Diels Alder reactions enantioselective

Dipolar cydoadditions are one of the most useful synthetic methods to make stereochemically defined five-membered heterocydes. Although a variety of dia-stereoselective 1,3-dipolar cydoadditions have been well developed, enantioselec-tive versions are still limited [29]. Nitrones are important 1,3-dipoles that have been the target of catalyzed enantioselective reactions [66]. Three different approaches to catalyzed enantioselective reactions have been taken (1) activation of electron-defident alkenes by a chiral Lewis acid [23-26, 32-34, 67], (2) activation of nitrones in the reaction with ketene acetals [30, 31], and (3) coordination of both nitrones and allylic alcohols on a chiral catalyst [20]. Among these approaches, the dipole/HOMO-controlled reactions of electron-deficient alkenes are especially promising because a variety of combinations between chiral Lewis acids and electron-deficient alkenes have been well investigated in the study of catalyzed enantioselective Diels-Alder reactions. Enantioselectivities in catalyzed nitrone cydoadditions sometimes exceed 90% ee, but the efficiency of catalytic loading remains insufficient. 

As for the oxo-Diels-Alder reaction, not much has been reported other Lewis acids are usually superior [26]. As for the aza-Diels-Alder reaction, enantioselective reactions between imino dienophiles 60 and diene 61, using a chiral binaphtholzirco-nium catalyst 23, are known (Eq. 26) [27]. 

Kresze and co-workers have looked at the possibility of effecting nitroso Diels-Alder reactions enantioselectively. In a preliminary experiment, the optically active a-chloronitroso compound in Eq. (15)... 

Scheme 4, Diels-Alder reactions enantioselectively catalyzed by 10 mol% 7,...

Swindell CS, Tao M (1993) Chiral Auxiliary-Mediated Asymmetric Induction in a Thermal Inverse Electron Demand Hetero-Diels-Alder Reaction - Enantioselective Synthesis of the Taxol A-Ring Side Chain. J Org Chem 58 5889... 

Chiral substituents in dienophiles can be used to make Diels-Alder reactions enantioselective. Some examples of chiral dienophiles that have been used successfully are collected in Scheme 6.2. Because of the lower temperature required and the greater stereoselectivity observed in Lewis acid catalyzed reactions, the best enantioselectivity is often observed in the catalyzed reactions. Chiral esters and amides of acrylic acid are particularly useful because the chiral auxiliary can be easily recovered by hydrolysis of the adduct. The cycloaddition proceeds to give two diastereomeric products, which can be separated and purified. Hydrolysis then gives enantiomerically pure carboxylic acid. 

What is the influence of ligands on the Lewis acid on the rate and selectivity of the Diels-Alder reaction If enantioselectivity can be induced in water, how does it compare to other solvents Chapter 3 deals with these topics. 

The first example of enantioselective catalysis of a Diels-Alder reaction was reported in 1979 . Since then, an extensive set of successful chiral Lewis-acid catalysts has been prepared. Some selected examples will be presented here together with their mechanistic interpretation. For a more complete... 

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. 

Likewise, the influence of the ligand catalyst ratio has been investigated. Increase of this ratio up to 1.75 1 resulted in a slight improvement of the enantioselectivity of the copper(L-tryptophan)-catalysed Diels-Alder reaction. Interestingly, reducing the ligand catalyst ratio from 1 1 to 0.5 1 resulted in a drop of the enantiomeric excess from 25 to 18 % instead of the expected 12.5 %. Hence, as anticipated, ligand accelerated catalysis is operative. 

Finally the influence of the temperature and addition of ethanol on the enantioselectivity of the Diels-Alder reaction was studied. Table 3.3 summarises the results for different aqueous media. Apparently, changes in temperature as well as the presence of varying amounts of ethanol have only a modest influence on the selectivity of the Cu(tryptophan)-catalysed Diels-Alder reaction in aqueous solution. However, reaction times tend to increase significantly at lower temperatures. Also increasing the alcohol content induces an increase of the reaction times. 

In summary, when using a ligand catalyst ratio of 1.75 1 at pH 5-6 the enantioselectivity of the Diels-Alder reaction between 3.8c and 3.9 is dictated by the activated complexes involving ligand, copper(ir) ion, dienophile and diene. Considering that four different products are formed in this reaction (see Scheme 3.5), at least four different activated complexes are involved However, each of these complexes hus two degrees of freedom that determine the stereochemical outcome of the... 

Clearly, complete understanding of solvent effects on the enantioselectivity of Lewis-acid catalysed Diels-Alder reactions has to await future studies. For a more detailed mechanistic understanding of the origins of enantioselectivity, extension of the set of solvents as well as quantitative assessment of the strength of arene - arene interactions in these solvent will be of great help. 

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. 

Of all the work described in this thesis, this discovery is probably the most significant. Given the fact that the arene - arene interactions underlying the observed enantioselectivity of ftie Diels-Alder reactions described in Chapter 3 are also encountered in other organic reactions, we infer that, in the near future, the beneficial influence of water on enantioselectivity can also be extended to these transformations. Moreover, the fact that water can now be used as a solvent for enantioselective Lewis-add catalysed reactions facilitates mechanistic studies of these processes, because the number of equilibria that need to be considered is reduced Furthermore, knowledge and techniques from aqueous coordination chemistry can now be used directly in enantioselective catalysis. 

In summary, the work in this thesis provides an overview of what can be achieved with Lewis-acid and micellar catalysis for Diels-Alder reactions in water as exemplified by the reaction of3-phenyl-l-(2-pyridyl)-2-propene-l-ones with cyclopentadiene. Extension of the observed beneficial effect of water on rates and particularly enantioselectivities to other systems is envisaged. 

Throughout this thesis reference has been made to hydrophobic effects. Enforced hydrophobic interactions are an important contributor to the acceleration of uncatalysed and also of the Lewis-acid catalysed Diels-Alder reactions which are described in this thesis. Moreover, they are likely to be involved in the beneficial effect of water on the enantioselectivity of the Lewis-acid catalysed Diels-Alder reaction, as described in Chapter 3. Because arguments related to hydrophobic effects are spread over nearly all chapters, and ideas have developed simultaneously, we summarise our insights at the end of this thesis. 

Also the arene-arene interactions, as encountered in Chapter 3, are partly due to hydrophobic effects, which can be ranked among enforced hydrophobic interactions. Simultaneous coordination of an aromatic oc amino acid ligand and the dienophile to the central copper(II) ion offers the possibility of a reduction of the number of water molecules involved in hydrophobic hydration, leading to a strengthening of the arene-arene interaction. Hence, hydrophobic effects can have a beneficial influence on the enantioselectivity of organic reactions. This effect is anticipated to extend well beyond the Diels-Alder reaction. 

We have investigated the effect of solvents on the enantioselectivity. It turned out that water (74% ee) favours the enantioselectivity of the Cu (L-abrine) catalysed Diels-Alder reaction between Ic and 2 as compared to chloroform (44% ee), ethanol (39% ee), THF (24% ee) and acetonitrile (17% ee). The... 

Because the Corey synthesis has been extensively used in prostaglandin research, improvements on the various steps in the procedure have been made. These variations include improved procedures for the preparation of norbomenone (24), alternative methods for the resolution of acid (26), stereoselective preparations of (26), improved procedures for the deiodination of iodolactone (27), alternative methods for the synthesis of Corey aldehyde (29) or its equivalent, and improved procedures for the stereoselective reduction of enone (30) (108—168). For example, a catalytic enantioselective Diels-Alder reaction has been used in a highly efficient synthesis of key intermediate (24) in 92% ee (169). 

Diels-Alder reaction of 2-bromoacrolein and 5-[(ben2yloxy)meth5i]cyclopentadiene in the presence of 5 mol % of the catalyst (35) afforded the adduct (36) in 83—85% yield, 95 5 exo/endo ratio, and greater than 96 4 enantioselectivity. Treatment of the aldehyde (36) with aqueous hydroxylamine, led to oxime formation and bromide solvolysis. Tosylation and elimination to the cyanohydrin followed by basic hydrolysis gave (24). 

Catalytic enantioselective addition to imines, in particular, aza-Diels-Alder reaction 99CRV1069. 

Catalytic enantioselective hetero-Diels-Alder reactions are covered by the editors of the book. Chapter 4 is devoted to the development of hetero-Diels-Alder reactions of carbonyl compounds and activated carbonyl compounds catalyzed by many different chiral Lewis acids and Chapter 5 deals with the corresponding development of catalytic enantioselective aza-Diels-Alder reactions. Compared with carbo-Diels-Alder reactions, which have been known for more than a decade, the field of catalytic enantioselective hetero-Diels-Alder reactions of carbonyl compounds and imines (aza-Diels-Alder reactions) are very recent. 

Brmsted acid-assisted chiral Lewis acid 8 was also applied to the intramolecular Diels-Alder reaction of an a-unsubstituted triene derivative. ( , )-2,7,9-Decatrienal reacts in the presence of 30 mol% of the catalyst to afford the bicyclo compound in high yield and good enantioselectivity [lOd] (Scheme 1.17). 

Yamamoto et al. have reported a chiral helical titanium catalyst, 10, prepared from a binaphthol-derived chiral tetraol and titanium tetraisopropoxide with azeotropic removal of 2-propanol [16] (Scheme 1.22, 1.23, Table 1.9). This is one of the few catalysts which promote the Diels-Alder reaction of a-unsubstituted aldehydes such as acrolein with high enantioselectivity. Acrolein reacts not only with cyclo-pentadiene but also 1,3-cyclohexadiene and l-methoxy-l,3-cyclohexadiene to afford cycloadducts in 96, 81, and 98% ee, respectively. Another noteworthy feature of the titanium catalyst 10 is that the enantioselectivity is not greatly influenced by reaction temperature (96% ee at... 

In most of the successful Diels-Alder reactions reported, dienes containing no heteroatom have been employed, and enantioselective Diels-Alder reactions of multiply heteroatom-substituted dienes, e.g. Danishefsky s diene, are rare, despite their tremendous potential usefulness in complex molecular synthesis. Rawal and coworkers have reported that the Cr(III)-salen complex 15 is a suitable catalyst for the reaction of a-substituted a,/ -unsubstituted aldehydes with l-amino-3-siloxy dienes [21] (Scheme 1.28, Table 1.12). The counter-ion of the catalyst is important and good results are obtained in the reaction using the catalyst paired with the SbFg anion. 

Evans et al. reported that the his(oxazolinyl)pyridine (pybox) complex of copper(II) 17 is a selective catalyst of Diels-Alder reactions between a-bromoacrolein or methacrolein and cydopentadiene affording the adducts in high enantioselectivity [23] (Scheme 1.30). Selection of the counter-ion is important to achieve a satisfactory reaction rate and enantioselectivity, and [Cu(pyhox)](ShFg)2 gave the best result. This catalyst is also effective for the Diels-Alder reaction of acrylate dieno-philes (vide infra). 

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