CHAPTER

Introduction 1

1.1 Conjugate additions The history of conjugate addition reactions is relatively long. A conjugate addition of a carbon nucleophile, now generally known as Michael reaction or Michael addition (vide infra) after the American scientist Arthur Michael (1853-1942), was first described by Komnenos who allowed diethyl sodiomalonate 1.1 to react with diethylethylidenemalonate 1.2 (Scheme 1.1).1 However, Michael2 demonstrated that this method was capable of wide elaboration and in many modifications established an important and essential synthetic tool. Prior to these discoveries, there had not been a general method available for the conversion of unsaturated compounds into saturated higher analogues.

EtO C Na CO2Et 2 EtO C CO Et EtO C CO Et + 2 2 2 2 CO2Et Na EtO2C EtO2C CO2Et EtO2C CO2Et 1.1 1.2 Scheme 1.1 Conjugate additions of diethyl sodiomalonate with diethylethylidenemalonate.

Nowadays conjugate additions of carbon nucleophiles are among the most widely used reactions for carbon-carbon bond formation in organic synthesis. 3, 4

1.2 Nomenclature of reaction types The "conjugate addition" or "1,4-addition" refers to the addition of any class of nucleophile to an unsaturated system in conjugation with an activating group, usually an electron withdrawing group. Originally, these reactions were restricted chiefly to a,b- unsaturated carbonyl compounds. Consequently, a numbering scheme was developed for these substrates with the numbering beginning at the carbonyl oxygen (Scheme 1.2).

3 4 2 1,4-addition R + RM O1 OM Scheme 1.2

1 Komnenos, T. Liebigs Ann. Chem. 1883, 218, 145. 2 For an early report: Michael, A. J. Prakt. Chem. 1887, 35, 249. 3 For a review on the Michael reaction see: Bregmann, E.D., Ginsburg, D., Pappo, R. Org. React. 1959, 10, 179. 4 Perlmutter, P. in Conjugate Addition Reactions in Organic Synthesis; Tetrahedron Organic Chemistry Series, No 9, Pergamon, Oxford, 1992.

1 Chapter 1

Additions to to a,b-unsaturated carbonyl compounds fall under the more restrictive term "Michael addition". This "Michael addition" refers to the addition of stabilized carbanions to unsaturated systems in conjugation with a carbonyl group. Whereas the term "conjugate addition" has a broader connotation.

1.3 Chirality and conjugate additions The history of chirality in organic chemistry begins in 1815 when the French physicist Jean Baptiste Biot discovered that certain organic substances were able to twist the plane of polarization of light passed through them, a phenomenon that is called optical activity. In a famous experiment in 1848 Pasteur5 solved part of the enigma when he resolved racemic tartaric acid as the sodium ammonium salt into both enantiomers, and recognized that a solution of the non-superimposable mirror image crystal forms of each other were able to twist polarized light in opposite direction to each other; (natural) dextro-(+)-tartaric acid rotates the plane to the right whereas the other, (-)-tartaric acid, rotates the plane in opposite direction.6 Pasteur postulated that the molecular structures of (+)- and (-)-tartaric acid must be related to their three dimensional structure. The two acids are thus enantiomorphous at the molecular level, nowadays called enantiomers. By the time Pasteur came to this insight, his interests had shifted from chemistry to microbiology, and it was not van't Hoff in 18747 and Le Bel independently proposed a theory for enantiomerism. Van't Hoff specified the three dimensional arrangement quite precisely: the four linkages to a carbon atom point towards the corners of a regular tetrahedron and two non-superimposable arrangements (enantiomers) are thus possible (Figure 1.1). d d

c a a c

b b Figure 1.1 Tetrahedral carbon.

Enantiomerism has fascinated those working in the field of conjugate addition reactions since the time of one of the first reports of such a reaction. Before Komnenos1 reported the first reaction of a carbon nucleophile to an a,b-unsaturated carbonyl compound, the addition of other nucleophiles had already been described. In 1878 Loydl reported the preparation of malic acid via the reaction of sodium hydroxide and fumaric acid in water.8

5 http://www.pasteur.fr/Pasteur/WLP.html 6 Eliel, E.L., Wilen, S.H. in Stereochemistry of Organic Compounds John Wiley & Sons, Inc., New York, 1994, 3. 7 For a later edition of a translation of the original report see: van't Hoff, J.H. in Die Lagerung der Atome im Raum, Friedrich Vieweg und Sohn, Braunschweig, dritte Auflage, 1908. 8 Loydl, F. Liebigs Ann. Chem. 1878, 192, 80.

2 Introduction

The malic acid prepared in this way was identical to the natural malic acid with respect to almost all physical properties. There was only one major difference; it was "optically inactive". Earlier Kekulé9 and Pasteur10 also had prepared "optically inactive" malic acid. Why there was a difference between the natural and the synthetic malic acid was at that moment still not clear but Loydl was the first to recognize that the lack of optical activity of synthetic malic acid, taking the theory of van't Hoff7 into account, was caused by the three- dimensional structure of two opposite non-superimposable molecular structures of which the synthetic malic acid consisted (Figure 1.2).8 Also Michael11 concerned himself with the scientific discussion about the verity of the van't Hoff-Le Bel hypothesis going on at the end of the nineteenth century.12

Anders gestatted sich jedoch die Sache, wenn mann den Vorstellungen, welche van't Hoff *) über die Lagerung der Atome im Raume dargelegt hat und der mit diesen Vorstellungen in im Zusammenhange stehenden Theorie der optischen Activität nachgeht……Umwandlung der Fumarsäure in Aepfelsäure das auftreten gleicher Molecule, zweier gleich stark, aber in entgegengesetztem Sinne optisch-activer Aepfelsäuren als wahrscheinlich erscheinen. Die thatsächlich beobachtete Inactivität aus Fumarsäure erhaltenen Aepfelsäure wäre also das Resultat einer in einer Mischung zweier optisch-activen Säuren stattfindenden Compensation. Die Richtigkeit dieser Vermuthung mub sich zweifellos exprimentell feststellen, und ich behalte mir vor, die Untersuchung in diesem Sinne Weiter forzusetzen, so wie die Maleïnsäure mit in den Kreis der Untersuchung zu siehen. *) Die Lagerung der Atome im Raum, van't Hoff, von D. Hermann 1877.

Figure 1.2 Part of the publication of Loydl (1878).

O O

N N O O H H N N O O O H H O

(R) (S) Figure 1.3 Enantiomers of thalidomide.

1.4 Relevance of chirality in organic chemistry Stereochemistry has evolved into a major field of research that it is nowadays.6,13 Chirality is important in the context of biological activity because, at a molecular level asymmetry dominates biological processes. In bioactive compounds in which a stereogenic center is present great differences are usually observed for the activities of the enantiomers. This phenomenon is observed for almost all bioactive substances, such as drugs, insecticides,

9 Kekulé, A. Liebigs Ann. Chem. 1860, 117, 120. 10 Pasteur, L. Liebigs Ann. Chem. 1852, 82, 324 11 Michael, A. J. Pract. Chem. 1892, 46, 400; ibid. 1892, 46, 424. 12 For a detailed review on this subject see for example: Ramsay, O.B. in van't Hoff-Le Bel Centennial ACS Symposium Series 12, Washington, D.C., 1975. 13 Helmchen, G., Hoffmann, R.W., Mulzer, J., Schaumann, E. Eds. in Stereoselective Synthesis; Methods in Organic Chemistry, Houben Weyl, Volume E 21 b, Georg Thieme Verlag, Stuttgart, 1995.

3 Chapter 1 herbicides, flavors and fragrances.14 The most impressive example in this respect is the 'thalidomide tragedy'. Thalomide, commercially sold under the name Softenon, was prescribed in racemic form (Figure 1.3). The (R)-enantiomer of the drug was effective against morning sickness of pregnant women. The mirror image, however, had devastating effects on the development of an unborn foetus.15 Another example is the smell of both enantiomers of limonene, one enantiomer smells of lemons, whereas its mirror image smells of oranges.

Chiral Pool Racemates Prochiral substrates

Resolution Synthesis Asymmetic Synthesis Kinetic Crystallization Catalysis Biocatalysis Enzymatic Chemical Enantiomers Diastereoisomers

Enantiomerically pure Compounds

Scheme 1.3 Routes to enantiomerically pure compounds.14

For many applications of chiral compounds, the racemic form will no longer be accepted. As a consequence the demand for effective methods to produce enantiomerically pure compounds will undoubtedly increase.16 There are various methods available to prepare only one enantiomer of a chiral product. In general three main paths are considered to achieve this need (Scheme 1.3):

· Use of the chiral pool · Separation of racemic materials · Asymmetric synthesis

The chiral pool refers to readily available natural products (isolated from natural sources or produced by fermentation); these compounds can be converted into synthetic compounds by chemical manipulations.17 For example in our research group a multifunctional enantiomerically pure synthon 5(R)-(l)-menthyloxy-2[5H]-furanone has been developed, which has proven to be a versatile building block in a large range of chemical conversions into enantiomerically pure natural and unnatural products.18 In many cases,

14 Sheldon, R.A. in Chirotechnology, Marcel Dekker Inc., New York, 1993, 39. 15 The tragedy could not have been averted because racemisation occurs in vivo: Ericksson, T., Björkman, S., Roth, B., Fyge, Å., Höglund, P. Chirality 1995, 7, 44 and references therein. 16 Fox, J. Chem. Ind. 1993, 270; Burke, M. Chem. Ind. 1994, 10. 17 Blaser, H.-U. Chem. Rev. 1992, 92, 935. 18 See for example: Feringa , B.L., de Lange, B, Jansen, J.F.G.A., de Jong, J.C., Lubben, M. Faber, W., Schudde, E.P. Pure Appl. Chem. 1992, 64, 1865; Rispens, M.T., Keller, E., de Lange, B., Zijlstra,

4 Introduction however, only one of the enantiomers is available when one starts with a chiral natural product. Therefore many desired enantiomers have to be prepared in an alternative way. Furthermore, for larger scale applications it is not always possible to find the suitable starting material from a natural source. Although revolutionary developments have been made in catalytic asymmetric synthesis, resolution of racemates is still the most important methodology for the industrial synthesis of enantiopure products.19 Methods for resolution include kinetic resolution: either chemical20 or enzymatic,21 or classical resolution: either via preferential crystallization or via diastereomer separation. Intrinsically the yields can not exceed 50%, however higher yields can be obtained when the remaining enantiomer racemises in situ.21,22 Originally it was believed that the synthesis of enantiomerically pure compounds from prochiral substrates was only possible using biochemical methods. Indeed powerful methods, using enzymes, cell cultures or microorganisms or antibodies, have been developed to fulfil this demand. In many cases however these processes are substrate specific.23 Organic synthesis, on the other hand, has produced a variety of flexible stereoselective reactions that can complement biological processes.6 Using stoichiometric or catalytic amounts of chiral auxiliaries optically active compounds can be obtained. The most attractive and challenging class of stereoselective synthesis methods revolve around asymmetric catalysis, since using a small amount of catalyst, large amounts of desired product can be attained selectively often with enantiomeric excesses (e.e.'s)24 exceeding 95%. These reactions include asymmetric reductions, asymmetric oxidations and asymmetric carbon-carbon bond formation. Although for conjugate additions several effective catalytic systems have been developed, more than a century after the first examples of the reaction type appeared in the literature, chemists are challenged to develop highly selective catalytic versions of this type of carbon-carbon bond forming reaction.

1.5 Enantioselective Michael additions Catalytic asymmetric Michael additions are among the most important methods for the generation of carbon-carbon bonds with simultaneous formation of new stereogenic

R.W.J., Feringa, B.L. Tetrahedron Asymm. 1994, 5, 607; van Oeveren, A. 5-Alkoxy-2-(5H)-furanones in Asymmetric Synthesis, Ph.D. Thesis, University of Groningen, 1996 and references cited therein. 19 Collins, A.N., Sheldrake, G.N., Crosby, J. Eds. In Chirality in Industry II, Wiley, Chichester, 1997. 20 See for example: Faber, W.S., Kok, J., de Lange, B., Feringa, B.L. Tetrahedron 1994, 50, 4775 and references therein. 21 van der Deen, H., Cuiper, A.D., Hof, R.P., van Oeveren, A., Feringa, B.L., Kellogg, R. M. J. Am. Chem. Soc. 1996, 118, 3801 and references therein. 22 Jacques, J., Collet, A., Wilen, S.H. in Enantiomers, Racemates, and Resolutions, Wiley, New York, 1981; see also Ref 14. 23 Arnold, F.H. in New Enzymes for Organic Synthesis, Springer, Berlin, 1997; Wong C.H., Whitesides, G.M. in Enzymes in Synthetic Organic Chemistry, Pergamon, Tetrahedron Organic Chemistry Series, Vol. 12, Oxford, 1994. 24 e.e. = (xR-xS)/ (xR+xS)*100%

5 Chapter 1 centers. Since the field of asymmetric 1,4-additions has recently been reviewed,25 only the most important and recent examples will now be shown. In particular 1,3-dicarbonyl compounds are important Michael donors for the enantioselective construction of carbon-carbon bonds. Catalytic asymmetric conjugate additions can be divided into two types (Scheme 1.4). Type A reactions induce the stereocenter at the Michael donor site, whereas type B reactions give the stereocenter at the Michael acceptor side. Although for the enantioselective Michael addition of indan-1-one-2- carboxylate 1.3 to methyl vinyl ketone (MVK) 1.4 catalysts have been developed, for example chinona alkaloids26 or chiral crown ethers27 which give the desired Michael adduct with modest to high e.e.'s (Scheme 1.5), these catalysts do not show comparable results with many other substrates.28 In fact only a few effective catalytic versions of type A reactions starting from prochiral substrates are known today.

R1 R1 O O O * R2 Type A R2 + O O O R3 R3 donor acceptor

R1 R1 O O O R Type B 2 R2 + * O O O R1 R1

Scheme 1.4 Classification of catalytic enantioselective conjugate additions. O

quinine 1.5 (e.e. 76 %) OMe + OMe O or chiral crown 1.6 O O (e.e. 99 %) O O 1.3 1.4 K-tOBu

N OH O O O OMe O O O N 1.5 1.6 Scheme 1.5 Catalytic enantioselective Michael addition of 1.3 to 1.4.

25 Feringa, B.L., de Vries, A.H.M. in Advances in Catalytic Processes, JAI Press Inc., Vol. 1, 1995, 151. 26 Helder, R., Wynberg, H. Tetrahedron Lett. 1975, 4057. 27 Cram, D.J., Sogah, G.D.Y. J. Chem. Soc., Chem. Commun. 1981, 625. 28 Hermann, K., Wynberg, H. J. Org. Chem. 1979, 44, 2238.

6 Introduction

O O O O

OR + OR O

O

O O R2= OH or R2 n=1-3 OH e.e. up 64 %

1.7 Scheme 1.6 Catalytic enantioselective type A Michael addition using 2'-substituted- 2,2'dihydroxy-1,1'-binaphthyl ethers as a chiral base.

In a recent example of a chiral base catalyzed Michael addition of b-ketoesters moderate e.e.'s were achieved using catalytic amounts (10 mol%) 2'-substituted-2,2'- dihydroxy-1,1'-binaphthyl (BINOL) ethers 1.7 (Scheme 1.6).29 Using these chiral BINOL derived ethers e.e.'s up to 64 % could be achieved in the Michael addition of b-ketoesters.

NC RhH(CO)(PPh3) O O R2 (S,S)-(R,R)-TRAP O + R XR O X=O,N 2 1 XR1 CN 1.9

Me Ph2P e.e.'s 72-89 % Fe Fe (S,S)-(R,R)-TRAP 1.8 PPh Me 2 Scheme 1.7 Rhodium catalyzed enantioselective Michael addition.

Ito and co-workers reported a rhodium catalyzed enantioselective Michael addition of a-cyanocarboxylates to vinyl ketones.30 A catalyst, prepared in situ from a trans chelating diphosphine ligand, 2.2'-bis[1-(diphenylphophino)ethyl]-1,1'-biferrocene (TRAP, 1.8) (Scheme 1.7), was employed. The use of i-propyl-a-cyanocarboxylate (1.9, X=O) gave the highest enantioselectivity with MVK, whereas reactions of 1.9 with a variety of vinyl ketones proceeds with enantioselectivities ranging from 72% to 89%. The reaction is proposed to

29 Tamai, Y., Kamifuku, A., Koshiishi, E., Miyano, S. Chem. Lett. 1995, 957. 30 Sawanura, M., Hamashima, H., Ito, Y. J. Am. Chem. Soc. 1992, 114, 8295.

7 Chapter 1 proceed via the binding of the cyano nitrogen group of cyanoacetic ester to the rhodium. It should be noted that carbon-carbon bond formation takes place rather distant from the metal center and still remarkably high enantioselectivity is observed. This method was extended to N-methoxy-n-methylcarboxamides again with high enantioselectivity.31 On the other hand, for type B reactions several successful asymmetric catalysts with broader scope have been reported. Yamaguchi was the first to report on the catalytic asymmetric Michael addition of simple dialkylmalonates 1.1032 and more recently nitroalkanes33 to prochiral enones, using a rubidium salt of proline 1.11. The reactions are proposed to proceed via the formation of an intermediate chiral iminium salt 1.12 (Scheme 1.8). A similar concept was also used in the enantioselective Michael additions of dialkylmalonates to prochiral enones using proline based quarternary ammonium salts.34

R R * N CO2Rb i PrO C O (i PrO2C)2HC O 2 H 1.11 + or or O i PrO2C O

1.10 * CH(CO2iPr)2

- CH(CO2iPr)2 e.e.'s 49-76 %

+ NR2 N R2N= - O2C 1.12 Scheme 1.8 Rubidium catalyzed enantioselective Michael additions.

The most important development, however, was reported by Shibasaki and co- workers who used several chiral heterobimetallic BINOL catalysts for various organic reactions. A prominent example is the enantioselective Michael addition of dialkylmalonates to prochiral cyclic enones.35 These chiral heterobimetallic complexes, which have both a Lewis acidic and a Brönsted basic site, were also used for the enantioselective aldol reaction

31 Sawanura, M., Hamashima, H., Shinoto, H., Ito, Y. Tetrahedron Lett. 1995, 36, 6479. 32 Yamaguchi, M., Shiraishi, T., Hirama, M. Angew. Chem., Int. Ed. Engl. 1993, 32, 1176. 33 Yamaguchi, M., Shiraishi, T., Igarashi, Y., Hirama, M. Tetrahedron Lett. 1994, 35, 8233. 34 Kawara, A., Taguchi, T. Tetrahedron Lett. 1994, 35, 8805. 35 Sasai, H., Arai, T., Shibasaki, M. J. Am. Chem. Soc. 1994, 116, 1571; Sasai, H., Arai, T., Satow, Y., Houk, K.N., Shibasaki, M. J. Am. Chem. Soc. 1995, 117, 6194; see also ref 40.

8 Introduction of nitroalkanes to various aldehydes,36 asymmetric hydrophosphorylation of imines,37 or aldehydes38 and the epoxidation of a,b-unsaturated ketones.39,40 Various methods to prepare these catalysts were developed. Although often new complexes had to be developed for the different types of reactions, these heterobimetallic complexes have proven to be very effective catalysts for a broad range of organic reactions.41

OH OH * O O O O * La La * La(OiPr)3 O O La:BINOL=2:3 n

O O -H+ O O * La * R O OR O O 1 1 R2 O R1O O O O * R2 La n OR1 O O OR R O R2 1 1 O O

* O La O O O O n

R1O OR1 O R2 n OR1 OR R2 1 O Scheme 1.9 Possible mechanism for the catalytic asymmetric Michael reaction promoted by alkali metal free La-(S)-BINOL.

36 Sasai, H., Suzuki, T., Arai, S., Arai, T., Shibasaki, M. J. Am. Chem. Soc. 1992, 114, 4418; Sasai, H., Suzuki, T., Itoh, N., Shibasaki, M. Tetrahedron Lett. 1993, 34, 851; Sasai, H., Itoh, N., Suzuki, T., Shibasaki, M. Tetrahedron Lett. 1993, 34, 855; Sasai, H., Kim., W.-S. Suzuki, T., Shibasaki, M. Tetrahedron Lett. 1994, 35, 6123; Sasai, H., Yamada, Y.M.A., Shibasaki, M. Tetrahedron 1994, 50 12313; Sasai, H., Suzuki, T., Itoh, N., Tanaka, K., Date, T., Okamura, K., Shibasaki, M., J. Am. Chem. Soc. 1993, 115, 10372; Sasai, H., Tokanaga, T., Watanabe, S., Suzuki, T., Itoh, N., Shibasaki, M. J. Org. Chem. 1996, 60, 7388; Iseki, K., Oishi, S., Sasai, H., Shibasaki, M. Tetrahedron Lett. 1996, 37, 9081. 37 Sasai, H., Arai, S., Tahara, Y., Shibasaki, M. J.Org. Chem. 1995, 60, 6656. 38 Sasai, H., Bougauchci, M., Arai, T., Shibasaki, M. Tetrahedron Lett. 1997, 38, 2717. 39 Bouchauchi, M., Watanabe, S., Arai, T., Sasai, H., Shibasaki, M. J. Am. Chem. Soc. 1997, 119, 2329. 40 This work has recently been reviewed: Shibasaki, M., Sasai, H., Arai, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 1236. 41 Steinhagen, H., Helmchen, G. Angew., Chem., Int. Ed. Engl. 1996, 35, 2339.

9 Chapter 1

Despite the fact that the enantioselective nitroaldol reaction could be catalyzed effectively with several BINOL rare earth metal-lithium bimetallic complexes, with high enantioselectivities,35 these complexes gave only low e.e.'s in the Michael addition of dialkylmalonates to cyclic enones. When, however, a lithium free lanthanum (S)-BINOL complex was used, enantioselectivities ranging from 78 to 95% were obtained (Scheme1.9). More recently the application of heterobimetallic lanthanum-earth alkali metal catalysis was extended with the development of a heterobimetallic complex prepared in situ from lithium aluminum hydride and (R)-BINOL. Using this chiral heterobimetallic complex a catalytic asymmetric tandem Michael-aldol reaction could be performed with very high enantioselectivity.42 The scope and limitations of this new type of catalyst will be discussed in more detail in Chapter 6.

1.6 Organic chemistry in aqueous media Most synthetic reactions are currently performed in organic solvents. The use of water as the reaction medium is usually avoided since a large number of reactants decompose when brought into contact with water. Furthermore, many organic reactants are sparsely soluble in water. Despite these disadvantages, water is becoming increasingly popular as a medium for organic reactions. Being the most abundant solvent on earth, it is very cheap, it is non- hazardous to the environment and non-toxic. Moreover, aqueous solvents can have beneficial effects on rates and selectivities of important organic transformations such as, for example, Diels Alder reactions, aldol condensations and Michael additions.43 Finally, the use of water often simplifies work-up procedures. These features, in combination with ever more strict legislation concerning industrial chemical processes, has led to increased efforts to transfer reactions from organic to aqueous solvents.44 On an industrial scale, the first and highly successful example of this development is the Ruhr Chemie Rhone-Poulenc hydroformylation process.45 Also in the field of Lewis-acid catalysis water is becoming increasingly popular, even though this solvent imposes severe restrictions on the applicability of Lewis acids. Active

Lewis acids like BF3, TiCl4 and AlCl3 react violently with water and cannot be used. Moreover, coordination of the Lewis acid to the reactants is not as efficient in water as in solvents like dichloromethane or benzene. Hence, applications of Lewis-acid catalysis in water are still limited.

42 Arai, T., Sasai, H., Aoe, K., Okamura, K., Date, T., Shibasaki, M. Angew. Chem., Int Ed. Engl. 1996, 35, 104 43 For a review see: Lubineau, A., Augé, J., Queneau, Y. Synthesis 1994, 741. 44 Recent reviews: Kalck, P., Monteil, F. Adv. Organometal. Chem. 1992, 34, 219; Herrmann, W.A., Kohlpainter, C.W. Angew. Chem., Int. Ed. Engl. 1993, 32, 1524; Haggins, J. Chem. Eng. News 1994, 28; Roundhill, D.M. Adv. Organometal. Chem. 1995, 38, 155. 45 Kuntz, E.G. Chemtech 1987, 570.

10 Introduction

An extensive review of Lewis-acid catalysis in water was published by Hay in 1987.46 Most of the efforts in this field have been concerned with hydrolysis reactions of coordinated reactants. In 1993, Li reviewed carbon-carbon bond forming reactions in water.47 In neither review much attention was paid to aqueous carbon-carbon bond forming reactions catalyzed by Lewis acids. This is a rapidly developing, though relatively new field in organic chemistry and Kobayashi has already reviewed his pioneering work on this subject.48 A more recent overview of the progress made in this field will be provided in Chapter 2.

1.7 Aims and survey of this thesis As outlined in this section selective carbon-carbon bond formations, especially conjugate addition reactions, are of great interest to organic chemists. A number of catalytic asymmetric conjugate additions with high yields and enantioselectivities have been developed. Currently, the interest in carbon-carbon bond formation in aqueous media is growing rapidly. In Chapter 2 a recent overview of the progress made in the field of Lewis acid catalyzed carbon-carbon bond formation in aqueous media will be provided. An even larger challenge is to perform catalytic enantioselective carbon-carbon bond formations in water. The main aim of this project is the development of Lewis acid catalyzed asymmetric conjugate additions in water. To achieve this goal, we tried to tackle this problem via two approaches (Figure 1.4). First of all we have developed new methods for Lewis acid catalyzed Michael additions in water (A), as outlined in Chapters 3 and 4. Chapter 3 deals with the investigation of copper Schiff base catalyzed Michael additions of b-ketoesters in water. In Chapter 4 the scope and limitations of ytterbium triflate (Yb(OTf)3) catalyzed Michael additions of b-ketoesters and a-nitroesters are described. Simultaneously we investigated novel routes towards catalytic asymmetric conjugate additions in organic solvents (C). This work is summarized in Chapters 6 and 7. Chapter 6 describes the results of investigations of the heterobimetallic BINOL catalysts in the first enantioselective Michael addition of a-nitroesters in organic solvents. In Chapter 7 the use of novel chiral phosphorous amidites in the enantioselective copper catalyzed conjugate addition of diethylzinc to cyclic enones and double activated esters will be discussed. Investigations of water soluble ligands for Lewis acid catalyzed asymmetric Michael additions in water (B) are outlined in Chapter 5.

46 Hay, R.W. in Comprehensive Coordination Chemistry, Chapter 61.4, G. Wilkinson, R.D. Gillard and J.A. McCleverty, eds., Pergamon Press, Oxford, 1987. 47 Li, C. Chem. Rev. 1993, 93, 2023. 48 Kobayashi, S. Synlett 1994, 689.

11 Chapter 1

A: Lewis acid catalyzed Michael additions in water.

B: Asymmetric Lewis acid catalyzed Michael additions in water. C: Catalytic asymmetric conjugate additions. Figure 1.4 Schematic representation of the strategy of this project.

12