Lewis acid catalysis for

As an alternative to lithium enolates. silyl enolates or ketene acetals may be used in a complementary route to pentanedioates. The reaction requires Lewis acid catalysis, for example aluminum trifluoromethanesulfonate (modest diastereoselectivity with unsaturated esters)72 74 antimony(V) chloride/tin(II) trifluoromethanesulfonate (predominant formation of anti-adducts with the more reactive a,/5-unsaturated thioesters)75 montmorillonite clay (modest to good yields but poor diastereoselectivity with unsaturated esters)76 or high pressure77. 

Nishiyama H., Motoyama Y. Other Transition Metal Reagents Chiral Transition-Metal Lewis Acid Catalysis for Asymmetric Organic Synthesis in Lewis Acid Reagents 1999 225, Ed Yamamoto H., Pb. Oxford Univ. Press, Oxford Keywords asymmetric Diels-Alder reactions, chiral transition metal Lewis-acid catalysis, asymmetric synthesis... 

Lewis acids as water-stable catalysts have been developed. Metal salts, such as rare earth metal triflates, can be used in aldol reactions of aldehydes with silyl enolates in aqueous media. These salts can be recovered after the reactions and reused. Furthermore, surfactant-aided Lewis acid catalysis, which can be used for aldol reactions in water without using any organic solvents, has been also developed. These reaction systems have been applied successfully to catalytic asymmetric aldol reactions in aqueous media. In addition, the surfactant-aided Lewis acid catalysis for Mannich-type reactions in water has been disclosed. These investigations are expected to contribute to the decrease of the use of harmful organic solvents in chemical processes, leading to environmentally friendly green chemistry. 

It is clear that the analysis of thio effects, rescue experiments and other experiments with derivatives have contributed significantly to our understanding of the mechanism of the action of the large group I intron ribozyme of Tetmhymena. All the available data appear to support the Lewis acid catalysis for activation of the attacking nucleophile and enhancement of the leaving group that is shown in Fig. IIB. 

The class of 3-silyl-substituted reagents provides, upon addition with aldehydes, allylic silanes that offer many options for further derivatization. Oxidative processes are described in previous sections (see the sections on Preparation of 1,2-Diols and 1,4-Diols). If the appropriate silicon substituents are chosen, formal [3+2] cycloadditions with aldehydes can be promoted under Lewis acid catalysis. For example, the mismatched addition of the Z-3-propyl-3-benzhydryldimethyl allylsilane 183 to an a-benzyloxy aldehyde proceeds with low diastereofacial selectivity in favor of product 184 however, after protection of the secondary alcohol, an efficient [3+2] annulation provides the polysubsubstituted furan 185 in good yield and acceptable stereoselectivity (Scheme 24). ° The latter is brought forward to a tricyclic unit found in the antitumor natural product angelmicin B. 

Lewis acid catalysis for aza Diels-Alder reactions of 2-aza-l,3-butadienes [254], In analogy to the hitherto discussed aza Diels-Alder reactions, evidence for a non-concerted mechanism of these transformations has emerged. Thus, Mellor et al. have found that under suitable conditions azaanthraquinone 3-34 does not only form the expected cycloadduct 3-37 upon treatment with a-methylstyrene and formaldehyde, but the tertiary alcohol 3-36 is also generated presumably via cation 3-35. Alcohol 3-36 is easily converted into the cycloadduct 3-37 and 3-35 is therefore supposed to act as intermediate in a non-concerted multistep sequence (Fig. 3-12) [255,256]. More recent studies on N-arylimines performed by Laschat et al. have corrobated the assumption that non-concerted processes represent a noteworthy mechanistic pathway in reactions of 2-aza-l,3-buta-dienes with suitable dienophiles [257]. 

Barron, A. R. In his lecture during International Symposium of Lewis Acid Catalysis for Selective Organic Synthesis, Nagoya, 1999. 

Silyl enol ethers need Lewis acid catalysis for efficient Michael reactions, such as the more substituted (and conjugated) isomer 110 forming a 1,5-diketone 111 from cyclohexenone in good yield.39 This product 111 is a mixture of diastereoisomers as have been many of the products in this chapter. We have also seen some reactions giving single diastereoisomers but without explanation. It is high time that we addressed the question of stereoselectivity and this is the subject of the next chapter. 

Vinyl silanes resemble alkenes in reactivity they combine with reactive electrophiles such as bromine without catalysis but need Lewis acid catalysis for reaction with carbon electrophiles. Reaction usually occurs 189 at the silyl end of the alkene so that the intermediate 190 enjoys the P-silyl stabilisation of the carbocation. The silyl group is removed by a nucleophile, usually a halide ion.45... 

Transformations such as Diels-Alder reactions, ene-reactions and condensations of enoxysilanes with carbonyl compounds often require Lewis acid catalysis. For this reason, many organometallic reagents bearing chiral residues have recently been used as Lewis acids in asymmetric synthesis. Mary of these chiral Lewis acids feature structures similar to those described in Chapter 2. 

The benefits of pressure or Lewis acid catalysis for the addition of nucleophiles to carbonyl compounds is also well established, e.g. in various aldol processes or allylation reactions. The combination of the two methods, however, has rarely been applied. 

In studies directed toward the synthesis of ingenol, Kuwajima investigated Lewis acid catalysis for seven-membered ring formation. Initial cyclization and subsequent rearrangement provides a bridged bicyclo[4.4.1] system (Eq. 6), incorporating the rather exotic in-out... 

In 2010, Scheldt and coworkers reported cooperative N-heterocyclic car-bene/Lewis acid catalysis for highly stereoselective annulation reactions. This cooperative catalysis process integrating titanium(iv) and triazolium-derived NHCs allowed the synthesis of ds-cyclopentenes 69 with a broad substrate scope and high enantioselectivity (Scheme 20.33). 

Recently, Scheldt and co-workers [86] introduced the Lewis acid/NHC cocatalysis, which opens new opportunities for NHC-catalyzed reactions. For example, these authors reported a cooperative NHC/Lewis acid catalysis for the stereoselective annulations of enals with enones (Scheme 7.68). 

The simpler mechanism shown below was ruled out on the basis that intermediate 47 is similar to the one produced from the reaction of aldehydes with TMSA, which requires Lewis acid catalysis for rearrangement whereas the reaction in question needs no catalyst. 

Cooperative NHC/Lewis Acid Catalysis for the Synthesis of 7-Lactams... 

The [3 + 2] cycloaddition between hydrazones and olefins was accelerated in the presence of a catalytic amount of Hf(OTf)4 under mild conditions. The corresponding pyrazolidine derivatives were obtained in moderate to high yields using this novel Lewis acid catalysis for [3+2] cycloaddition reactions (eq 16). ... 

The regioselectivity benefits from the increased polarisation of the alkene moiety, reflected in the increased difference in the orbital coefficients on carbon 1 and 2. The increase in endo-exo selectivity is a result of an increased secondary orbital interaction that can be attributed to the increased orbital coefficient on the carbonyl carbon ". Also increased dipolar interactions, as a result of an increased polarisation, will contribute. Interestingly, Yamamoto has demonstrated that by usirg a very bulky catalyst the endo-pathway can be blocked and an excess of exo product can be obtained The increased di as tereo facial selectivity has been attributed to a more compact transition state for the catalysed reaction as a result of more efficient primary and secondary orbital interactions as well as conformational changes in the complexed dienophile" . Calculations show that, with the polarisation of the dienophile, the extent of asynchronicity in the activated complex increases . Some authors even report a zwitteriorric character of the activated complex of the Lewis-acid catalysed reaction " . Currently, Lewis-acid catalysis of Diels-Alder reactions is everyday practice in synthetic organic chemistry. 

The second important influence of the solvent on Lewis acid - Lewis base equilibria concerns the interactions with the Lewis base. Consequently the Lewis addity and, for hard Lewis bases, especially the hydrogen bond donor capacity of tire solvent are important parameters. The electron pair acceptor capacities, quantified by the acceptor number AN, together with the hydrogen bond donor addities. O, of some selected solvents are listed in Table 1.5. Water is among the solvents with the highest AN and, accordingly, interacts strongly witli Lewis bases. This seriously hampers die efficiency of Lewis-acid catalysis in water. 

A combination of the promoting effects of Lewis acids and water is a logical next step. However, to say the least, water has not been a very popular medium for Lewis-acid catalysed Diels-Alder reactions, which is not surprising since water molecules interact strongly with Lewis-acidic and the Lewis-basic atoms of the reacting system. In 1994, when the research described in this thesis was initiated, only one example of Lewis-acid catalysis of a Diels-Alder reaction in water was published Lubineau and co-workers employed lanthanide triflates as a catalyst for the Diels-Alder reaction of glyoxylate to a relatively unreactive diene . No comparison was made between the process in water and in organic solvents. 

Searching for a suitable system for studying Lewis-acid catalysis of Diels-Alder reactions in water, several points have to be considered. 

In organic solvents Lewis-acid catalysis also leads to large accelerations of the Diels-Alder reaction. Table 2.2 shows the rate constants for the Cu -catalysed Diels-Alder reaction between 2.4a and 2.5 in different solvents. 

In summary, the effects of a number of important parameters on the catalysed reaction between 2.4 and 2.5 have been examined, representing the first detailed study of Lewis-acid catalysis of a Diels-Alder reaction in water. Crucial for the success of Lewis-acid catalysis of this reaction is the bidentate character of 2.4. In Chapter 4 attempts to extend the scope of Lewis-acid catalysis of Diels-Alder reactions in water beyond the restriction to bidentate substrates will be presented. 

In Chapter 2 the Diels-Alder reaction between substituted 3-phenyl-l-(2-pyridyl)-2-propene-l-ones (3.8a-g) and cyclopentadiene (3.9) was described. It was demonstrated that Lewis-acid catalysis of this reaction can lead to impressive accelerations, particularly in aqueous media. In this chapter the effects of ligands attached to the catalyst are described. Ligand effects on the kinetics of the Diels-Alder reaction can be separated into influences on the equilibrium constant for binding of the dienoplule to the catalyst (K ) as well as influences on the rate constant for reaction of the complex with cyclopentadiene (kc-ad (Scheme 3.5). Also the influence of ligands on the endo-exo selectivity are examined. Finally, and perhaps most interestingly, studies aimed at enantioselective catalysis are presented, resulting in the first example of enantioselective Lewis-acid catalysis of an organic transformation in water. 

Giovanni Boocaletti is gratefully acknowledged for the large number of experiments that paved the way to enantioselective Lewis-acid catalysis in water. Furthermore, we kindly thank the Syncom company for the use of the chiral HPLC column. 

The merits of (enantioselective) Lewis-acid catalysis of Diels-Alder reactions in aqueous solution have been highlighted in Chapters 2 and 3. Both chapters focused on the Diels-Alder reaction of substituted 3-phenyl-1-(2-pyr idyl)-2-prop ene-1-one dienophiles. In this chapter the scope of Lewis-acid catalysis of Diels-Alder reactions in water is investigated. Some literature claims in this area are critically examined and requirements for ejfective Lewis-acid catalysis are formulated. Finally an attempt is made to extend the scope of Lewis-acid catalysis in water by making use of a strongly coordinating auxiliary. 

On the basis of the studies described in the preceding chapters, we anticipated that chelation is a requirement for efficient Lewis-acid catalysis. This notion was confirmed by an investigation of the coordination behaviour of dienophiles 4.11 and 4.12 (Scheme 4.4). In contrast to 4.10, these compounds failed to reveal a significant shift in the UV absorption band maxima in the presence of concentrations up to one molar of copper(ir)nitrate in water. Also the rate of the reaction of these dienophiles with cyclopentadiene was not significantly increased upon addition of copper(II)nitrate or y tterbium(III)triflate. 

Scheme 4.6. Schematic representation of the use of a coordinating auxiliary for Lewis-acid catalysis of a Diels-Alder reaction.

In a second attempt to extend the scope of Lewis-acid catalysis of Diels-Alder reactions in water, we have used the Mannich reaction to convert a ketone-activated monodentate dienophile into a potentially chelating p-amino ketone. The Mannich reaction seemed ideally suited for the purpose of introducing a second coordination site on a temporary basis. This reaction adds a strongly Lewis-basic amino functionality on a position p to the ketone. Moreover, the Mannich reaction is usually a reversible process, which should allow removal of the auxiliary after the reaction. Furthermore, the reaction is compatible with the use of an aqueous medium. Some Mannich reactions have even been reported to benefit from the use of water ". Finally, Lewis-acid catalysis of Mannich-type reactions in mixtures of organic solvents and water has been reported ". Hence, if both addition of the auxiliary and the subsequent Diels-Alder reaction benefit from Lewis-acid catalysis, the possibility arises of merging these steps into a one-pot procedure. 

Careful examination of literature reporting Lewis-acid catalysis of Diels-Alder reactions in combination with kinetic investigations indicate that bidentate (or multidentate) reactants are required in order to ensure efficient catalysis in water. Moreover, studies of a number of model dienophiles revealed that a potentially chelating character is not a guarantee for coordination and subsequent catalysis. Consequently extension of the scope in this direction does not seem feasible. 

First of all, given the well recognised promoting effects of Lewis-acids and of aqueous solvents on Diels-Alder reactions, we wanted to know if these two effects could be combined. If this would be possible, dramatic improvements of rate and endo-exo selectivity were envisaged Studies on the Diels-Alder reaction of a dienophile, specifically designed for this purpose are described in Chapter 2. It is demonstrated that Lewis-acid catalysis in an aqueous medium is indeed feasible and, as anticipated, can result in impressive enhancements of both rate and endo-exo selectivity. However, the influences of the Lewis-acid catalyst and the aqueous medium are not fully additive. It seems as if water diminishes the catalytic potential of Lewis acids just as coordination of a Lewis acid diminishes the beneficial effects of water. Still, overall, the rate of the catalysed reaction... 

Chapter 5 also demonstrates that a combination of Lewis-acid catalysis and micellar catalysis can lead to accelerations of enzyme-like magnitudes. Most likely, these accelerations are a consequence of an efficient interaction between the Lewis-acid catalyst and the dienophile, both of which have a high affinity for the Stem region of the micelle. Hence, hydrophobic interactions and Lewis-acid catalysis act cooperatively. Unfortunately, the strength of the hydrophobic interaction, as offered by the Cu(DS)2 micellar system, was not sufficient for extension of Lewis-acid catalysis to monodentate dienophiles. 

We conclude that, when employirg hard Lewis-acids in aqueous solution, the term Lewis-acid catalysis should be used with caution, and only after evidence for a direct interaction between Lewis-acid and substrate has been obtained. 

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