
37 88 94 (−) 4 34d i-Pr 38 93 88 (−) 5 34e c-Hex 39 94 94 (−) 6 34f
TBDPSOC2H4 40 91 92 (+) 7 34g C6H5C2H4 41 91 93 (+)
a Conditions: 34 (0.2 mmol, 1 eq., 0.4 M in t-BuOMe) added over
5 h to EtMgBr (1.2 eq.), CuCl (5 mol%), L2 (6 mol%) in t-BuOMe at
40 oC, 16 h.b Full conversion after 16 h, determined by GC-MS. c
Isolated yields. d Determined by chiral HPLC (see Experimental
Section).e The absolute configuration of the product is not
known.
2.3.7 The influence of the 2-pyridyl group and limitations of
the system The influence of the 2-pyridyl group was examined by
applying the asymmetric conjugate addition to the corresponding
p-tolyl substituted ,-unsaturated sulfone 42 instead of 2-pyridyl
substituted sulfone 34a (Scheme 10).
Scheme 10 Asymmetric conjugate addition of EtMgBr to sulfone 42.
In this experiment the reaction rate and enantiomeric excess
decreased dramatically. This effect of the 2-pyridyl group has also
been noted by Carretero19, 41, 44, 47 and Charette45 and co-workers
for related systems. As already mentioned in section 2.1.3-2.1.5,
the 2-pyridyl group seems to be necessary both in terms of
enantioselectivity and reactivity.
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Catalytic Asymmetric Conjugate Addition of Grignard Reagents to
α,β-Unsaturated Sulfones
A limitation of this methodology is that ,-unsaturated sulfones
substituted with a phenyl group at the β-position unfortunately
give only moderate ee’s under the optimized conditions (Table 8).
Table 8 Asymmetric conjugate addition of EtMgBr to vinyl phenyl
sulfones.a, b
Entry R Product Yieldc (%) eed (%)
1 H 33a 75 47 (R) 2 CF3 33b 65 51e 3 Br 33c 76 70e
a Conditions: 34a (1 eq.,0.4 M in t-BuOMe) added over 5 h to
EtMgBr (1.2 eq.), CuCl (5 mol%), L2 (6 mol%) in t-BuOMe at 40 oC,
16 h.b Full conversion after 16 h, determined by GC-MS. c Isolated
yields. d Determined by chiral HPLC.e The absolute configuration of
the product is not known.
2.4 Conclusion In summary, we have developed a novel
copper-catalyzed asymmetric conjugate addition reaction of Grignard
reagents to a range of aliphatic ,-unsaturated sulfones. This
procedure has a broad scope for aliphatic substrates and provides
-substituted 2-pyridylsulfones in both excellent yields (88-97%)
and enantioselectivities (88-94%). These enantioenriched sulfones
are versatile intermediates in the preparation of a wide variety of
functionalized chiral building blocks.
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Chapter2-Final-nocode.docx
Chapter 2
2.5 Experimental section General Chromatography: Merck silica
gel type 9385 230-400 mesh, TLC: Merck silica gel 60, 0.25 mm.
Components were visualized by staining with a solution of a mixture
of KMnO4 (10 g) and K2CO3 (10 g) in H2O (500 mL). Progress and
conversion of the reaction were determined by GC-MS (GC, HP6890: MS
HP5973) with an HP1 or HP5 column (Agilent Technologies, Palo Alto,
CA). Mass spectra were recorded on a AEI-MS-902 mass spectrometer
(EI+) or a LTQ Orbitrap XL (ESI+). 1H- and 13C-NMR were recorded on
a Varian AMX400 (400 and 100.59 MHz, respectively) or a Varian
VXR300 (300 and 75 MHz, respectively) using CDCl3 as solvent.
Chemical shift values are reported in ppm with the solvent
resonance as the internal standard (CHCl3: 7.26 for 1H, 77.0 for
13C). Data are reported as follows: chemical shifts, multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m
= multiplet), coupling constants (Hz), and integration. Carbon
assignments are based on APT 13C-NMR experiments. Optical rotations
were measured on a Schmidt + Haensch polarimeter (Polartronic MH8)
with a 10 cm cell (c given in g/100 mL). Enantioselectivities were
determined by HPLC analysis using a Shimadzu LC-10ADVP HPLC
equipped with a Shimadzu SPD-M10AVP diode array detector. Elemental
analysis was performed on a EuroVector Euro EA-3000 Elemental
Analyzer. All reactions were carried out under a nitrogen
atmosphere using flame dried glassware. t-BuOMe was purchased as
anhydrous grade, stored on 4Å MS and used without further
purification. All copper-salts and chiral ligands (L2-L5) were
purchased from Aldrich or Acros and used without further
purification. Grignard reagents were purchased from Aldrich
(MeMgBr, EtMgBr) or prepared from the corresponding alkylbromides
and magnesium turnings in Et2O following standard procedures.
Grignard reagents were titrated using s-BuOH and catalytic amounts
of 1,10-phenanthroline. Racemic 1,4-addition products were
synthesized by reaction of the ,-unsaturated sulfones (32a-c,
34a-g) with the corresponding Grignard reagent at –40 °C in THF in
the presence of a stoichiometric amount of CuI.
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27
Chapter2-Final-nocode.docx
Catalytic Asymmetric Conjugate Addition of Grignard Reagents to
α,β-Unsaturated Sulfones
Synthesis of 2-(methylsulfonyl)pyridine19
To a solution of 2-mercaptopyridine (11.11 g, 100 mmol) in dry
THF (200 mL) and acetonitrile (20 mL), cooled to 0 oC, DBU (16.75
g, 110 mmol) was added. The resulting mixture was stirred at 0 oC
for 5 min before methyl iodide (15.61 g, 110 mmol) was added
slowly. The ice bath was removed and the mixture was stirred
overnight. The reaction mixture was washed with water (100 mL) and
the aqueous layer was extracted with ethyl acetate (3 x 100 mL).
The combined organic layers were dried (MgSO4), filtered and
concentrated. The residue was purified by flash chromatography
(n-hexane/ethyl acetate, 2:1) to afford the methyl 2-pyridyl
sulfide (A) as a colorless oil; yield: 12.26 g (98%). 1H-NMR (300
MHz): 8.42 (m, 1H), 7.47 (m, 1H), 7.16 (m, 1H), 6.96 (m, 1H), 2.55
(s, 3H). 13C-NMR (75 MHz): 159.9, 149.3, 135.6, 121.3, 119.0, 13.1.
To a solution of A (12.26 g, 98 mmol) in ethyl acetate (125 mL)
were added H2O (15 mL) and Na2WO4·2H2O (3.23 g, 9.8 mmol). The
resulting mixture was cooled to 0 ºC before an aqueous solution of
H2O2 (3 eq, 30%, 30 mL, 294 mmol) was added dropwise. The reaction
mixture was stirred at 0 oC for 30 min and at rt for 1 h, cooled to
0 oC and saturated aqueous NaHSO3 (25 mL) was added slowly. The
organic layer was separated and the aqueous layer was extracted
with ethyl acetate (2 x 50 mL). The combined organic layers were
dried (NaSO4), filtered and concentrated. The residue was purified
by flash chromatography (n-hexane/ ethyl acetate, 2:1) to afford
the sulfone as a colorless oil; yield: 14.35 g (93%). 1H-NMR (300
MHz): 8.77-8.70 (m, 1H), 8.12-7.89 (m, 2H), 7.62-7.49 (m, 1H), 3.21
(s, 3H). 13C-NMR (75 MHz): 157.8, 149.9, 138.3, 127.4, 121.0, 39.9.
General procedure for the synthesis of ,-unsaturated sulfones
(34a-g) To a solution of 20 mmol of 2-(methylsulfonyl)pyridine
(3.14 g) in dry THF (40 mL), cooled to 78 oC, a 1.6 M solution of
n-BuLi in hexane (13.75 mL, 22 mmol, 1.1 eq) was added. The mixture
was stirred at 78 oC for 30 min followed by addition of the
aldehyde (22 mmol, 1.1 eq.) at 78 oC and the reaction mixture was
slowly warmed to room temperature. The reaction mixture was
quenched with saturated aqueous NH4Cl (25 mL). The organic layer
was separated and the aqueous layer was extracted with ethyl
acetate (3 x 50 mL). The combined organic layers were dried with
Na2SO4, filtered and concentrated in vacuo. Generally, the crude
alcohol can be used without further purification for the next
dehydration step. If the resulting 2-pyridylsulfonylalcohol was not
completely pure, a simple flash chromatography on silica gel
(pentane/Et2O) of this intermediate was performed before the
dehydration step. The crude alcohol was dissolved in dry DCM
(150
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28
Chapter2-Final-nocode.docx
Chapter 2
mL) under nitrogen atmosphere and 80 mmol of DMAP (9.77 g, 4
eq.) was added and the reaction mixture was cooled down to 0 oC.
Subsequently, 40 mmol of methanesulfonyl chloride (4.58 g, 2 eq.)
was added and the mixture was stirred while slowly warming to room
temperature overnight. The reaction mixture was quenched with
saturated aqueous NH4Cl (100 mL). The layers were separated and the
aqueous layer was extracted with DCM (3 x 50 mL). The combined
organic layers were dried with Na2SO4, filtered and the solvent
evaporated in vacuo. The crude product was purified by flash
chromatography on silica gel (Pentane:Et2O 2:1-1:1) to yield the
pure ,-unsaturated sulfone. (E)-2-(Styrylsulfonyl)pyridine
(32a)45
White solid, yield: 67%. Mp: 101.6 oC. 1H NMR (400 MHz, CDCl3)
8.75 (br d, J = 4.7 Hz, 1H), 8.15 (dt, J= 7.7, 0.9 Hz, 1H), 7.96
(dt, J = 7.7, 7.7, 1.5 Hz, 1H), 7.79 (d, J = 15.5 Hz, 1H),
7.63-7.58 (m, 3H), 7.46 – 7.38 (m, 3H), 7.12 (d, J = 15.5 Hz, 1H).
13C NMR (100 MHz, CDCl3): 158.5 (s), 150.4 (d), 145.1 (d), 138.2
(d), 132.3 (s), 131.4 (d), 129.1 (d), 128.8 (d),
127.1 (d), 124.5 (d), 121.9 (d). HRMS (EI+, m/z): calcd. for
C13H11NO2S [M]+: 245.0510; found: 245.0502. Anal. Calcd for
C13H11NO2S: C, 63.65; H, 4.52; N, 5.71; S, 13.04. Found: C, 63.43;
H, 4.57; N, 5.50; S, 13.05. (E)-2-(Hept-1-enylsulfonyl)pyridine
(34a)47, 48
Colorless oil, yield: 75%. 1H NMR (400 MHz, CDCl3): 8.73 (d, J =
4.1 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.94 (dt, J = 7.8, 7.8, 1.7
Hz, 1H), 7.51 (ddd, J = 7.6, 4.7, 0.9 Hz, 1H), 7.12 (td, J = 15.1,
6.8, 6.8 Hz, 1H), 6.53 (td, J = 15.2, 1.6, 1.6 Hz, 1H) 2.28 (dq, J
= 6.8, 1.6 Hz, 2H), 1.54-1.43 (m, 2H), 1.36-1.20 (m, 4H), 0.9-0.8
(m, 3H).
13C NMR (100 MHz, CDCl3): 158.4, 150.6, 150.2, 138.2, 127.4,
127.1, 121.9, 31.8, 31.1, 27.1, 22.3, 13.9. The physical and
spectroscopic properties were in accordance with those described in
literature. (E)-2-(Dec-1-enylsulfonyl)pyridine (34b)
Colorless oil, yield: 50%. 1H NMR (400 MHz, CDCl3): 8.71 (d, J =
4.6 Hz, 1H), 8.06 (dd, J = 7.9, 0.7 Hz, 1H), 7.86 ( td, J = 7.6,
1.6 Hz, 1H), 7.50 (dd, J = 7.6, 4.7 Hz, 1H), 7.10 (dt, J = 14.8,
6.8 Hz, 1H), 6.52 (dd, J = 15.2, 0.6 Hz, 1H), 2.27 (dd, J = 14.0,
6.9 Hz, 2H), 1.50-1.40
(m, 2H), 1.35-1.12 (m 10H), 0.84 (m, 3H). 13C NMR (100 MHz,
CDCl3): 158.5 (s), 150.3
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29
Chapter2-Final-nocode.docx
Catalytic Asymmetric Conjugate Addition of Grignard Reagents to
α,β-Unsaturated Sulfones
(d), 150.2 (d), 138.1 (d), 127.5 (d), 127.0 (d), 121.7 (d), 31.7
(t), 31.7 (t), 29.1 (t), 29.0 (t), 28.9 (t), 27.4 (t), 22.5 (t),
14.0 (q). HRMS (ESI+, m/z): calcd. for C15H24NO2S [M+H]+,
282.15223; found, 282.15232.
(E)-2-(4-Methylpent-1-enylsulfonyl)pyridine (34c)
Colorless oil, yield: 53%. 1H NMR (400 MHz, CDCl3): 8.70 (dd, J
= 2.8, 1.9 Hz, 1H), 8.05 (dd, J = 7.9, 1.0 Hz, 1H), 7.92 (tt, J =
7.8, 7.8, 1.9, 1.9 Hz, 1H), 7.49 (dddd, J = 7.8, 4.7, 2.0, 1.2 Hz,
1H), 7.05 (dtd, J = 9.8, 7.5, 7.5, 2.3 Hz, 1H), 6.50 (m, 1H),
2.2-2.1 (m, 2H), 1.79 (m, 1H), 0.89 (dd, J = 6.7, 2.3 Hz, 6H). 13C
NMR (100 MHz, CDCl3): 158.4 (s), 150.2 (d), 149.1
(d), 138.1 (d), 128.5 (d), 127.0 (d), 121.7 (d), 40.7 (t), 27.5
(d), 22.1 (q). HRMS (EI+, m/z): calcd. for C11H15NO2S [M]+,
224.0745; found, 224.0734.
(E)-2-(3-Methylbut-1-enylsulfonyl)pyridine (34d)47, 48
Colorless oil, yield: 62%. 1H NMR (400 MHz, CDCl3): 8.72 (dd, J
= 4.7, 0.8 Hz, 1H), 8.07 (dd, J = 7.9, 0.8 Hz, 1H), 7.93 (tt, J =
7.8, 7.8, 1.5, 1.5 Hz, 1H), 7.60-7.42 (m, 1H), 7.09 (ddd, J = 15.3,
6.2, 1.5 Hz, 1H), 6.49 (td, J = 15.3, 1.5, 1.5 Hz, 1H), 2.55 (m,
1H), 1.08 (dd, J = 6.8, 1.5 Hz, 6H). 13C NMR (100 MHz, CDCl3):
158.5 (s), 155.8 (d), 150.2 (d), 138.1 (d), 127.0 (d),
125.4 (d), 121.8 (d), 30.9 (d), 20.7 (q). HRMS (EI+, m/z):
calcd. for C9H10NO2S [M – CH3]+: 196.0432; found: 196.0422.
(E)-2-(2-Cyclohexylvinylsulfonyl)pyridine (34e)
Colorless oil, yield: 41%. 1H NMR (400 MHz, CDCl3): 8.70 (br d,
J = 4.1 Hz, 1H), 8.05 (td, J = 7.9, 0.8, 0.8 Hz, 1H), 7.92 (dt, J =
7.8, 7.7, 1.7 Hz, 1H), 7.49 (ddd, J = 7.7, 4.7, 0.9 Hz, 1H), 7.04
(dd, J = 15.3, 6.3 Hz, 1H), 6.5 (dd, J = 15.3, 1.4 Hz, 1H), 2.21
(m, 1H), 1.86-1.68 (m, 4H), 1.68-1.59 (m, 1H), 1.33-1.06 (m, 5H).
13C NMR (100 MHz, CDCl3): 158.5 (s), 154.5
(d), 150.2 (d), 138.1 (d), 126.9 (d), 125.6 (d), 121.7 (d), 40.1
(d), 31.1 (t), 25.6 (t), 25.5 (t). HRMS (EI+, m/z): calcd. for
C13H16NO2S [M – H]+: 250.0902; found: 250.0915.
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30
Chapter2-Final-nocode.docx
Chapter 2
(E)-2-(4-(tert-Butyldiphenylsilyloxy)but-1-enylsulfonyl)pyridine
(34f) Colorless oil, yield: 58%. 1H NMR (400 MHz, CDCl3): 8.70 (m,
1H), 8.09 (br d, J = 7.8 Hz, 1H), 7.91 (dt, J = 7.9, 7.8, 1.8 Hz,
1H), 7.61 (dd, J = 7.8, 1.4 Hz, 4H), 7.54-7.45 (m, 1H), 7.46-7.29
(m, 6H), 7.15 (td, J = 15.2, 6.8, 6.8 Hz, 1H), 6.68 (td, J = 15.2,
1.4, 1.4 Hz, 1H), 3.79 (t, J = 6.0, 6.0 Hz, 2H), 2.51 (dq, J = 6.3,
6.2, 6.2, 1.3 Hz, 2H), 0.96 (s, 9H).
13C NMR (100 MHz, CDCl3): 158.4 (s), 150.3 (d), 146.8 (d), 138.0
(d), 135.4 (d), 133.2 (s), 129.7 (d), 129.3 (d), 127.7 (d), 127.0
(d), 121.8 (d), 61.4 (t), 34.8 (t), 26.6 (q), 19.0 (s). HRMS (EI+,
m/z): calcd. for C21H20NO3SiS [M–C4H9]+: 394.0933; found: 394.0945.
(E)-2-(4-Phenylbut-1-enylsulfonyl)pyridine (34g)49
White solid, yield: 48%. Mp: 106.6 oC (Lit: 96-98 oC).49 1H NMR
(400 MHz, CDCl3): 8.72 (d, J = 4.6 Hz, 1H), 8.05 (dd, J = 7.8, 0.7
Hz, 1H), 7.93 (dt, J = 7.7, 7.7, 1.5 Hz, 1H), 7.69-7.37 (m, 1H),
7.28-7.13 (m, 6H), 6.68-6.41 (m, 1H), 2.8 (t, J = 7.6 Hz, 2H), 2.61
(q, J = 7.6 Hz, 2H). 13C NMR (100 MHz, CDCl3): 158.4 (s), 150.2
(d),
148.8 (d), 139.9 (s), 138.1 (d), 128.5 (d), 128.4 (d), 128.3
(d), 127.0 (d), 126.3 (d), 121.8 (d), 33.7 (t), 33.4 (t). HRMS
(ESI+, m/z): calcd. for C15H16NO2S [M+H]+: 274.08963; found:
274.08962. Anal. Calcd for C15H15NO2S: C, 65.91; H, 5.53; N, 5.12.
Found: C, 65.65; H, 5.63; N, 4.92. General procedure for the
asymmetric conjugate addition of Grignard reagents to ,-unsaturated
sulfones CuCl (12.5 mol, 1.24 mg, 5 mol%) and (R)-(+)-Tol-Binap
(L2, 15.0 mol, 10.18 mg, 6 mol%) were dissolved in 4 mL of dry
t-BuOMe under a nitrogen atmosphere. The mixture was stirred for 15
min and cooled down to 40 oC and the Grignard reagent (1.2 eq) was
added. After stirring for 15 min, the substrate (0.25 mmol,
dissolved in 0.5 mL of t-BuOMe) was added over 5 h and the mixture
was stirred overnight. Aqueous saturated NH4Cl solution (2 mL) was
added and the mixture was warmed up to room temperature. The
mixture was diluted with Et2O and the layers were separated. The
aqueous layer was extracted with DCM (3 x 10 mL) and the combined
organic layers were dried with anhydrous Na2SO4, filtered and the
solvent evaporated in vacuo. The crude product was purified by
flash chromatography on silica (Pentane: Et2O, 4:1-1:1) to afford
the products as colorless to pale yellow oils.
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31
Chapter2-Final-nocode.docx
Catalytic Asymmetric Conjugate Addition of Grignard Reagents to
α,β-Unsaturated Sulfones
(+)-2-(2-Ethylheptylsulfonyl)pyridine (35a) Following the
general procedure for the asymmetric Cu-catalyzed conjugate
addition, 35a was isolated in 97% yield. Enantiomeric excess: 93%
determined by chiral HPLC analysis, Chiralpak AD column, 1.0
mL/min, n-heptane: i-PrOH 99:1, 40 oC, 210 nm, retention times
(min): 32.5 (minor) and 38.5 (major). []D = +2.8 (c 1.0,
CHCl3). 1H NMR (400 MHz, CDCl3): 8.74 (ddd, J = 4.7, 1.7, 0.9
Hz, 1H), 8.10 (td, J = 7.8, 1.0, 1.0 Hz, 1H), 7.96 (td, J = 7.8,
1.0, 1.0 Hz, 1H), 7.54 (ddd, J = 7.7, 4.7, 1.2 Hz, 1H), 3.33 (d, J
= 6.1 Hz, 2H), 2.02-1.92 (m, 1H), 1.56-1.42 (m, 2H), 1.43-1.34 (m,
2H), 1.31-1.10 (m, 6H), 0.84 (dt, J = 7.4, 7.2, 5.9 Hz, 6H). 13C
NMR (100 MHz, CDCl3): 157.9 (s), 150.2 (d), 138.1 (d), 127.2 (d),
121.9 (d), 55.2 (t), 34.0 (d), 32.5 (t), 31.8 (t), 25.6 (t) 25.5
(t), 22.5 (t), 14.0 (q), 10.1 (q). HRMS (EI+, m/z): calcd. for
C12H18NO2S [M - C2H5]+: 240.1058; found: 240.1068.
()-2-(2-Methylheptylsulfonyl)pyridine (35b)
Following the general procedure for the asymmetric Cu-catalyzed
conjugate addition, 35b was isolated in 80% yield. Enantiomeric
excess: 89% determined by chiral HPLC analysis, Chiralcel OD-H 0.5
mL/min, n-heptane: i-PrOH 98:2, 40 oC, 210 nm, retention times
(min): 46.9 (minor) and 49.1 (major). []D = 1.4 (c 1.0, CHCl3).
1H
NMR (400 MHz, CDCl3): 8.75 (d, J = 4.6 Hz, 1H), 8.10 (dd, J =
7.8, 0.9 Hz, 1H), 7.96 (tt, J = 7.6, 1.4Hz, 1H), 7.55 (dd, J = 6.9,
4.7 Hz, 1H), 3.43 (dd, J = 14.2, 4.6 Hz, 1H), 3.20 (dd, J = 14.2,
8.0 Hz, 1H), 2.13 (qt, J = 13.7, 13.7, 6.9, 6.8, 6.8 Hz, 1H), 1,
1.48-1.12 (m, 8H), 1.06 (d, J = 6.7 Hz, 3H), 0.85 (t, J = 7.0, 7.0
Hz, 3H). 13C NMR (100 MHz, CDCl3): 158.0 (s), 105.2 (d), 138.1 (d),
127.2 (d), 121.9 (d), 57.9 (t), 36.6 (t), 31.6 (t), 28.2 (d), 26.0
(t), 22.5 (t), 19.8 (q), 14.0 (q). HRMS (EI+, m/z): calcd. for
C12H18NO2S [M – CH3]+: 240.1058; found: 240.1070.
(+)-2-(2-Butylheptylsulfonyl)pyridine (35c)
Following the general procedure for the asymmetric Cu-catalyzed
conjugate addition, 35c was isolated in 88% yield. Enantiomeric
excess: 93% determined by chiral HPLC analysis, Chiralpak AD-H 0.5
mL/min, n-heptane: i-PrOH 98:2, 40 oC, 210 nm, retention times
(min): 35.0 (minor) and 36.7 (major). []D = +9.2 (c 1.0, CHCl3).
1H
NMR (400 MHz, CDCl3): 8.74 (ddd, J = 4.6, 1.5, 0.8 Hz, 1H), 8.09
(td, J = 7.8, 1.0, 1.0
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32
Chapter2-Final-nocode.docx
Chapter 2
Hz, 1H), 7.95 (dt, J = 7.8, 7.8, 1.7 Hz, 1H), 7.54 (ddd, J =
7.6, 4.7, 1.2 Hz, 1H), 3.33 (d, J = 6.1 Hz, 2H), 2.06-1.95 (m, 1H),
1.50-1.30 (m, 4H), 1.30-1.10 (m, 10H), 0.84 (t, J = 7.0, 7.0 Hz,
6H). 13C NMR (100 MHz, CDCl3): 158.0 (s), 150.1 (d), 138.1 (d),
127.2 (d), 122.0 (d), 55.6 (t), 33.1 (t), 32.8 (t), 32.7 (d), 31.8
(t), 28.0 (t) 25.5 (t), 22.6 (t), 22.5 (t), 14.0 (q), 13.9 (q).
HRMS (EI+, m/z): calcd. for C12H18NO2S [M–C4H9]+: 240.1058; found:
240.1069. ()-2-(2-Phenethylheptylsulfonyl)pyridine (35d)
Following the general procedure for the asymmetric Cu-catalyzed
conjugate addition, 35d was isolated in 87% yield. Enantiomeric
excess: 87% determined by chiral HPLC analysis, Chiralcel OD-H, 0.5
mL/min, n-heptane: i-PrOH 97:3, 40 oC, 210 nm, retention times
(min): 53.6 (major) and 57.1 (minor). []D = 9.8 (c 1.0, CHCl3). 1H
NMR (400 MHz, CDCl3): 8.76-8.73 (m, 1H), 8.04 (dq, J = 7.6, 0.8 Hz,
1H), 7.93 (tdd, J = 7.8, 7.8, 1.7, 0.8 Hz,
1H), 7.53 (ddt, J = 7.6, 4.8, 1.0 Hz, 1H), 7.31-7.21 (m, 2H),
7.21-7.07 (m, 3H), 3.40 (t, J = 5.6, 5.6 Hz, 2H), 2.58 (t, J = 8.1,
8.1 Hz, 2H), 2.12-1.96 (m, 1H), 1.92-1.66 (m, 2H), 1.54-1.38 (m,
2H), 1.36-1.05 (m, 6H), 0.86 (t, J = 7.1, 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3): 157.1 (s), 150.2 (d), 141.7 (s), 138.1 (d), 128.3 (d),
127.2 (d), 125.8 (d), 122.1 (d), 55.4 (t), 34.9 (t), 33.0 (t), 32.4
(d), 32.3 (t), 31.7 (t), 25.4 (t), 22.5 (t), 14.0 (q). HRMS (ESI+,
m/z): calcd. for C20H28NO2S [M+H]+: 346.18353; found: 346.18350.
(+)-2-(2-(But-3-enyl)heptylsulfonyl)pyridine (35e)
Following the general procedure for the asymmetric Cu-catalyzed
conjugate addition, 35e was isolated in 95% yield. Enantiomeric
excess: 94% determined by chiral HPLC analysis, Chiralpak AD-H, 0.5
mL/min, n-heptane: i-PrOH 98.5:1.5, 40 oC, 210 nm, retention times
(min): 53.0 (minor) and 54.4 (major). []D = +3.0 (c 1.0, CHCl3). 1H
NMR (400 MHz, CDCl3): 8.76-8.73 (m,
1H), 8.09 (dq, J = 7.8, 1.9, 1.0 Hz, 1H), 7.96 (ddt, J = 7.8,
7.8, 1.7, 0.9 Hz, 1H), 7.54 (tdd, J = 7.6, 4.7, 0.9, 0.9 Hz, 1H),
5.71 (tdd, J = 16.9, 10.2, 6.6, 6.6 Hz, 1H), 5.06-4.80 (m, 2H),
3.35 (dd, J = 6.0, 2.4 Hz, 2H), 2.15-1.91 (m, 3H), 1.62-1.33 (m,
4H), 1.32-1.09 (m, 6H), 0.84 (t, J = 7.1, 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3): 157.8 (s), 150.2 (d), 138.1 (d), 138.0 (d), 127.2 (d),
122.0 (d), 114.9 (t), 55.4 (t), 32.9 (t), 32.3 (t), 32.2 (d), 31.7
(t), 30.2 (t), 25.4 (t), 22.5 (t), 14.0 (q). HRMS (ESI+, m/z):
calcd. for C16H26NO2S [M+H]+: 296.16788; found: 296.16782.
SO
ON
35e
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33
Chapter2-Final-nocode.docx
Catalytic Asymmetric Conjugate Addition of Grignard Reagents to
α,β-Unsaturated Sulfones
2-(2-Phenylheptylsulfonyl)pyridine (35f)45 Following the general
procedure for the asymmetric Cu-catalyzed conjugate addition, 35f
was isolated as a white solid in 80% yield. Enantiomeric excess: 0%
determined by chiral HPLC analysis, Chiralpak AD, 1.0 mL/min,
n-heptane: i-PrOH 97:3, 40 oC, 210 nm, retention times (min): 23.8
and 25.7. M.p.: 85-87 oC. 1H NMR (400 MHz, CDCl3): 8.63-8.48 (m,
1H), 7.76-7.63 (m, 2H),
7.40-7.31 (m, 1H), 7.11-6.94 (m, 5H), 3.95 (dd, J = 14.6, 8.8
Hz, 1H), 3.56 (dd, J = 14.6, 5.3 Hz, 1H), 3.30-3.19 (m, 1H),
1.88-1.72 (m, 1H), 1.69-1.55 (m, 1H), 1.39-0.84 (m, 6H), 0.80 (t, J
= 6.6, 6.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): 157.5 (s), 149.8 (d),
141.4 (s), 137.6 (d), 128.3 (d), 127.8 (d), 126.7 (d), 126.6 (d),
122.1 (d), 57.8 (t), 40.7 (d), 36.4 (t), 31.4 (t), 26.6 (t), 22.4
(t), 13.9 (q). HRMS (ESI+, m/z): calcd. for C18H24NO2S [M+H]+:
318.15223; found: 318.15210. (+)-2-(2-Ethyldecylsulfonyl)pyridine
(36)
Following the general procedure for the asymmetric Cu-catalyzed
conjugate addition, 36 was isolated in 90% yield. Enantiomeric
excess: 92% determined by chiral HPLC analysis, Chiralpak AD, 1.0
mL/min, n-heptane: i-PrOH 99:1, 40 oC, 210 nm, retention times
(min): 25.8
(minor) and 30.1 (major). []D = +4.6 (c 1.0, CHCl3). 1H NMR (400
MHz, CDCl3): 8.73 (d, J = 4.6 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H),
7.95 (dt, J = 7.8, 7.8, 1.7 Hz, 1H), 7.53 (ddd, J = 7.6, 4.7, 1.0
Hz, 1H), 3.32 (d, J = 6.1 Hz, 2H), 2.02-1.90 (m, 1H), 1.57-1.41 (m,
2H), 1.42-1.31 (m, 2H), 1.30-1.11 (m, 12H), 0.94-0.74 (m, 6H). 13C
NMR (100 MHz, CDCl3): 157.9 (s), 150.1 (d), 138.1 (d), 127.2 (d),
121.9 (d), 55.2 (t), 33.9 (d), 32.6 (t), 31.8 (t), 29.6 (t), 29.4
(t), 29.2 (t), 25.8 (t), 25.6 (t), 22.6 (t), 14.0 (q), 10.1 (q).
HRMS (EI+, m/z): calcd. for C15H24NO2S [M–C2H5]+: 282.1528; found:
282.1535. ()-2-(2-Ethyl-4-methylpentylsulfonyl)pyridine (37)
Following the general procedure for the asymmetric Cu-catalyzed
conjugate addition, 37 was isolated in 88% yield. Enantiomeric
excess: 94% determined by chiral HPLC analysis, Chiralcel OD-H, 0.5
mL/min, n-heptane: i-PrOH 98:2, 40 oC, 210 nm, retention times
(min): 40.8 (major) and 46.7
(minor). []D = 6.2 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): 8.74
(br d, J = 4.5 Hz, 1H), 8.09 (br d, J = 7.8 Hz, 1H), 7.95 (dt, J =
7.8, 7.8, 1.7 Hz, 1H), 7.54 (ddd, J = 7.6, 4.7, 1.1 Hz, 1H),
3.34-3.27 (m, 2H), 2.07-1.95 (m, 1H), 1.62-1.40 (m, 3H), 1.22 (t, J
= 7.1, 7.1
SO
ON
37
-
34
Chapter2-Final-nocode.docx
Chapter 2
Hz, 2H), 0.85-0.75 (m, 9H). 13C NMR (100 MHz, CDCl3): 157.9 (s),
150.1 (d), 138.1 (d), 127.2 (d), 122.0 (d), 55.4 (t), 42.5 (t),
31.7 (d), 25.8 (t), 24.9 (d), 22.6 (q), 22.3 (q), 9.7 (q). HRMS
(EI+, m/z): calcd. for C12H18NO2S [M–CH3]+: 240.1058; found:
240.1065. ()-2-(2-Ethyl-3-methylbutylsulfonyl)pyridine (38)
Following the general procedure for the asymmetric Cu-catalyzed
conjugate addition, 38 was isolated in 93% yield. Enantiomeric
excess: 88% determined by chiral HPLC analysis, Chiralpak AD, 1.0
mL/min, n-heptane: i-PrOH 98:2, 40 oC, 210 nm, retention times
(min): 19.1 (major) and 30.3 (minor). []D = 9.0 (c 1.0, CHCl3). 1H
NMR (400 MHz, CDCl3): 8.75 (br d, J = 4.0 Hz,
1H), 8.09 (br d, J = 7.8 Hz, 1H), 7.96 (dt, J = 7.7, 7.7, 1.4
Hz, 1H), 7.54 (br dd, J = 7.0, 4.8 Hz, 1H), 3.39 (dd, J = 14.5, 4.5
Hz, 1H), 3.16 (dd, J = 14.5, 7.1 Hz, 1H), 1.97-1.86 (m, 1H),
1.84-1.76 (m, 1H), 1.56-1.34 (m, 2H), 0.84 (t, J = 7.4, 7.4 Hz,
3H), 0.80 (d, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3): 157.7 (s),
150.2 (d), 138.0 (d), 127.2 (d), 122.1 (d), 52.8 (t), 40.0 (d),
28.5 (d), 23.3 (t), 19.0 (q), 18.0 (q), 11.3 (q). HRMS (EI+, m/z):
calcd. for C9H12NO2S [M–C3H7]+: 198.0589; found: 198.0592.
()-2-(2-Cyclohexylbutylsulfonyl)pyridine (39)
Following the general procedure for the asymmetric Cu-catalyzed
conjugate addition, 39 was isolated in 94% yield. Enantiomeric
excess: 94% determined by chiral HPLC analysis, Chiralpak AS, 1.0
mL/min, n-heptane: i-PrOH 95:5, 40 oC, 210 nm, retention times
(min): 12.6 (minor) and 14.1 (major). []D = 3.4 (c 1.0, CHCl3). 1H
NMR (400 MHz,
CDCl3): 8.74 (br d, J = 3.1 Hz, 1H), 8.15-8.03 (m, 1H),
8.01-7.89 (m, 1H), 7.61-7.46 (m, 1H), 3.46 (td, J = 8.8, 4.2, 4.2
Hz, 1H), 3.16 (ddd, J = 14.5, 7.1, 4.5 Hz, 1H), 1.87-1.36 (m, 8H),
1.30-0.80 (m, 9H). 13C NMR (100 MHz, CDCl3): 157.8 (s), 150.1 (d),
138.0 (d), 127.2 (d), 122.1 (d), 53.2 (t), 39.6 (d), 39.1 (d), 29.4
(t), 28.8 (t), 26.4 (t), 23.3 (t), 11.4 (q). HRMS (EI+, m/z):
calcd. for C13H18NO2S [M – C2H5]+: 252.1058; found: 252.1060.
(+)-2-(4-(tert-Butyldiphenylsilyloxy)-2-ethylbutylsulfonyl)pyridine
(40)
Following the general procedure for the asymmetric Cu-catalyzed
conjugate addition, 40 was isolated in 91% yield. Enantiomeric
excess: 92% determined by chiral HPLC analysis, Chiralcel OD-H, 0.5
mL/min, n-heptane: i-PrOH 97:3, 40 oC, 210 nm, retention times
(min): 31.4 (major) and 33.6 (minor). []D =
SO
ON
39
-
35
Chapter2-Final-nocode.docx
Catalytic Asymmetric Conjugate Addition of Grignard Reagents to
α,β-Unsaturated Sulfones
+2.5 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): 8.68 (ddd, J =
4.6, 1.5, 0.7 Hz, 1H), 8.08 (br d, J = 7.8 Hz, 1H), 7.89 (dt, J =
7.8, 7.8, 1.7 Hz, 1H), 7.72-7.55 (m, 4H), 7.49 (ddd, J = 7.7, 4.7,
1.0 Hz, 1H), 7.46-7.31 (m, 6H), 3.66 (t, J = 6.3, 6.3 Hz, 2H), 3.42
(dq, J = 14.5, 14.5, 14.5, 6.1 Hz, 2H), 2.26-2.11 (m, 1H),
1.82-1.60 (m, 2H), 1.58-1.42 (m, 2H), 1.00 (s, 9H), 0.82 (t, J =
7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): 157.8 (s), 150.1 (d), 138.0
(d), 135.5 (d), 133.5 (s), 129.6 (d), 127.6 (d), 127.1 (d), 121.9
(d), 61.2 (t), 55.2 (t), 35.1 (t), 31.5 (d), 26.7 (q), 25.5 (t),
19.0 (s), 10.1 (q). HRMS (EI+, m/z): calcd. for C23H26NO3SiS
[M–C4H9]+: 424.1403; found: 424.1399.
(+)-2-(2-Ethyl-4-phenylbutylsulfonyl)pyridine (41)
Following the general procedure for the asymmetric Cu-catalyzed
conjugate addition, 41 was isolated in 91% yield. Enantiomeric
excess: 93% determined by chiral HPLC analysis, Chiralpak AD-H, 0.5
mL/min, n-heptane: i-PrOH 97:3, 40 oC, 210 nm, retention times
(min): 60.1 (minor) and 62.4 (major). []D = +12.4 (c
1.0, CHCl3). 1H NMR (400 MHz, CDCl3): 8.74 (br d, J = 4.7 Hz,
1H), 8.05 (br d, J = 7.8 Hz, 1H), 7.93 (dt, J = 7.6, 7.6, 1.4 Hz,
1H), 7.53 (ddd, J = 7.6, 4.7, 0.8 Hz, 1H), 7.33-7.20 (m, 2H),
7.19-7.08 (m, 3H), 3.40 (dd, J = 6.1, 1.8 Hz, 2H), 2.60-2.54 (m,
2H), 2.08-1.97 (m, 1H), 1.90-1.65 (m, 2H), 1.66-1.46 (m, 2H), 0.87
(t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): 157.8 (s), 150.2
(d), 141.7 (s), 138.1 (d), 128.3 (d), 128.3 (d), 127.2 (d), 125.8
(d), 122.0 (d), 55.0 (t), 34.4 (t), 33.7 (d), 32.3 (t), 25.6 (t),
10.0 (q). HRMS (ESI+, m/z): calcd. for C17H23NO2S [M + H]+:
304.13658; found: 304.13639.
-
36
Chapter2-Final-nocode.docx
Chapter 2
2.6 References (1) Perlmutter, P. In Conjugate Addition
Reactions in Organic Synthesis; Tetrahedron Organic
Chemistry Series 9; Pergamon Press, Oxford, U.K., 1992. (2)
Rossiter, B.; Swingle, N. Chem. Rev. 1992, 92, 771. (3) Tomioka,
K.; Nagaoka, Y. In Comprehensive Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A.
and Yamamoto, H., Eds.; Springer: New York, 1999, Vol. 3, 1105.
(4) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346. (5) Krause, N.;
Hoffmann-Roder, A. Synthesis 2001, 171. (6) Feringa, B. L.; Naasz,
R.; Imbos, R.; Arnold, L. A. In Modern Organocopper Chemistry;
Krause, N., Ed; VCH: Weinheim, Germany, 2002, 224. (7) Alexakis,
A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221. (8) Hayashi, T.;
Yamasaki, K. Chem. Rev. 2003, 103, 2829. (9) Woodward, S. Angew.
Chem. Int. Ed. 2005, 44, 5560. (10) López, F.; Minnaard, A. J.;
Feringa, B. L. Acc. Chem. Res. 2007, 40, 179. (11) López, F.;
Minnaard, A. J.; Feringa, B. L. In The Chemistry of Organomagnesium
Compounds;
Rappoport, Z.; Marek, I., Eds.; Wiley: Chichester, U.K., 2008;
Part 2, Chapter 17. (12) Harutyunyan, S. R.; den Hartog, T.;
Geurts, K.; Minnaard, A. J.; Feringa, B. L. Chem. Rev.
2008, 108, 2824. (13) Barton, D.; Ollis, W. D. Comprehensive
Organic Chemistry; Pergamon Press: Oxford, U.K.,
1979. (14) Trost, B. M. Bull. Chem. Soc. Jpn. 1988, 61, 107.
(15) Prilezhaeva, E. N. Russ. Chem. Rev. 2000, 69, 367. (16) Patai,
S.; Rappoport, L.; Stirling, C. J. M., Eds.; The Chemistry of
Sulfoxides and Sulfones; John
Wiley & Sons: Chichester, UK, 1988. (17) Kresze, G. Methoden
der Organischen Chemie (Houben-Weyl) 1985, 669. (18) Kelly, S. E.
In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon
Press: Oxford, U.K., 1991; Vol. 1, 792. (19) Llamas, T.; Gómez
Arrayás, R.; Carretero, J. C. Angew. Chem. Int. Ed. 2007, 46, 3329.
(20) Llamas, T.; Gómez Arrayás, R.; Carretero, J. C. Angew. Chem.
2007, 119, 3393. (21) Fuchs, P. L.; Braish, T. F. Chem. Rev. 1986,
86, 903. (22) Nigel S., S. Tetrahedron 1990, 46, 6951. (23)
Hardinger, S. A.; Fuchs, P. L. J. Org. Chem. 1987, 52, 2739. (24)
Hutchinson, D. K.; Fuchs, P. L. J. Am. Chem. Soc. 1987, 109, 4755.
(25) Carretero, J. C.; Dominguez, E. J. Org. Chem. 1993, 58, 1596.
(26) Rendler, S.; Oestreich, M. Angew. Chem. 2007, 119, 504. (27)
Lipshutz, B. H.; Servesko, J. M.; Taft, B. R. J. Am. Chem. Soc.
2004, 126, 8352. (28) Lipshutz, B. H.; Tanaka, N.; Taft, B. R.;
Lee, C. -T. Org. Lett. 2006, 8, 1963. (29) Rainka, M. P.; Aye, Y.;
Buchwald, S. L. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5821.
(30) Moritani, Y.; Appella, D. H.; Jurkauskas, V.; Buchwald, S. L.
J. Am. Chem. Soc. 2000, 122,
6797. (31) Yun, J.; Buchwald, S. L. Org. Lett. 2001, 3,
1129.
-
37
Chapter2-Final-nocode.docx
Catalytic Asymmetric Conjugate Addition of Grignard Reagents to
α,β-Unsaturated Sulfones
(32) Lipshutz, B. H.; Servesko, J. M.; Petersen, T. B.; Papa, P.
P.; Lover, A. A. Org. Lett. 2004, 6, 1273.
(33) Hughes, G.; Kimura, M.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 11253. (34) Lee, D.; Kim, D.; Yun, J. Angew. Chem. 2006,
118, 2851. (35) Czekelius, C.; Carreira, E. M. Org. Lett. 2004, 6,
4575. (36) Czekelius, C.; Carreira, E. M. Angew. Chem. 2003, 115,
4941. (37) Simpkins, N. S. In Sulphones in Organic Chemistry;
Tetrahedron Organic Chemistry Series 10;
Pergamon Press: Oxford, U.K., 1993. (38) Mauleón, P.; Carretero,
J. C. Org. Lett. 2004, 6, 3195. (39) Mauleón, P.; Carretero, J. C.
Chem. Commun. 2005, 4961. (40) Desrosiers, J. –N.; Charette, A. B.
Angew. Chem. Int. Ed. 2007, 46, 5955. (41) Mauleón, P.; Carretero,
J. C. Org. Lett. 2004, 6, 3195. (42) Hayashi, T.; Yamasaki, K.
Chem. Rev. 2003, 103, 2829. (43) Itami, K.; Mitsudo, K.; Nokami,
T.; Kamei, T.; Koike, T.; Yoshida, J. -I. J. Organomet. Chem.
2002, 653, 105. (44) Mauleón, P.; Carretero, J. C. Chem. Commun.
2005, 4961. (45) Desrosiers, J. -N; Bechara, W. S.; Charette, A. B.
Org. Lett. 2008, 10, 2315. (46) Mao, B.; Geurts, K.;
Fañanás-Mastral, M.; Van Zijl, A. W.; Fletcher, S. P.; Minnaard, A.
J.;
Feringa, B. L. Org. Lett. 2011, 13, 948. (47) Mauleón, P.;
Alonso, I.; Rivero, M. R.; Carretero, J. C. J. Org. Chem. 2007, 72,
9924. (48) Mauleón, P.; Carretero, J. C. Org. Lett. 2004, 6, 3195.
(49) Wnuk, S. F.; Garcia, P. I.; Wang, Z. Org. Lett. 2004, 6,
2047.
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38
Chapter2-Final-nocode.docx
Chapter 2
-
Chapter 3 Catalytic Asymmetric Conjugate Addition of Dialkylzinc
Reagents to α,β-Unsaturated Sulfones
In this chapter a highly efficient method is reported for the
copper-catalyzed asymmetric conjugate addition of dialkylzinc
reagents to ,-unsaturated 2-pyridylsulfones using a monodentate
phosphoramidite ligand.*
* Parts of this chapter have been published: Bos, P. H.; Maciá,
B.; Fernández-Ibáñez, M. Á.; Minnaard, A. J.; Feringa, B.L. Org.
Biomol. Chem. 2010, 8, 47.
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40
Chapter3-Final-nocode.docx
Chapter 3
3.1 Introduction As already described both in the introductory
chapter of this thesis as well as in Chapter 2, the conjugate
addition of organometallic reagents to ,-unsaturated compounds is
one of the most versatile methods for the formation of C-C bonds.1,
2 This transformation is used as a key step in the synthesis of
numerous natural products and biologically active compounds and has
been the subject of intensive research over the past decades.3-12
The development of a catalytic method for the enantioselective
conjugate addition reaction of organometallic reagents to
,-unsaturated sulfones is an important goal in extending the
current methodology.
3.1.1 The use of sulfones in organic chemistry As already
described in the introduction of Chapter 2, the utility of sulfones
for organic synthesis was already recognized in the late 1970’s.13
Sulfonyl-containing intermediates have frequently been used in the
total synthesis of a large number of biologically active natural
compounds.14 As a result, methods for their synthesis have been
well developed.13, 15 Sulfones bearing a stereocenter at the
-position are highly versatile intermediates in the preparation of
a wide variety of functionalized chiral molecules in organic
chemistry. Their ease of derivatization provides facile access to a
wide range of building blocks, including aldehydes and ketones,
alkynes, alkenes, alkanes, and haloalkanes.14, 16 For this reason,
methods to synthesize sulfones with a stereocenter at the -position
are highly sought after. For a more detailed discussion and
examples from literature, see Chapter 2.
3.1.2 Asymmetric copper-catalyzed conjugate addition of
diorganozinc reagents to ,-unsaturated compounds The asymmetric
copper-catalyzed conjugate addition of diorganozinc reagent to
,-unsaturated compounds was introduced in 1996. Using the chiral
phosphoramidite ligand Monophos (L1), good yields and enantiomeric
excess (up to 90%) were obtained for the addition of diethylzinc to
chalcone 1 (Scheme 1).17, 18
Ph Ph
Et2Zn 1.5 eq.Cu(OTf)2 2 mol%
(S)-L1 4 mol%Toluene-50 oC
1 2Ph
O
Ph
OOO
P N
Monophos(S)-L184% yield
90% ee Scheme 1 Asymmetric copper-catalyzed conjugate addition
of Et2Zn to chalcone 1.17
-
41
Chapter3-Final-nocode.docx
Catalytic Asymmetric Conjugate Addition of Dialkylzinc Reagents
to α,β-Unsaturated Sulfones
Another important development was the incorporation of a chiral
amine moiety in the design of the phosphoramidite ligand. Absolute
levels of stereocontrol could be reached using ligand L2 in the
conjugate addition of diethylzinc to cyclohexenone (Scheme
2).18
Scheme 2 Asymmetric copper-catalyzed conjugate addition of Et2Zn
to cyclohexenone.18 These breakthroughs initiated the development
of a whole range of copper-catalyzed asymmetric conjugate addition
reactions of diorganozinc reagents to a wide variety of
,-unsaturated compounds and developments in this area of research
have been reviewed extensively.4, 6, 7, 12, 19-21 A small selection
of products accessible through this reaction includes:
α-halo-β-substituted cyclohexenones (5)22, Meldrum’s acid
derivatives (6)23, malonic ester derivatives (7)24, β-chiral nitro
compounds (8)25, 26 β-chiral N-acylpyrrolidinones (9)27 and chiral
enamines (10)28, and is shown in Scheme 3. Although a large
diversity of ligands have been used for these transformations,12,
19 phosphoramidites have shown to be the ligands of choice to
achieve high enantioselectivity in numerous cases. For this reason,
among others, phosphoramidite ligands are being recognized as
privileged ligands in asymmetric catalysis.4, 21
Scheme 3 Selection of chiral products accessible through
copper-catalyzed conjugate addition of dialkylzinc reagents.
-
42
Chapter3-Final-nocode.docx
Chapter 3
3.1.3 Conjugate addition of organometallic reagents to
,-unsaturated sulfones In 2008, Charette et al. reported a method
for the catalytic asymmetric conjugate addition of diorganozinc
reagents to vinyl sulfones (Scheme 4).29
Scheme 4 Catalytic asymmetric conjugate addition of diorganozinc
reagents.29 Using a copper(I) salt in combination with a bidentate
ligand (Binap), optically active sulfones 12 were obtained with
enantioselectivities up to 98% ee. Several diorganozinc reagents
were reported, yields are modest to excellent (52-93%) but the
system is limited to the use of primary diorganozinc reagents and
elevated temperatures (60 oC) are necessary. Again, the 2-pyridyl
sulfone group was essential in order to get satisfactory results.
In experiments were this moiety was replaced by a phenyl- or simply
a methyl group no addition product was isolated.29
3.2 Goal The aim of this research project was to develop
methodology for the catalytic asymmetric conjugate addition of
diorganozinc reagents to aryl substituted ,-unsaturated sulfones.
This would give a general procedure that is complementary to the
asymmetric conjugate addition protocol using Grignard reagents
described in Chapter 2 of this thesis. The resulting optically
active sulfones with a stereocenter at the -position have been
shown to be highly versatile intermediates in organic chemistry due
to their ease of derivatization and provide access to a wide range
of synthetically relevant building blocks. Major advantage of the
conjugate addition of diorganozinc reagents, compared to the
related conjugate reduction, is that this approach is more modular
and thus circumvents the necessity to introduce the substituents at
the stereogenic center in the earl