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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

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

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

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)

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


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


3.3.1 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


4.3.1 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


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


4.6 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


5.3.1 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


5.6 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


6.3.1 Screening of ligands and conditions 157


6.3.2 Copper-catalyzed ring opening with organolithium reagents 159

6.3.3 System limitations 160

6.4 Conclusion and Future Prospects 162


6.6 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


7.3.1 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


7.6 References 197

Summary 199 Nederlandse Samenvatting 205 Acknowledgement 211

Chapter 1 Introduction

2

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.

3


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

4


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).

5


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.

6


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.

7


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.

8


Chapter 1

1.5 References (1) Beller, M.; Bolm, C., Eds.; In Transition Metals for Organic Synthesis, Vol. 1, 2nd Edition; Wiley-VCH: Weinheim, Germany, 2004. (2) Trost, B. M. Science 1983, 219, 245. (3) Trost, B. M. Science 1985, 227, 908. (4) Trost, B. M. Science 1991, 254, 1471. (5) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; In Comprehensive Asymmetric Catalysis; Springer-Verlag, Berlin, Heidelberg, 1999. (6) Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G. J. Chem. Soc. A, 1966, 1711. (7) Komarov, I. V.; Börner, A. Angew. Chem. Int. Ed. 2001, 40, 1197. (8) Knowles, W. S. Angew. Chem. Int. Ed. 2002, 41, 1999. (9) Genet, J. -P. Acc. Chem. Res. 2003, 36, 908. (10) Jerphagnon, T.; Renaud, J. -L.; Bruneau, C. Tetrahedron Asymmetry 2004, 15, 2101. (11) Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35, 226. (12) Minnaard, A. J.; Feringa, B. L.; Lefort, L.; De Vries, J. G. Acc. Chem. Res. 2007, 40, 1267. (13) Tani, K.; Yamagata, T.; Otsuka, S.; Akutagawa, S.; Kumobayashi, H.; Taketomi, T.; Takaya, H.; Miyashita, A.; Noyori, R. J. Chem. Soc., Chem. Commun. 1982, 600. (14) Lane, B. S.; Burgess, K. Chem. Rev. 2003, 103, 2457. (15) Jacobsen, E. N.; Markó, I.; Mungall, W. S.; Schröder, G.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968. (16) Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2024. (17) Riant, O.; Mostefaï, N.; Courmarcel, J. Synthesis 2004, 2943. (18) Roy, A. K. In Advances in Organometallic Chemistry, Vol. 55; West, R.; Hill, A. F.; Fink, M. J., Eds.; Academic Press: Amsterdam, The Netherlands, 2007. (19) Hayashi, T. Acc. Chem. Res. 2000, 33, 354. (20) Hayashi, T. In Comprehensive Asymmetric Catalysis Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.,

Eds.; Springer-Verlag, Berlin, Heidelberg, 1999, 2, 887. (21) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20, 3437. (22) Noyori, R. Angew. Chem. Int. Ed. 2002, 41, 2008. (23) Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2024. (24) Chauvin, Y. Angew. Chem. Int. Ed. 2006, 45, 3741. (25) Grubbs, R. H. Angew. Chem. Int. Ed. 2006, 45, 3760. (26) Schrock, R. R. Angew. Chem. Int. Ed. 2006, 45, 3748. (27) Negishi, E. -I. Angew. Chem. Int. Ed. 2011, 50, 6738. (28) Suzuki, A. Angew. Chem. Int. Ed. 2011, 50, 6723. (29) Skoda-Földes, R.; Kollár, L. Curr. Org. Chem. 2002, 6, 1097. (30) Brennführer, A.; Neumann, H.; Beller, M. Angew. Chem. Int. Ed. 2009, 48, 4114. (31) Liu, Q.; Zhang, H.; Lei, A. Angew. Chem. Int. Ed. 2011, 50, 10788. (32) Breit, B.; Seiche, W. Synthesis 2001, 1. (33) Diéguez, M.; Pàmies, O.; Claver, C. Tetrahedron: Asymmetry 2004, 15, 2113. (34) Klosin, J.; Landis, C. R. Acc. Chem. Res. 2007, 40, 1251.

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Introduction

(35) Bini, L.; Müller, C.; Vogt, D. Chem. Commun. 2010, 46, 8325. (36) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (37) Fürstner, A. Angew. Chem. Int. Ed. 2000, 39, 3013. (38) Connon, S. J.; Blechert, S. Angew. Chem. Int. Ed. 2003, 42, 1900. (39) Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42, 4592. (40) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4490. (41) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633. (42) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, , 2419. (43) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2001, 40, 4544. (44) Negishi, E. -I.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42, 1821. (45) King, A. O.; Okukado, N.; Negishi, E. -I. J. Chem. Soc., Chem. Commun. 1977, 683. (46) Phapale, V. B.; Cárdenas, D. J. Chem. Soc. Rev. 2009, 38, 1598. (47) Phan, N. T. S.; Van Der Sluys, M.; Jones, C. W. Adv. Synth. Catal. 2006, 348, 609. (48) Whitcombe, N. J.; Hii, K. K.; Gibson, S. E. Tetrahedron 2001, 57, 7449. (49) Farina, V. Adv. Synth. Catal. 2004, 346, 1553. (50) De Vries, J. G. Can. J. Chem. 2001, 79, 1086. (51) Shibasaki, M.; Vogl, E. M.; Ohshima, T. Adv. Synth. Catal. 2004, 346, 1533. (52) Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918. (53) Denmark, S. E.; Regens, C. S. Acc. Chem. Res. 2008, 41, 1486. (54) Van't Hoff, J. H. Arch. Neerl. Sci. Exactes Nat. 1874, 9, 445. (55) Van't Hoff, J. H. Voorstel tot Uitbreiding der Tegenwoordig in de Scheikunde Gebruikte Structuur-Formules in de Ruimte, Greven, Utrecht, 1874. (56) Van't Hoff, J. H. Bull. Soc. Chim. Fr. 1875, 23, 295. (57) Van'T Hoff, J. H. La Chimie dans L'Espace, Rotterdam 1875. (58) Le Bel, J. A. Bull. Soc. Chim. Fr. 1874, 22, 337. (59) Blaser, H. U.; Schmidt, E. Asymmetric Catalysis on Industrial Scale; Wiley, New York, 2004. (60) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley, New York, 1994. (61) Ojima, I. Catalytic Asymmetric Synthesis; Wiley, New York, 2000. (62) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; In Comprehensive Asymmetric Catalysis; Springer-Verlag, Berlin, Heidelberg, 1999. (63) Perlmutter, P. In Conjugate Addition Reactions in Organic Synthesis; Tetrahedron Organic Chemistry Series 9; Pergamon Press: Oxford, U.K., 1992. (64) Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771. (65) Tomioka, K.; Nagaoka, Y. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A. and Yamamoto, H., Eds.; Springer: New York, 1999; Vol. 3, pp 1105. (66) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346. (67) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171. (68) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. In Modern Organocopper Chemistry; Krause, N. Ed.; VCH: Weinheim, Germany, 2002, 224. (69) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221. (70) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829. (71) Woodward, S. Angew. Chem. Int. Ed. 2005, 44, 5560. (72) Guo, H. -C.; Ma, J. -A. Angew. Chem. Int. Ed. 2006, 45, 354.

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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.

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.

12

Chapter2-Final-nocode.docx

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


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

14


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

15



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


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.

17



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

18


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).

19



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


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

21



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).

22


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.

23



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

24


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.

25



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.

26


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.

27



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

28


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

29



(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.

30


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.

31



(+)-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

32


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

33



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


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



+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


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.

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(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.

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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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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

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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.

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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

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