Endo selectivity, in the Diels-Alder reaction

Although exo-endo selectivity in the Diels-Alder reaction of olefinic dienophiles has been extensively studied both experimentally and theoretically [31], exo-endo selectivity of the transition structure in the reaction of acetylenic dienophiles has not previously been investigated, because the adducts produced via exo- or endo-transi-tion-state assembly are identical diastereomerically. We used ab initio molecular orbital calculations at the RHF/6-31G level [32] to identify the transition struetures of simple processes of this type, i.e. acid-free and BFs-promoted reactions of cyclopenta-diene and propynal (Fig. 9). As expected, our calculations showed that the exo transition structures are more stable than the endo structures by 0.8 kcal mol" for the former reaction and by 2.0 and 2.4 kcal moF for anti and syn pairs, respectively, for the latter. These calculations strongly suggest the predominance of an exo transition structure and its enhancement by coordination of the Lewis acid. 

The effects of diene structure on endo selectivity in the Diels-Alder reaction have been examined. In the case of spiro[2,4]hepta-1,3-diene, interactions of the dienophile with the methylene groups of the cyclopropane have a major controlling influence on the stereoselectivity. ... 

Briefly explain why maleic anhydride shows greater endo selectivity in the Diels-Alder reaction than does ethyl acrylate. 

In 1980, Breslow showed that water as solvent enhanced both the rate and the endo selectivity in the Diels-Alder reaction. Such a seminal discovery prompted Lubineau to investigate HDAR but also numerous other reactions in water. By grafting a sugar to a diene at the anomeric position, Lubineau solved two problems. First, the reactants were now entirely soluble in water since this was considered as a prerequisite at that time. Actually Grieco devised a water-soluble diene synthesis using a carboxylate group as the hydrophilic part. Second the carbohydrate part could be easily removed by enzymatic hydrolysis. 

A theoretical study of endo-selectivity in the Diels-Alder reaction between butadienes and cyclopropene has shown that neither electron delocalization nor the electrostatic interaction shows preference of enrto-addition over e o-addition. l-Amino-3-siloxybuta-1,3-dienes are highly reactive dienes which show high endo-selectivity in Diels-Alder additions. The aldehyde 2-methylene-5-trimethylsilyl-pent-4-yn-l-al (161) has been shown to be a versatile dienophile reacting with Danishefsky s diene (162) to produce 4 + 2-cycloadducts (163) with endo-selectivity (Scheme 62). " ... 

Concerted cycloaddition reactions provide the most powerful way to stereospecific creations of new chiral centers in organic molecules. In a manner similar to the Diels-Alder reaction, a pair of diastereoisomers, the endo and exo isomers, can be formed (Eq. 8.45). The endo selectivity in the Diels-Alder arises from secondary 7I-orbital interactions, but this interaction is small in 1,3-dipolar cycloaddition. If alkenes, or 1,3-dipoles, contain a chiral center(s), the approach toward one of the faces of the alkene or the 1,3-dipole can be discriminated. Such selectivity is defined as diastereomeric excess (de). 

The endo selectivity in many Diels-Alder reactions has been attributed to attractive secondary orbital interactions. In addition to the primary stabilizing HOMO-LUMO interactions, additional stabilizing interactions between the remaining parts of the diene and the dienophile are possible in the endo transition state (Figure 3). This secondary orbital interaction was originally proposed for substituents having jr orbitals, e.g. CN and CHO, but was later extended to substituents with tt(CH2) type of orbitals, as encountered in cyclopropene57. 

Table 4 Influence of AlCb on the Regio and Endo Selectivity of the Diels-Alder Reaction between ( )-2,4-Pentadiene and Methyl Acrylate in Benzene (Scheme 49)...

It was first found that a chiral Yb catalyst, prepared in situ from Yb(OTf)3, (R)-(+)-l,T-bi-2-naphthol [(l )-BINOL], and a tertiary amine, in dichloromethane, was quite effective in enantioselective Diels-Alder reactions [36]. Some additives were also found to be effective not only in stabilizing the catalyst but also in controlling enantiofacial selectivity in the Diels-Alder reaction. When 3-acetyl-l,3-oxazolidin-2-one was combined with the chiral catalyst as an additive, the (2S,3R) form of the endo adduct was obtained in 93 % ee. When, on the other hand, 3-phenylacetylacetone was mixed with the catalyst as an additive, the (2R,3S) form of the endo adduct was obtained in 81 % ee [37]. 

This phenomenon is well known in most cycloadditions, i.e., additions in which two components are combined which have two enantiofaces each. Thus altogether four combinations are possible leading to two enantiomeric pairs of exo-endo-diastereomers (Scheme 31) [Diels-Alder addition, reaction (94)]. In the arbitrary combination shown is in the endo- and R in the exo-position. Rndo-selectivity in the Diels-Alder reaction (and other cycloadditions) means that the substituent with the higher potential for 7t-7t-interactions with the diene... 

Moreover, after screening several additives other than 29, it was found that some additives were effective not only in stabilizing the catalyst but also in controlling the enantiofacial selectivities in the Diels-Alder reaction. Selected examples are shown in Table 25. When 3-acetyl-l,3-oxazolidin-2-one (30) was combined with the original catalyst system (to form catalyst A), the endo adduct was... 

Moreover, after screening several additives other than 31, it was found that some additives were effective not only in stabilizing the catalyst but also in controlling the enantiofacial selectivities in the Diels-Alder reaction. Selected examples are shown in table 29. When 3-acetyl-l,3-oxazolidin-2-one (32) was combined with the original catalyst system (to form catalyst A), the endo adduct was obtained in 93% ee and the absolute configuration of the product was 2S, 3R. On the other hand, when acetyl acetone derivatives were mixed with the catalyst, reverse enantiofacial selectivities were observed. The endo adduct with an absolute configuration of 2R, 3S was obtained in 81% ee when 3-phenylacetylacetone (PAA) was used as an additive (catalyst B). In these cases, the chiral source was the same (Tf)-binaphthol. Therefore, the enantioselectivities were controlled by the achiral ligands, 3-acetyl-l,3-oxazolidin-2-one and PAA (Kobayashi and Ishitani 1994). 

Endo rule Selectivity favoring the endo adduct in the Diels-Alder reaction. 

Cyclopropene shows an endo selectivity in its Diels-Alder reactions with the tropylium ion, cyclopentene, and acenaphthene because of Ti-alkyl interactions. " Hoffmann calculations show that in the Diels-Alder reaction of butadiene and cyclo-propenone the two reactants do not approach each other in parallel planes. ... 

The isopropylidenated enonates 9—12 have less conformational freedom than the tetraacetates 5—8 and were thus expected to show higher diastereofacial selectivities in the Diels—Alder reaction. This was borne out in the experimental data. The D-lvxo enonate 11 in particular gave a readily separable mixture after reaction with cyclopentadiene under thermal conditions, and afforded a 55% isolated yield of the crystalline si-exo product, mp 88—89 , along with 30% of the si-endo product. The structures of these products were confirmed as before by degradative sequences. The diastereofacial selectivity was >9 1 in favor of si-face attack ... 

As additional evidence for hydrophobic effects in the Diels-Alder reaction, there was a great inaease in the preference for an endo geometry in the Diels-Alder reactions in water [11], as expected if the transition state becomes more compact to minimize exposure of hydrocarbon segments to the water solvent. This endo preference was also inaeased to some extent when LiCl was added, and decreased when GnCl was the additive. Other evidence has also been cited for a hydrophobic effect on Diels-Alder reactions [12], and the water effect on geometric selectivity has been used in synthetic applications [13]. 

Another form of selectivity can arise when substitirted dienes and dienophiles are employed in the Diels-Alder reaction. Two different cycloadducts denoted as endo and exo can then be formed (Figure 1.2). 

In 1961 Berson et al. were the first to study systematically the effect of the solvent on the endo-exo selectivity of the Diels-Alder reaction . They interpreted the solvent dependence of the endo-exo ratio by consideririg the different polarities of the individual activated complexes involved. The endo activated complex is of higher polarity than the exo activated complex, because in the former the dipole moments of diene and dienophile are aligned, whereas in the latter they are pointing in... 

Table 2.9 shows the endo-exo selectivities for the Diels-Alder reaction between 2,4c and 2,5 catalysed by Bronsted-acid and four different metal ions in water. 

In contrast, investigation of the effect of ligands on the endo-exo selectivity of the Diels-Alder reaction of 3.8c with 3.9 demonstrated that this selectivity is not significantly influenced by the presence of ligands. The effects of ethylenediamine, 2,2 -bipyridine, 1,10-phenanthroline, glycine, L-tryptophan and L-abrine have been studied. The endo-exo ratio observed for the copper(II)-catalysed reaction in the presence of these ligands never deviated more than 2% from the endo-exo ratio of 93-7 obtained for catalysis by copper aquo ion. 

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... 

Recently, enhanced endo selectivity has been reported in the Diels-Alder reaction of fE -l-acetoxybuta-l,3-dienes with methyl fi-nitroacrylate The selectivity is compared with that of the reaction using l-methoxybuta-l,3-dienes and 1-trimethylsilyloxybuta-1,3-di-enes The degree of electron richness of a diene is an important consideration in endo eKO selectivity issues In particular, electron-rich dienes favor the formation of fixc-nitrocycload-ducts fEq 8 9 ... 

The optically active a-sulfinyl vinylphosphonate 122 prepared in two different ways (Scheme 38) is an interesting reagent for asymmetric synthesis [80]. This substrate is an asymmetric dienophile and Michael acceptor [80a]. In the Diels-Alder reaction with cyclopentadiene leading to 123, the endo/exo selectivity and the asymmetry induced by the sulfinyl group have been examined in various experimental conditions. The influence of Lewis acid catalysts (which also increase the dienophilic reactivity) appears to be important. The 1,4-addition of ethanethiol gives 124 with a moderate diastereoselectivity. 

Theoretical considerations in the same fashion enable predication of the possible configuration of the transition state. Eq. (3.25 b) for the multicentre interaction is utilized. Hoffmann and Woodward 136> used such methods to explain the endo-exo selectivity of the Diels-Alder reaction (Fig. 7.28). The maximum overlapping criteria of the Alder rule is in this case valid. The prevalence of the endo-addition is experimentally known 137>. 

A typical regioselectivity and endo/exo selectivity has been reported in the Diels-Alder reaction of 2-(/V-acylamino)- 1,3-diene with nitroalkenes (Eq. 8.27).43 Thus, exo products are predominantly formed, which is general for the Diels-Alder reaction of nitroalkenes with sterically hindered dienes. 

Cadogan and coworkers160 developed a fructose-derived l,3-oxazin-2-one chiral auxiliary which they applied in the Diels-Alder reactions of its iV-enoyl derivatives 246 with cyclopentadiene using diethylaluminum chloride as the Lewis acid catalyst. The reactions afforded mixtures of endo 247 and exo 248 (equation 68). The catalyst binds to the chiral dienophile in a bidentate fashion (co-ordination to both carbonyl groups). As a consequence, the dienophile is constrained to a rigid conformation which accounts for the almost complete diastereofacial selectivities observed. 

This explains the experimentally confirmed predictions that polar solvents attenuate the endo-preference, while non-polar solvents increase the cwdo-selectivity of Diels-Alder reactions. The strong correlation between the polarity of the solvent and the endo/exo ratios in the Diels-Alder reaction led to the empirical polarity scale 2 = log endo/exo) using the reaction of cyclopentadiene with methyl acrylate as the standard144. The importance of solvent polarity has also been discerned on the basis of experimental142 and theoretical investigations145. Dependence on the polarizability was also noted146. 

Okamura and Nakatani [65] revealed that the cycloaddition of 3-hydroxy-2-py-rone 107 with electron deficient dienophiles such as simple a,p-unsaturated aldehydes form the endo adduct under base catalysis. The reaction proceeds under NEtj, but demonstrates superior selectivity with Cinchona alkaloids. More recently, Deng et al. [66], through use of modified Cinchona alkaloids, expanded the dienophile pool in the Diels-Alder reaction of 3-hydroxy-2-pyrone 107 with a,p-unsaturated ketones. The mechanistic insight reveals that the bifunctional Cinchona alkaloid catalyst, via multiple hydrogen bonding, raises the HOMO of the 2-pyrone while lowering the LUMO of the dienophile with simultaneous stereocontrol over the substrates (Scheme 22). 

Since silyl cations are highly reactive and moisture sensitive, the salts (S)-2a and (S)-2b were prepared in situ from the air and moisture stable precursor (S)-5 via a hydride transfer [34, 35] with trityl tetrakis[3,5-bis(trifluoromethyl)phenyl]borate [Tr][TFPB] or trityl tetrakis[pentafluorophenyl]borate [Tr][TPFPB], The authors showed by Si-NMR studies that the desired salts were formed. The silyl salt (5)-2a was then tested in the Diels-Alder reaction as shown in Scheme 5. A good reactivity was found, and the product was obtained in 95% yield with higher than 95% endo selectivity at -40 °C in 1 h. However, only 10% ee was achieved. 

The authors investigated the salts in the Diels-Alder reaction. In analogy to the NMR experiments similar reactivities were found. As presented in Scheme 44, the salts gave up to 91% yield in high endo-selectivity with cyclopentadiene and an unsaturated amide in 4 h. The highest yield was obtained with salt 45, while for example salt 47 gave only 7% and salt 49 gave only traces. 

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