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.