Carbo Diels-Alder reactions

The Diels-Alder cycloaddition in aqueous medium was also successfully exploited in the synthesis of biotinylated oligonucleotides by bioconjugation of diene-modificated oligonucleotides and biotinmaleimide.  

Optically active compounds (ee 11-77%) were recently prepared (yields 13-81%) by a one-pot procedure in a water suspension using inclusion complexes of N-alkylmaleimides 

The Diels-Alder adducts 15-18, subjected to strong basic conditions followed by in situ Nef-cyclodehydration reaction in acidic medium, gave by one-pot procedure 1,4-dihydrodibenzo [l),d]furans 23-25 in 48-50% overall yields. 

The catalytic effect of thiourea derivative 26 (a bidentate hydrogen-bond donor) was investigated in the Diels-Alder reaction of methyl vinyl ketone (27) with cyclopentadi-ene (5) in cyclohexane (that has negligible interactions with the solutes), chloroform (a weak hydrogen-bond donor), and in water (a high polar solvent) to give 5-norbornene-2-methylketone (28) (Table 5.2). 

The reaction rate was faster in water than in the organic solvents, but the catalytic effect (c.e., expressed in terms of percent increase of yield Table 5.2) was less in the polar reaction medium because water does not favor the complexation of dienophile by the catalyst. An analogous result was obtained. s jjj jjjg Diels-Alder reaction of 3-(4-nitrophenyl)-l-(2-pyridyl)-2-propen-l-one (a bidentate dienophile) with cyclopentadiene (5) in water and MeCN catalyzed by Cu(N03)2. In sole water, the cycloaddition was 287 times faster than in MeCN but the catalytic effect of Cu(N03)2 (expressed in terms of relative reaction rates) in water was 808, while in MeCN it was 158,000. 

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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. 

Gothelf presents in Chapter 6 a comprehensive review of metal-catalyzed 1,3-di-polar cycloaddition reactions, with the focus on the properties of different chiral Lewis-acid complexes. The general properties of a chiral aqua complex are presented in the next chapter by Kanamasa, who focuses on 1,3-dipolar cycloaddition reactions of nitrones, nitronates, and diazo compounds. The use of this complex as a highly efficient catalyst for carbo-Diels-Alder reactions and conjugate additions is also described. 

Frontier-molecular-orbital Interactions for Carbo-Diels-Alder Reactions... 

The reactivity of the carbo-Diels-Alder reaction, as well as the other reactions considered in this chapter, can be accounted for by a simple FMO line of reasoning, i.e., the energy term from second-order perturbation theory... 

Fig. 8.1 Frontier-orbital interaction for carbo-Diels-Alder reactions, (a) The interaction of a dienophile with a low-energy LUMO, in the absence and presence of a Lewis acid (LA),...

Most Lewis acid-catalyzed carbo-Diels-Alder reactions belong to the interactions outlined to the left in Fig. 8.1 and in the following only theoretical calculations of this type will be considered. 

The FMOs of acrolein to the left in Fig. 8.2 are basically slightly perturbed butadiene orbitals, while the FMOs of protonated acrolein resemble those of an allyl cation mixed in with a lone-pair orbital on the oxygen atom (Fig. 8.2, right). Based on the FMOs of protonated acrolein, Houk et al. [2] argued that the predominant interaction in a normal electron-demand carbo-Diels-Alder reaction is between the dienophile LUMO and diene HOMO (Fig. 8.1, left). This interaction is greatly... 

The carbo-Diels-Alder reaction of acrolein with butadiene (Scheme 8.1) has been the standard reaction studied by theoretical calculations in order to investigate the influence of Lewis acids on the reaction course and several papers deal with this reaction. As an extension of an ab-initio study of the carbo-Diels-Alder reaction of butadiene with acrolein [5], Houk et al. investigated the transition-state structures and the origins of selectivity of Lewis acid-catalyzed carbo-Diels-Alder reactions [6]. Four different transition-state structures were considered (Fig. 8.4). Acrolein can add either endo (N) or exo (X), in either s-cis (C) or s-trans (T), and the Lewis acid coordinates to the carbonyl in the molecular plane, either syn or anti to the alkene. 

The mechanism of the carbo-Diels-Alder reaction has been a subject of controversy with respect to synchronicity or asynchronicity. With acrolein as the dieno-phile complexed to a Lewis acid, one would not expect a synchronous reaction. The C1-C6 and C4—C5 bond lengths in the NC-transition-state structure for the BF3-catalyzed reaction of acrolein with butadiene are calculated to be 2.96 A and 1.932 A, respectively [6]. The asynchronicity of the BF3-catalyzed carbo-Diels-Alder reaction is also apparent from the pyramidalization of the reacting centers C4 and C5 of NC (the short C-C bond) is pyramidalized by 11°, while Cl and C6 (the long C-C bond) are nearly planar. The lowest energy transition-state structure (NC) has the most pronounced asynchronicity, while the highest energy transition-state structure (XT) is more synchronous. 

The endo exo selectivity for the Lewis acid-catalyzed carbo-Diels-Alder reaction of butadiene and acrolein deserves a special attention. The relative stability of endo over exo in the transition state accounts for the selectivity in the Diels-Alder cycloadduct. The Lewis acid induces a strong polarization of the dienophile FMOs and change their energies (see Fig. 8.2) giving rise to better interactions with the diene, and for this reason, the role of the possible secondary-orbital interaction must be considered. Another possibility is the [4 + 3] interaction suggested by Singleton... 

The influence of alkyl substituents on the asynchronous transition-state structure of the BF3-catalyzed carbo-Diels-Alder reaction of a,/ -unsaturated aldehydes with 1,1-dimethyl-l,3-butadiene derivatives has been investigated by Dai et al. [13]. 

In a combined experimental and theoretical investigation it was found that the / -alkyl group in the dienophile gave a steric interaction in the transition-state structure which supported the asynchronous transition-state structure for the Lewis acid-catalyzed carbo- and hetero-Diels-Alder reactions. The calculated transition-state energies were of similar magnitude as obtained in other studies of these BF3-catalyzed carbo-Diels-Alder reactions. 

A frequently used catalytic system used for the catalytic enantioselective carbo-Diels-Alder reaction of N-alkenoyl-l,3-oxazolidin-2-one 4 is the chiral TADDOL-Ti(IV) 6 [14] complexes (Scheme 8.2 see Ghapter 1 in this book, by Hayashi) [15]. 

Fig. 8.7 The different transition-state shapes for the carbo-Diels-Alder reaction in the pressence of a strong Lewis acid (left) - a three center interaction - and a weak Lewis acid (right) [12]...

Yamamoto et al. have developed a catalytic enantioselective carbo-Diels-Alder reaction of acetylenic aldehydes 7 with dienes catalyzed by chiral boron complexes (Fig. 8.10) [23]. This carbo-Diels-Alder reaction proceeds with up to 95% ee and high yield of 8 using the BLA catalyst. The reaction was also investigated from a theoretical point of view using ab-initio calculations at a RHF/6-31G basis set. 

A series of investigation using, e.g., semi-empirical calculations have also been performed [24]. These calculations are often used in relation with experimental investigations, as well as, e.g., the carbo-Diels-Alder reaction of acrolein with dienes. 

We are now able to understand the Lewis acid-catalyzed normal electron-demand carbo-Diels-Alder reaction from a theoretical point of view. The calculated influence of the Lewis acids on the reaction rate, regio- and stereoselectivity in an... 

Fig. 8.10 The catalytic enantioselective carbo-Diels-Alder reaction of acetylenic aldehydes 7 with cyclopentadiene 2 catalyzed by chiral...

The number of theoretical investigations of hetero-Diels-Alder reaction is very limited. The few papers dealing with this class of reactions have shown that the influence of the Lewis acid on the reaction course can to a high extent be compared to those found the carbo-Diels-Alder reactions. At the present stage of investigations, however, more work is needed if we are to understand the influence and control of selectivity in Lewis acid-catalyzed hetero-Diels-Alder reaction - we are probably at the beginning of a new era in this field. 

Keywords water, Lewis acids, carbo-Diels-Alder reactions, hefero-Diels-Alder reactions... 

The presence of one or more heteroatoms in either the 4jt or In component allows the synthesis of six-memebered heterocycles via the Diels-Alder process. These strategies have been successfully developed (218) leading to a diverse array of natural products. Similar to the carbo-Diels-Alder reaction, many of these processes are amenable to Lewis acid acceleration, and several have been developed using chiral catalysts. 

A simple, commercially available chiral alcohol, a,a,a a -tetraaryl-l,3-dioxo-lane-4,5-dimethanol (TADDOL, 7a), catalyzes the hetero- and carbo-Diels-Alder reactions of aminosiloxydienes with aldehydes and a-substituted acroleins to afford the dihydropyrones and cyclohexenones, respectively, in good yields and high enan-tioselectivities. More recently, it was reported that axially chiral biaryl diols 7b and 7c were more highly effective catalysts for enantioselective hetero-Diels-Alder reactions (Scheme 12.5). ... 

The intermolecular Diels-Alder reaction (sec. 11.4) is shown first. Example 1 from Table 10.1 is a carbo-Diels-Alder reaction taken from the Cha and co-workers synthesis of clavepictine Example 2 is a... 

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