Diels-Alder reactions racemic catalysts

The design and application of chiral, non-racemic Lewis acids for the asymmetric Diels-Alder reaction has recently been a subject of considerable interest.9 Several methods have been developed in many laboratories1 2 3 4 5 6 7 10 but catalysts are still needed that are more efficient in governing the stereochemical course of the cycloaddition reaction. 

The rac-isomers have a twofold axis and therefore C2-symmetry. The meso-isomer has a mirror plane as the symmetry element and therefore Cs-symmetry. For polymerisation reactions the racemic mixture can be used since the two chains produced by the two enantiomers are identical when begin- and end-groups are not considered. Note When catalysts of this type are to be used for asymmetric synthesis, e.g. as Lewis acids in Diels-Alder reactions, separation of the enantiomers is a prerequisite [25],... 

In addition, it was possible to show that salt (5)-2a could catalyze the aza-Diels-Alder reaction as presented in Scheme 6. Benzylidene-2-methoxyaniline and Danishefsky s diene in the presence of 10 mol% catalyst at 0 °C gave the desired product in 74% yield in just 2 h. Unfortunately, the obtained product was racemic. 

Enzymatic DKRs have also been applied in domino one-pot processes [97]. The combination of a lipase-catalyzed resolution with an intramolecular Diels-Alder reaction led to interesting building blocks for the synthesis of natural products such as compactin [98,99] or forskolin [100-102], A ruthenium catalyst is employed for the racemization of the slow reacting enantiomer of the starting material. The DKR with lipase B from C. antarctica delivered high enantiomeric excesses which could mainly be contained through the Diels-Alder reaction (Fig. 12). 

Mikami et al. studied the Diels-Alder reaction between a-methylstyrene and n-butyl glyoxylate catalyzed by a titanium binolate catalyst.76-78 Addition of 0.5 equivalents of (Zf)-BINOL to 1 equivalent of the racemic catalyst accelerated the reaction and gave the product with 89.8% ee (Scheme 20). Enantiopure catalyst derived solely from (/ )-BINOL gave the product with 94.5% ee. Here the amplification originates from the creation of a new chiral complex 9 of higher efficiency (rate and enantioselectivity) with respect to each enantiomer of the original racemic catalyst. 

Subsequently, Posner published the completely regioselective and highly stereoselective cyclo additions of racemic 3-(p-tolylsulfinyl)-2-pyrone (141) (Scheme 70) with 1,1-dimethoxyethylene [133],vinylether,and vinylthioethers [134]. With the first dienophile, the best diastereoselectivity (an 88 12 ratio of the two endo-adducts) was achieved at room temperature in toluene or hexane as the solvent (48 h). A 10 1 endo/exo mixture of cycloadducts was obtained with vinyl-ether in the presence of ZnBr2 as the catalyst, whereas a total endo selectivity was observed in reactions of 141 with vinylthioethers [134] conducted under high pressures. The bridged bicyclic lactone cycloadducts 142 have been used as versatile synthons in the synthesis of shikimic acid derivatives. Although enantio-merically pure samples of compound 141 could be obtained [134] it was not used as a starting material for asymmetric Diels-Alder reactions (the low yield of (S)-141 precluded this). 

After having developed a reliable route to the enantiopure carboxylic acid 4a, we next turned our attention to gain access to the enantiopure decalin fragment. One of the most efficient approaches to this structural motif is the intramolecular Diels-Alder reaction. The first systematic studies in the racemic series were performed by Roush and co-workers in 1981 (Roush and Hall 1981). Evans (Evans et al. 1984, 1988) and Oppolzer (Oppolzer and Dupuis 1985) showed that chiral auxiliaries in combination with strong Lewis acids allowed the generation of the endo adducts with excellent diastereoselectivities (Scheme 5). Recently, chiral Lewis acid catalysts were successfully used by Evans (Evans et al. 1999) and Corey (Zhou et al. 2003). 

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... 

There is the potential with some substrates that the Lewis acidity of the lanthanide ion can catalyze a reaction. For example, the addition of Eu(hfc)3 to a racemic mixture of dimethylpenta-2,3-dienoates (39) caused an enrichment of the (5 )-isomer °. Over nine days the mixture converted to an 89 11 mixture. Lanthanide tris( S-diketonates) are well known catalysts for Diels-Alder reactions, and NMR spectroscopy of the reactants with Eu(hfc)3 was used to understand the stereoselectivity of the europium-catalyzed cycloadditions . ... 

When catalyst 333 was applied in the cycloaddition reaction of 2-methoxy-l,3-butadiene (334) with /-(o-tolyl)maleimide (335), the conesponding cycloadduct 337a was obtained with only 58% ee. However, an ee of 95% was observed when catalyst 338 and N-(o-t-butylphenyl)maleimide (336) were employed (equation 94). The meta methyl substituents on the phenyl groups of catalyst 338 proved crucial for producing 337 with high enantioselectivity. In contrast, the Diels-Alder reaction of maleic anhydride with 2-methoxy-1,3-butadiene using catalyst 338 afforded a racemic adduct. These results were considered to result from a different complexation behavior of the catalyst in the case of maleic anhydride in comparison with, V-arylmaleimides-, ... 

The great advantage of asymmetric activation of the racemic BINOL-Ti(0 Pr)2 complex (2) is highlighted in a catalytic version (Table 3, Run 5). High enantioselectivity (80.0% ee) is obtained by adding less than the stoichiometric amount (0.25 molar amount) of additional (R)-BINOL. A similar phenomenon of enantiomer-selective activation has been observed in aldol and (hetero-) Diels-Alder reactions catalyzed by a racemic BINOL-Ti(0 Pr)2 catalyst (2) [52]. 

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. 

Mikami and coworkers conducted the Diels-Alder reaction with a catalyst prepared by mixing enantiomerically pure R)-56 and racemic 56 and observed a positive nonlinear effect however, they found no asymmetric amplification when they prepared the catalyst by mixing enantiomerically pure R)-56 and enantiomerically pure (S)-56 (i.e., linear correlation between catalyst and product ee). Introduction of molecular sieves restores the asymmetric amplification in the latter case, apparently by equilibration of R) R) and (S)(S) dimers into catalytically less active R) S) dimers. As expected, the reaction rate was faster for R)-56 than for ( )-56 derived from racemic binaphthol hgand ca. 5-fold faster). 

Yamamoto and Maruoka also reported a conceptually new method of in situ generating the chiral catalyst 12 for asymmetric hetero-Diels-Alder reactions by discrimination of the racemic 12 with a chiral ketone [ 16]. As shown in Scheme 7, sequential treatment of ( )-12 (0.1 equivalent) with d-3-bromocamphor (0.1 equivalent), the diene 10a (1.05 equivalent), and benzaldehyde (1 equivalent) at -78 °C in CH2CI2 and stirring of the mixture at this temperature for 3 h afforded the hetero-Diels-Alder adducts 14 and 15, after acidic workup, in 78% and 19% yields, respectively. The optical yield of the major cis isomer 14 was 82%. Although the extent of asymmetric induction is not as satisfactory as that with optically pure 12, one recrystallization of the cis adduct 14 of 82% ee from hexane gave the essentially pure 14 (>98% ee with 60% recovery), thereby enhancing the practicability of this method. 

In the reaction of isoprene (IP) with methyl vinyl ketone (MVK), the sdectivities of the two isomers produced in this reaction can be improved from 4 1 to 20 1 by the addition of a mUd Lewis acid such as zinc(ii) iodide (5 mol%) to the ionic liquid [BMIM][PF6] (Scheme 5.2-70). One of the key benefits of this is that the ionic liquid and catalyst can be recycled and reused after solvent extraction or direct distillation of the product from the ionic liquid. The reaction was also carried out in the chiral ionic liquid [BMIM][lactate] (Fig. 5.2-4). This was found to give the fastest reaction rates of all the ionic liquids tested, and the lowest endoxxo selectivity. The products of the Diels-Alder reaction were found to be racemic and no chiral induction was observed [171]. 

In 2006, the Bode group documented NHC-catalyzed highly enantiose-lective 1-oxodiene Diels-Alder reactions of a broad range of enones with racemic a-chloroaldehydes as the dienophile precursors. This process affords a diverse set of highly enantioenriched 3,4,6-trisubstituted dihydro-pyran-2-ones from readily available starting materials under mild conditions (room temperature, 1.5 equiv. of NEtj, 6 h). The use of readily accessible racemic a-chloroaldehydes as enolate precursors greatly expands the scope of enantioselective NHC-catalyzed Diels-Alder reactions. It also makes possible, for the first time, asymmetric annulations with exceptional enantiose-lectivity under reliable eonditions with less than 1 mol% of a chiral NHC catalyst (Scheme 7.77). 

Yamamoto reported the discrimination of enantiomers of the racemic organoa-luminium reagent 172 through reaction with terpene-derived chiral ketones [98]. The resulting mixture served as a catalyst for the hetero-Diels-Alder reaction of benzaldehyde and the diene 173. ds-174 was obtained as the major stereoisomer in... 

Among several terpene derived chiral ketones examined, 3-d-bromocamphor was found to be most satisfactory and 3d-bromocamphor is responsible for the generation of (S)-catalyst. Combination of the racemic catalyst and chiral ketone in a 1 1 ratio gave a better results, suggesting that decomplexation of one enantiomeric organoaluminum reagent and the chiral ketone is more readily facilitated by the addition of aldehyde, thereby allowing the enantioselective activation of the aldehyde for the asymmetric hetero-Diels-Alder reaction. 

The CAB process is quite general for simple dienes and aldehydes. The a-sub-stituent on the dienophile increases the enantioselectivity (acrolein vs methacrolein). When there is a P-substitution in the dienophile, as in crotonaldehyde, the cycloadduct is nearly racemic. Conversely, for a substrate with substituents at both a-and P-positions, high ees are observed, as with 2-methylcrotonaldehyde and cy-clopentadiene (90% ee, exo endo = 97 3). a-Bromoacrolein is a useful dienophile in the Diels-Alder process because of the exceptional synthetic versatility of its resulting adducts e.g., an important intermediate for prostaglandin synthesis [19a]. In the presence of 10 mol% of 3a, a-bromoacrolein and cyclopentadiene in dichloro-methane undergo a smooth Diels-Alder reaction to give the (S)-bromoaldehyde cycloadduct in quantitative yield, 95% ee and 94 6 (exo endo CHO) diastereoselectivity (Equation 20). Similar results are obtained for the catalyst 3b in propionitrile. Other examples are listed below [20]. 

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