Acrylic acid Cyclopentadiene

The Diels-Alder reaction of a diene with a substituted olefinic dienophile, e.g. 2, 4, 8, or 12, can go through two geometrically different transition states. With a diene that bears a substituent as a stereochemical marker (any substituent other than hydrogen deuterium will suffice ) at C-1 (e.g. 11a) or substituents at C-1 and C-4 (e.g. 5, 6, 7), the two different transition states lead to diastereomeric products, which differ in the relative configuration at the stereogenic centers connected by the newly formed cr-bonds. The respective transition state as well as the resulting product is termed with the prefix endo or exo. For example, when cyclopentadiene 5 is treated with acrylic acid 15, the cw fo-product 16 and the exo-product 17 can be formed. Formation of the cw fo-product 16 is kinetically favored by secondary orbital interactions (endo rule or Alder rule) Under kinetically controlled conditions it is the major product, and the thermodynamically more stable cxo-product 17 is formed in minor amounts only. 

Scott Oakes et al. (1999a, b) have shown how adoption of SC conditions can lead to a dramatic pressure-dependent enhancement of diastereoselectivity. In the case of sulphoxidation of cysteine derivatives with rert-butyl hydroperoxide, with cationic ion-exchange resin Amberlyst-15 as a catalyst, 95% de was realized at 40 °C and with SC CO2. By contrast, with conventional solvents no distereoselectivity was observed. Another example is the Diels-Alder reaction of acrylates with cyclopentadiene in SC CO2 at 50 °C, with scandium tris (trifluoromethanesulphonate) as a Lewis acid catalyst. The endoiexo ratio of the product was as high as 24 1, while in a solvent like toluene it was only 10 1. 

Although the above demonstrated that product control could be achieved in scC02, the difference in selectivity was relatively small. However, later work using a Lewis acid catalyst, scandium triflate, on the Diels-Alder reaction of n-butyl acrylate and cyclopentadiene (Scheme 7.7) showed that the endo exo ratio was again found to rise to a maximum and then decrease again as the pressure, and hence density, was increased (Figure 7.3) [19]. 

Yamamoto and colleagues developed achiral boron catalysts 379 and 380a-b derived from monoacylated tartaric acid and BH3 -THF as shown for 379 in equation 112. The cycloaddition of cyclopentadiene to acrylic acid (381) afforded endo 382 with 78% ee and 93% yield when catalyst 379 was employed (equation 113)239. 

For the Diels-Alder reaction, polymer-bound acrylic acid ester (73) was treated with cyclopentadiene. The cycloaddition product (74) was formed with an endo/exo ratio of 2.5 1 and with quantitative conversion. The subsequent enzymatic release delivered the corresponding alcohols (72, 75) in high yield and purity. 

As can be seen in Table 5, various oxazolidones of acrylic acid derivatives react with cyclopentadiene to afford the endo-adducts in good to high (64-91%) enantioselectivity by the combined use of a catalytic amount of the chiral titanium reagent and MS 4A. 

The reactions of various oxazolidones of B-substituted acrylic acids with cyclopentadiene were found to proceed with high asymmetric induction by using 1,3,5-trimethylbenzene as the... 

Cycloaddition reactions.l This surfactant increases the rate of Diels-Alder reactions. In addition, the endo/exo ratio is improved in the addition of acrylic acid derivatives to cyclopentadiene. 

Alder s endo rule applies not only to cyclic dienes like cyclopentadiene and to disubstituted dienophiles like maleic anhydride, but also to open chain dienes and to mo no-substituted dienophiles diphenylbutadiene and acrylic acid, for example, react by way of an endo transition structure 2.113 to give largely (9 1) the adduct 2,114 with all the substituents on the cyclohexene ring cis, and equilibration again leads to the minor isomer 2.115 with the carboxyl group trans to the two phenyl groups. 

Asymmetric Diels-AUer reactions The observation that simple acyloxy-boranes such as H2BOCOCH=CH2, prepared by reaction of BH3 with acrylic acid, can serve as Lewis acid catalysts for reactions of the a,P-unsaturated acids with cyclopentadiene (15, 2) has been extended to the preparation of chiral acyloxy-boranes derived from tartaric acid. The complex formulated as 3, prepared by reaction of BH3 with the monoacylated tartaric acid 2, catalyzes asymmetric Diels-Alder reactions of a,P-enals with cyclopentadiene with high enantioselectivity. The process is applicable to various dienes and aldehydes with enantioselectivities generally of 80-97 % ee. 

Simple diastereoselectivity may also occur in Diels-Alder reactions between electron-poor dienophiles and cyclopentadiene (Figure 15.30). Acrylic acid esters or fraus-crotonic acid esters react with cyclopentadiene in the presence or absence of A1C13 with substantial selectivity to afford the so-called emfo-adducts. When the bicyclic skeleton of the main product is viewed as a roof the prefix endo indicates that the ester group is below this roof, rather than outside (exo). However, methacrylic acid esters add to cyclopentadiene without any exo.endo-selectivity regardless whether the reaction is carried out with or without added A1C13 (Figure 15.30, bottom). 

Fig. 12.29. Simple diastereoselectivity of the additions of various acrylic acid derivatives to cyclopentadiene.

Consideration of the dipolarity of the two activated complexes can explain the observed trend. If the reactants are pictured as lying in roughly parallel planes, the dipole moments for the exo orientation are seen to be nearly opposite in direction, whereas for the endo orientation they are parallel. Therefore, the net dipole moment for the endo transition state is greater than that for the exo. Thus, the solvation of the endo activated complex will be more pronounced as the polarity of the solvent increases. This leads to a lowering of the activation enthalpy and preferential formation of the endo adduct. The logarithm of the endojexo product ratio in various solvents has been used to define an empirical solvent polarity scale [124] [cf. Section 7.3). Analogous solvent-dependent endolexo product ratios have been obtained in [4 -1- 2]cycloadditions of cyclopentadiene to other acrylic acid derivatives [560]. Theoretical calculations on exoj endo structures for activated complexes of [4 + 2]cycloadditions have shown that the observed endo preference in polar solvents is due to the influence of the medium, and that secondary orbital interactions are not involved [808]. The solvent has the decisive influence on the exo/endo selectivity. 

The fact that the rate of some Diels-Alder [4 + 2] cycloaddition reactions is affected, albeit only slightly, by the solvent was used by Berson et al. [52] in establishing an empirical polarity parameter called Q. These authors found that, in the Diels-Alder addition of cyclopentadiene to methyl acrylate, the ratio of the endo product to the exo product depends on the reaction solvent. The endo addition is favoured with increasing solvent polarity cf. Eq. (5-43) in Section 5.3.3. Later on, Pritzkow et al. [53] found that not only the endojexo product ratio but also the absolute rate of the Diels-Alder addition of cyclopentadiene to acrylic acid derivatives increases slightly with increasing solvent polarity. The reasons for this behaviour have already been discussed in Section 5.3.3. Since reaction (5-43) is kinetically controlled, the product ratio [endo]l[exo] equals the ratio of the specific rate constants, and Berson et al. [52] define... 

Chiral Lewis Acid. These chiral titanium reagents are widely used as chiral Lewis acid catalysts. The Diels-Alder reaction of methyl acrylate and cyclopentadiene affords the endo adduct in moderate enantioselectivity when a stoichiometric amount of the chiral titanium reagent (5) is employed (eq 6). Use of 3-(2-alkenoyl)-l,3-oxazolidin-2-ones as dienophiles greatly improves the optical purity of the cycloadduct when the 2-phenyl-2-methyl-1,3-dioxolane derivative (6) is used as a chiral ligand. Most importantly, the reaction proceeds with the same high enantioselectivity for the combination of various dienophiles and dienes even when 5-10 mol % of the chiral titanium reagent is employed in the presence of molecular sieves 4A (eqs 7 and 8). ... 

The fust use of an asymmetric Diels-Alder reaction in enantioselective synthesis, reported by Corey and Ensley (1975), involved both diene and dienophile face differentiations (Scheme 74). Addition of 5-(methoxymethyl)cyclopentadiene (304) to acrylic acid (305a) proceeded endo selectively and anti with respect to the diene substituent. Consequently, the relative configuration of the four new chiral centers in (30fo) was determined and, of four possible diastereoisomers, one was formed selectively. As expected, the diene added at the same rate to the two enantiotopic dienophile ir-faces, affording a 1 1 mixture of the enantiomers (lf )-(306a) and (15)-(306a). 

Another promising approach has been devised by Yamamoto and co-workers [8]. They found that the action of a controlled amount of diborane on a carboxylic acid leads to an (acyloxy)borane RC02BR 2 which behaves as a Lewis acid. The chiral (acyloxy)borane (CAB) complex 1 formed in situ from monoacyl tartaric acid and diborane is an excellent asymmetric catalyst (Eq. 8) for the Diels-Alder reaction of cyclopentadiene and acrylic acid (78 % ee) (Eq. 9) [8] or of cyclopentadiene and methacrolein (96 % ee) (Eq. 10) [9]. 

The asymmetric Diels-Alder reaction of optically active acrylate and cyclopentadiene is promoted by Et2AlCl as a Lewis acid giving the endo adduct preferentially with moderate diastereoselectivity the use of MAD once again enhances diastereo-selectivity (Sch. 131) [170]. 

The first examples of an asymmetric Diels-Alder reaction of a non-chiral diene and a dienophile catalyzed by a chiral Lewis acid were reported by Koga and coworkers in 1979 (Sch. 1 and 16) [3]. The catalysts 4,142 and 143 were prepared from (-)-menthol, (+)-neomenthol and (+)-borneol. The reaction of methacrolein and cyclopentadiene mediated by catalyst 4 gave a 98 2 mixture of exo to endo products and upon separation of these diastereomers by chromatography the exo product 3 was obtained in 69 % yield and 72 % ee. The exo .endo ratios for the other reactions in Sch. 16 were not reported. Low asymmetric induction was observed for acrolein and methyl acrylate with all three catalysts. Moderate induction was observed in the reaction of methacrolein with catalyst 4, and with catalyst 142, but in the latter the enantiomer of 3 was the predominant product. The reaction of methyl acrylate with cyclopentadiene mediated by 10 mol % catalyst 4 was also reported by Kobayashi, Matsumura and Furukawa to give the cycloadduct 141 in 2.9 % ee at 30 °C [37]. These workers also reported that catalyst 4 will give optically active product from the reaction of cyclopentadiene and acrylonitrile, although the optical yield was not determined. 

As far as stereoselectivity is concerned, the key step is the Diels-Alder reaction—in each case the diene (cyclopentadiene, shown in black) adds across the dienophile, an acrylic acid derivative. As you would expect from what we said in Chapter 35, both reactions are diastereoselective in that they generate mainly the endo product. In the hrst example, that is all there is to say the product that is formed is necessarily racemic because all the starting materials in the reaction were achiral. 

The Diels-Alder reaction (diene synthesis) is the addition of compounds containing double or triple bonds (dienophiles) to the 1,4 positions of conjugated dienes with the formation of six-membered hydroaromatic rings. Hydrocarbons most often used in the reaction are 1,3-butadiene, cyclopentadiene, and isoprene, and dienophiles used include maleic anhydride, acrolein, and acrylic acid. The literature on this process is thoroughly reviewed by Alder (1), Kloetzel (59), Holmes (48), and Norton (82). 

Another tartaric acid-derived complex catalyzes the Diels-Alder reaction of terf-butyl acrylate and cyclopentadiene with good levels of enantiomeric excess (Scheme 42) [120]. The use of a smaller ester substituent resulted in lower enan-tioselectivity for the derived cycloadduct. 

To generate dienophile 13, the auxiliary 12 was esterified with acrylic acid chloride. The reactions of the resin-bound acrylate ester 13 with isoprene, 2,3-dimethylbutadiene, cyclopentadiene and 1,3-cyclohexadiene were carried out in the presence of TiCf and yielded 80-98% of 14 after cleavage from the polymer (Scheme 12.7). Enantiomeric excesses (ee) from 40 to 99% have been reported. 

Esterification of 19 with acrylic acid chloride made diene 20 available. Subsequent stereoselective Diels-Alder cycloaddition with cyclopentadiene proceeded with complete diastereoselectivity in 55% yield. The asymmetric product 21 was cleaved from the polymer by exposure to light (Scheme 12.11). 

One of the most common auxiliaries is menthyl, where an acrylic acid derivative is attached to menthol to form a menthyl ester, 255. Morrison and Mosher22l showed that asymmetric induction is possible with 255 when it reacts with cyclopentadiene to give diastereomers 256 and 257, 22 as shown in Table 11.13.221 in the absence of a Lewis acid, however, the % ee is rather poor. Similarly, (-)-dimenthyl fumarate (258) reacted with butadiene to give 259 and 260, after reduction of the ester products with lithium aluminum hydride. Hydride reduction of esters (sec. 4.2.B) is a common method for removing ester auxiliaries. The work of... 

When the dienophile is acyclic, the endo rule is not always obeyed and the composition of the mixtures obtained depends on the structure of the dienophile and diene and on the reaction conditions. For example, in the addition of acrylic acid to cyclopentadiene, the endo and exo products were obtained in the ratio 75 25 but with a-substituted acrylic acids, the product ratio varies, depending on the nature of the a-substituent (3.68). Variable ratios are also obtained in reactions with P-substituted acrylic acids. With acrylic acid itself, the proportion of the endo adduct formed is increased by the presence of a Lewis acid catalyst. 

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