Stereoselectivity in the Diels-Alder reaction

Although the use of enzymes, as catalysts in the Diels-Alder reaction, has not been particularly successful,46 102 103 abzymes can be used to control regioselectivity and stereoselectivity in the Diels-Alder reaction.46 104 Biological catalysts have not been used on significant scale in the Diels-Alder reaction. Further, the use of abzymes would require a large investment initially, and any subtle change in the substituents on either the diene or dienophile may dramatically reduce asymmetric induction and yield. 

The exceptionally bulky Lewis acid MAD has a distinct steric effect on stereoselectivity in the Diels-Alder reaction of cyclic dienes and a,/3-unsaturated aldehydes, as exemplified by the MAD-mediated highly exo-selective cycloaddition of methacrolein and cyclopentadiene (Sch. 130) [169],... 

The factors that determine the steric course of these cycloaddition reactions are still not completely clear. It appears that a number of forces operate in the transition state and the precise composition of the product depends on the balance among these. The preference for the endo adduct, in which the dienophile substituents are oriented over the residual unsaturation of the diene in the transition state, has been rationalized by Woodward and Hoffmann in terms of secondary orbital interactions. In this explanation, the atomic orbital at C-2 (and/or C-3) in the HOMO of the diene interacts with the atomic orbital of the activating group in the LUMO of the dienophile. However, there is no evidence for this secondary orbital interaction and the stereoselectivities in the Diels-Alder reaction can be explained in terms of steric interactions, solvent effects, hydrogen-bonding, electrostatic and other forces (3.70). ... 

In 2006, Ishihara showed that a diammonium salt of commercially available chiral (S)-2,2 -diamino-l,T-binaphthalene (20) and bis(trifluoromethane)sulfon-imide (Tf2NH) exhibited excellent catalytic activity and stereoselectivity in the Diels-Alder reaction of a-acyloxyacroleins with cychc dienes (Scheme 7.33) [57]. 

The complex obtained from commercially available chiral a-amino acids (AA) with Cu + ion induces asymmetry in the Diels-Alder reaction of 31 (R = H) with 32. By using 10% Cu(II)-AA (AA = L-abrine) the cycloaddition occurs e/iJo-stereoselectively in 48 h at 0°C with high yield and with acceptable enantioselectivity ee = 1A%). This is the first example of enantioselective Lewis-acid catalysis of an organic reaction in water [9b]. 

In the field of polymer chemistry the regio- and stereoselectivity of the Diels-Alder reaction is used for the concerted synthesis of structurally homogeneous double-stranded ladder polymers [39], which are useful materials with nonlinear optical properties and high electrical conductivity. It has turned out that the repeated Diels-Alder method is superior to an alternative two-step process, in which first an open chain precursor is formed followed by polymer ring closure as structural defects can occur [40]. 

Similarly, ab initio calculations on the thermal reaction of propene forming methyl-cyclopentane suggested a three-step biradical reaction with 1,4-biradical and 1,5-biradical as intermediates. Quantum-chemical calculations have been carried out for the cyclization of the neocarzinostatin chromophore cyclonona-l,2,3,5-tetraen-7-yne to 1,5-didehydroindene biradical. The degree of stereoselectivity of the Diels-Alder reaction of 2-methylfuran and maleic acid in water has been found to reduce significantly in the presence of heavy atoms. Taking into account the relatively low concentration (3.5-7 m) of heavy-atoms, and the rapid fall off of the heavy-atom effect with distance, these results show that a large portion of the Diels-Alder reaction occurs via diradical intermediates. " ... 

However, a computational study124 shows that the Kishi model controls the stereoselectivity for (Z)-alkenes. Note also that in the Diels-Alder reactions of hexachloropentadiene with chiral alkenes, the inside alkoxy effect is attributed to electrostatic repulsion of the oxy group in the125 outside position with the chlorine atom of hexachloropentadiene in the 1-position. 

Complete stereoselectivity occurs in the Diels-Alder reaction through syn addition of the dienophile to the diene. Hence, the reaction of dimethyl fumarate and dimethyl maleate with cyclopentadiene yields the trans and cis adducts, respectively (Scheme 26.1).29... 

Explain the stereoselectivity and the complete regioselectivity observed in the Diels-Alder reaction of step n. 

The stereoselectivity of the Diels-Alder reaction between methyl acrylate and cyclopentadiene depends to some extent on solvent polarity [124] cf. Eq. (5-43) in Section 5.3.3. The endo/exo ratio for the cycloaddition product has been found to vary from 74 26 cmol/mol in triethylamine to 88 12 cmol/mol in methanol at about 30 °C. It has... 

In the Diels-Alder reaction, the typical dienophile will display lower stereoselectivity with acyclic dienes than with cyclic dienes. This is the case for the reactions of both methyl ciotonate and the prope-nyl tungsten complex (52b) with Danishefsky s diene (Scheme 9). Carbene complex (52b) gives a 58 42 selectivity in favor of the exo adduct (66), while methyl crotonate gives a similar selectivity of 66 34 in favor of the exo adduct (63) (64 and 65 are both derived from elimination of methanol from the endo adduct). This example reveals that the Diels-Alder reactions of caibene complexes are viable with functionalized and highly electron rich dienes. Furthermore, although the reaction of the carbene complex (52b) with Danishefsky s diene is not stereoselective, it does occur with a much greater rate and efficiency than that for the organic ester for which it can serve as synthon. 

The Diels-Alder reaction of a diene and a dienophile has become one of the most powerful carbon-carbon bond-forming processes [81]. In normal Diels-Alder reactions of an electron-poor dienophile with an electron-rich diene, the main interaction is between the HOMO of the diene and the LUMO of the dienophile. Coordination of a Lewis acid to the dienophile reduces its frontier orbital energies, and this increases the rate of the reaction. Regio- and stereoselectivity are also markedly affected by the Lewis acid. Recent extensive studies on the design of chiral Lewis acids have led to fruitful results in the control of the stereochemistry of a variety of pericyclic reactions. Several chirally modified Lewis acids have been developed for the asymmetric Diels-Alder reaction [82,83] and spectacular advances have recently been achieved in this area. Various kinds of polymer-supported chiral Lewis acid have also been developed. Polymer-supported A1 Lewis acids such as 62 have been used in the Diels-Alder reaction of cyclopentadiene and methacrolein (Eq. 20) [84] as has polymer-supported Ti alkoxide 63 [84]. These Ti catalysts are readily prepared and have high activity in the Diels-Alder reaction. 

Maffei, M., and Buono, G., Stereoselective synthesis of dimethyl- and diethyl- -2-(trimethylsilyl)vinyl phosphonates and their use in the Diels-Alder reaction. Phosphorus, Sulfur Silicon Relat. Elem., 79, 297, 1993. 

Al-Badri, H.. About-Jaudet. E.. and Collignon, N., Unusual and efficient (Z)-stereoselective Peterson synthesis of 2-diethoxyphosphonyl-l-alkoxy-3-methylpenta-l,3-dienes. Their use in the Diels-Alder reaction. Tetrahedron Lett.. 31. 2951, 1996. 

Both the geometrical characteristics of the transition states (attack directionality or pyramidalization of the reacting rites) and the structure of the reactive conformers can be altered by changing reaction conditions so that the relative energy level of the transition states, and therefore the stereoselection, can be changed. A classic example of the effect of reaction conditions is the difference in stereoselectivity of the Diels-Alder reaction of acrylates derivatives with dienes when performed thermally or in the presence of Lewis acids [71-74] (Figure 1.17) ( 9.3). In the thermal reaction, several conformers of the dienophile can intervene, while in the presence of Lewis acids, only the s-trans conformer of the ester takes part to the reaction. 

Worthwhile, that is, if the regio- and stereoselectivity of the Diels-Alder reaction are correct. Ths two alkyl groups attached to the diene in (33)... 

Phenyl vinylsulfonate (16) is an effective dienophile and reacts with furan derivatives, which are known as inert dienes in the Diels-Alder reaction. The sulfonate 16 can be prepared in 85% yield by reaction of / -chlorosulfonyl chloride with phenol in the presence of sodium hydroxide and stored indefinitely at 0°C24. The cycloaddition reaction proceeds at room temperature to give predominantly endo adducts as illustrated in equation ll25. When the reaction was carried out at higher temperature, the yield of the endo adduct and the stereoselectivity decreased due to the retro-Diels-Alder reaction. 

The compounds thus obtained have been used as starting materials for chiral crown ethers h 3> 15 (see Section 5.2.), having applications as enantioselective catalysts in Michael additions (Sections D.1.5.2.1. and D.1.5.2.4.). 3,3 -Dimethyl- and 3,3 -diphenyl-2,2 -dihydroxy-l,T-binaph-thyls 8 and 3 have been applied as ligands for the synthesis of chiral Lewis acids used as stereoselective catalysts in the Diels Alder reaction (Section D.1.6.1.1.1.3.). 

Schreiner et al. developed thiourea catalyst as a promising hydrogen donor, which has more benefit in solubility, synthesis and catalytic mrn over number compared with urea catalyst, in the Diels-Alder reaction of A-crotonyloxazolidinone and cyclopentadiene [22,23] (Table 9.7). A,A -Di[3,5-bis(trifluoromethyl)phenyl]thiourea accelerates the reaction and improves stereoselectivity (run 4) similar to a metal catalyst such as aluminium chloride (AICI3) (mn 2) or titanium chloride (TiCls) (run 3). 

In the Diels-Alder reaction of acrylic acid and E-pentadienoic acid, the temperature has a noticeable effect on the stereoselectivity (3.69). At low or moderate temperatures the endo adduct is the major product, but the proportion of the exo isomer increases as the temperature of the reaction increases. 

The introduction of a nitro or trifluoromethyl group at the C-3 position on the pyridine ring in 3-(2-pyridylsulfinyl)acrylates has been shown to enhance the reactivity and diastereoselectivity of the dienophile in the Diels-Alder reaction with furan and its derivatives [171]. Such a modification of the dienophile renders the addition of diethylaluminium chloride unnecessary in order to achieve the desired asymmetric cycloaddition. The cycloadduct (207), prepared with high stereoselectivity from the asymmetric Diels-Alder reaction between (5)-menthyl 3-(3-trifluoromethylpyrid-2-ylsulfinyl)acrylate (194) and 2-methoxyfuran (208), was converted in seven steps to the glyoxalase I inhibitor (209) [171] (Scheme 5.67). 

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