Racemic endo Diels-Alder products

We planned to test the RCDA reaction on the known diol 4 (an intermediate in Nicolaou s endiandric acid synthesis) or a derivative thereof (Scheme 3). These model compounds have substituents at the relevant positions on the cyclobutane ring. However, unlike the pre-kingianin isomeric pairs, which have the potential to afford eight racemic endo Diels-Alder products. 

Also the use of moisture stable ionic liquids as solvents in the Diels-Alder reaction has been carried out, and in all examples an enhanced reaction rate was observed [182,183]. The application of pyridinium-based ionic liquids allowed the utilization of isoprene as diene [184]. The chiral ionic liquid [bmim][L-lactate] was used as a solvent and accelerated the reaction of cyclopentadiene and ethyl acrylate, however, no enantiomeric excess was observed [183]. In addition several amino acid based ionic liquids have been recently tested in the Diels-Alder reaction. Similar exo. endo ratios were found but the product was obtained as racemate. The ionic liquids were prepared by the addition of equimolar amounts of HNO3 to the amino acids [185]. Furthermore, an enantiopure imidazolium salt incorporating a camphor motive was tested in the Diels-Alder reaction. No enantiomeric excess was found [186]. 

The ionic liquid [bmim][BF ] is known to catalyze the aza-Diels-Alder reaction in the synthesis of pyrano- and furanoquinolines [190]. This reaction was also catalyzed by the enantiopure bis-imidazolinium salt 67 in 67% yield with an endo. exo ratio of 60 40 (Scheme 69) [191]. The product was obtained as a race-mate. In addition the aza-Diels-Alder reaction with imines and Danishefsky s diene was catalyzed by the salt 67 giving racemic product. The salt and its analogues could be easily prepared via the oxidation of the corresponding aminals [192]. Investigation of the influence of the counter anion in achiral C2-substituted imidazolinium salts, which can be also described as 4,5-dihydroimidazolium or saturated imidazolium salts, in the aza-Diels-Alder reaction showed, that the catalytic activity increased, the more lipophilic the counter anion and therefore the more hydrophobic the salt was [193]. 

These results indicate that the sulfinyl group seems to be much more efficient in the control of the stereoselectivity of 1,3-dipolar cycloadditions (endo or exo adducts are exclusively obtained in de> 80%) than in Diels-Alder processes (mixtures of all four possible adducts were formed). Additionally, complete control of the regioselectivity of the reaction was observed. Despite these clearly excellent results, the following paper concerning asymmetric cycloaddition of cyclic nitrones and optically pure vinyl sulfoxides was reported nine years later [154]. (Meanwhile, only one paper [155], related to the synthesis of /1-nicotyri-nes, described the use of reaction of nitrones with racemic vinyl sulfoxides, but these substrates were merely used as a masked equivalent of acetylene dipolaro-phile). In 1991, Koizumi et al. described the reaction of one of the best dipolarophiles, the sulfinyl maleimide 109, with 3,4,5,6-tetrahydropyridine 1-oxide 194 [154]. It proceeded in CH2C12 at -78 °C to afford a 60 20 10 6 mixture of four products in ca. 90 % yield (Scheme 92). 

The Diels-Alder reactions of racemic N-(p-tolyl)-S-p-tolyl-S-vinylsulfoximine with dienes gave mixtures of diastereomeric cycloadducts in good yield (Table 18). When cyclopentadiene and 1,3-cyclohexadiene were employed as dienophiles, the endo diastereomeric products 268c and 268d (n = 1,2) predominated.120... 

The stability of (BIPHEP)PtX2 compounds with respect to racemization over several hours at room temperature suggested that these compounds could be employed as catalysts at room temperature or below. To explore this possibility, [BlPHEP]Pt(OTf)2 was employed in the asymmetric Diels-Alder reaction as illustrated in equation (6). Freshly generated [(l )-BlPHEP]Pt(OTf)2 promoted the asynunetric Diels Alder reaction forming the product in 94 6 endo exo ratio with the ee of the major diastereomer of 92 94%. The enantiomeric excess of the catalyst [(l )-BlPHEP]Pt(OTf)2 was not diminished over the course of the reaction, as determined by quenching the reaction at >90% conversion with (5, 5 )-DPEN and subsequent P NMR analysis of the resulting mixture. The facial selectivity of the asymmetric Diels-Alder reaction catalyzed by [(/f)-BlPHEP]Pt(OTf)2 was the same as observed with [(/ )-BINAP]Pt(OTf)2 with the same... 

The product of a Diels-Alder reaction between cyclopentadiene and benzyl acrylate must necessarily be racemic as both reagents are achiral. Though only one diastereoisomer—the endo product—is formed, it must be formed as an exactly 50 50 mixture of enantiomers. 

Diels-Alder reaction gives a racemic product one diastereoisomer (endo)... 

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 utility of such cycloadditions has been demonstrated by the elaboration of the cycloadducts to complex natural products [60]. For example, the adduct derived from a cyclopentadiene having a 2-bromoallyl sidechain has been converted to an intermediate employed in a previous (racemic) synthesis of gibberel-lic acid. As illustrated in Scheme 12, an exceptionally efficient synthesis of cassi-ol is realized by the successful execution of a rather difficult endo-selective Diels-Alder reaction using a slightly modified oxazaborolidine (11). The high catalyst loading is balanced by the fact that all the carbons and the quaternary center of the natural product are introduced in a single step. 

The diastereoselectivity inherent to the Diels-Alder reaction can be seen in most of the examples in preceding reactions. The reaction is not, however, enantioselective since there is no facial control for intermolecular reactions (some facial control is available for intramolecular reactions). The ortho rule, the endo rule (secondary orbital interactions), and steric interactions provide some orientational control but facial control is also required for enantioselectivity. When ethyl acrylate reacts with 2-methyl-1,3-pentadiene, it can approach from the bottom as in 247A or from the top as in 247B. Clearly, the two products (248A and 248B) are mirror images and enantiomers. This lack of facial selectivity leads to racemic mixtures in all Diels-Alder cyclizations discussed to this point. 

Palladium-catalyzed cross coupling of pyrone 252 with stannane 253 resulted in the intermediate 257, which underwent a Diels-Alder reaction to give cycloadducts 254 and 255 in a combined yield of 45%, favoring the endo product 255 (endo/exo = 2.5 1). In this reaction, the addition of Cul was cracial, as without Cul only traces of the cycloadducts were obtained. Further transformations of 255 resulted in racemic galanthamine (256). In 2000, the group of Trost [103] reported an enantioselective synthesis of this alkaloid applying a Pd-catalyzed asymmetric aUyUc alkylation and an intramolecular Heck reaction to assemble the... 

The key intermediates in all of our work are anhydrides 5 and 6, the kinetic and thermodynamic products respectively of the Diels-Alder reaction between cyclopentadiene and maleic anhydride (Scheme 3). Subsequent reaction of these anhydrides with an amino-ester gave the endo- and exc -isomers (7 and 8) of monomers containing a single amino-ester. We have shown that this synthesis is compatible with a wide range of amino-acids, and that in most cases it causes no racemization of the amino-acid stereocentre. When amino-acids which are particularly prone to racemization (e.g. cysteine and phenylglycine) are used however, then the synthesis shown in Scheme 3 does cause some racemization. To avoid this problem, a slightly modified synthesis was developed (Scheme 4) which does not involve any heating of the reaction mixture and hence does not cause any racemization. The syntheses shown in Scheme 3 and Scheme 4 can also be adapted to the preparation of 7-oxonorbornene... 

Section 24.3.1 noted that the Alder endo rule is applied to acyclic dienes as well as cyclic dienes, but it is more difficult to see the product in the former case. In order to form 21, an endo approach (22) of acrylonitrile to the diene is required. An exo approach used transition state 23, which leads to the other diastereomer, 20. There is disrotatory motion for both endo and exo approaches. When the alkene has a substituent containing a n-bond—particularly, a C=0 unit—endo approach is usually favored. An endo approach of the alkene combined with a disrotatory motion of the groups on the diene leads to formation of one diastereomer as the major product. The Diels-Alder reaction is diastereose-lective. Because the alkene may approach from either the bottom (see Figure 24.4) or the top, the product will he racemic. 

Even though the Diels-Alder reaction results in formation of predominantly one stereoisomeric form (endo with retention of the original dienophile configuration), the product is nevertheless formed as a racemic mixture. The reason for this is that either face of the diene can interact with the dienophile. When the dienophile bonds with one face of the diene, the product is formed as one enantiomer, and when the dienophile bonds at the other face of the diene, the product is the other enantiomer. In the absence of chiral influences, both faces of the diene are equally likely to be attacked. 

The dimerization of cyclopentadiene occurs primarily through an endo transition state, as is typical for Diels-Alder reactions, (a) In the reactants, draw red and blue shaded lobes for the orbitals that have favorable secondary interactions in the diene and dienophile, causing the preference for an endo transition state, (b) Using bond-line formulas, draw curved arrows to show the flow of electrons that leads to product formation, and draw a three-dimensional formula for the product, (c) The reaction produces a racemic mixture. Show how the reactants align in three dimensions to form each enantiomer. 

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