Stereoselectivity of Diels-Alder Reactions

The Stereoselectivity of Diels-Alder Reactions. One of the most challenging stereochemical findings is Alder s endo rule for Diels-Alder reactions. The favoured transition structure 6.180 has the electron-withdrawing substituents in the more hindered environment, under the diene unit, giving the kinetically more favourable but thermodynamically less favourable adduct 6.181. Heating eventually equilibrates the adducts in favour of the exo adduct 6.182, by a retro-cycloaddition re-addition pathway. 

Evans et al. also showed that the 1 1 mixture of BAN and (3, y-distearoyl-phos-photidylcholine (DSPC) gives a smectic A texture in the temperature range of 57.3 to 100°C [21]. This is the first notice of lyotropic lamellar liquid crystals formed in the ionic medium. Additionally, Seddon et al. [28] and Neve et al. [29] have described the long-chained A-alkylpyridinium or l-methyl-3-alkylimidazolium ions to display smectic liquid-crystalline phases above their melting points, when Cl or tetrachloro-metal anions like CoCl " and CuCl " are used as the counter ions. Lin et al. have also noted the liquid crystal behavior of 1-alkylimidazolium salts and the effect on the stereoselectivity of Diels-Alder reactions [30]. However, liquid crystals are classified as ionic liquid crystals (ILCs), and they are distinguished from liquid crystals that are dispersed in ionic liquids. Although the formation of micelles and liquid crystal phases in ionic liquids have been thus reported, there has been no mention of the self-assembly of developed nano-assemblies that are stably dispersed in ionic liquids. In the next section the formation of bilayer membranes and vesicles in ionic liquids is discussed. 

Berson, J.A., Hamlet, Z. and Mueller, W.A. (1962). The Correlation of Solvent Effects on the Stereoselectivities of Diels-Alder Reactions by Means of Linear Free Energy Relationships. A New Empirical Measure of Solvent Polarity. J.Am.Chem.Soc., 84,297-304. 

Endolexo selectivity can be influenced by Lewis acids, the solvent or for example high pressure. The stereoselectivity of Diels-Alder reactions can be controlled and even altered by the appropriate use of chelating and non-chelating Lewis acids, too. Thus, by effective shielding of one of the enantiotopic faces of the diene or dienophile attached to... 

The introduction of an atom other than carbon to either dienes or dienophiles will result in the hetero-Diels-Alder reaction. Owing to the nature (steric effect, electronic effect, etc.) of substituents on dienes and dienophiles, the Diels-Alder reaction might occur through a synchronous concerted, an asynchronous concerted, or a stepwise reaction mechanism. The stepwise and asynchronous concerted Diels-Alder reactions proceed via diradical intermediates, whereas the synchronous concerted mechanisms does not. It should be pointed out that most of the Diels-Alder reactions are concerted as a result, both the rate constants and the stereoselectivities of Diels-Alder reaction are only moderately sensitive to the changes in the nature of organic sol vents. However, it has been clearly shown that the applications of water to the reaction system can greatly accelerate such reactions. Other modifications on this reactions include the application of high pressure, Lewis acid, and ultrasound radiation.More information about this reaction can be easily attained from reviews and relevant books. 

Brasca, R., Kneeteman, M., Mancini, P.M.E., Fabian, W.M.F. (2011). Comprehensive DFT Study on site-, regio-, and stereoselectivity of Diels-Alder Reactions Leading to 5-Hydroxybenzofurans. European Journal of Organic Chemistry, 721-729, 2011, ISSN 1434-193X... 

Sultam-based chiral auxiliaries mediate the stereoselectivity of Diels-Alder reactions, and the reaction of various substituted furans with benzyne provided an insight into the... 

Aqueous cycloaddition using glyco-organic substrates. Facial stereoselectivity in Diels-Alder reactions of a chiral diene derived from D-glyceraldehyde [102]... 

Wada E., Yasuoka H., Pei W., Chin U., Kanemasa S. Lewis Add-Catalyzed Stereoselective Hetero Diels-Alder Reactions of (E)-l-Phenylsulfonyl-3-Alken-2-Ones With Vinyl Ethers. Synthetically Equivalent to Stereoselective Michael Type... 

Highly stereoselective hetero Diels-Alder reactions of a chiral liirylaldehyde (22) with Danishefiky s dioie were reported. In the presoice of Ln(OTf), exclusively 23 was obtained, while the reaction in the presence of Eu(thd)j produced 24 as the major product <96TA1199>. 

Diels-Alder catalysis.1 This radical cation can increase the endo-selectivity of Diels-Alder reactions when the dienophile is a styrene or electron-rich alkene. This endo-selectivity obtains even in intramolecular Diels-Alder reactions. Thus the triene 2, a mixture of (Z)- and (E)-isomers, cyclizes in the presence of 1 to 0° to the hydroindanes 3 and 4 in the ratio 97 3. Similar cyclization of (E)-2 results in 3 and 4 in the ratio 98 2 therefore, the catalyst can effect isomerization of (Z)-2 to (E)-2. Even higher stereoselectivity is observed when the styrene group of 2 is replaced by a vinyl sulfide group (SC6H5 in place of QHtOCT ). 

The great advantage of Diels Alder reaction in organic synthesis lies in its high stereoselectivity. Examples of Diels-Alder reactions are known for almost all types of n bonds acting as dienophiles. The diene system may be all carbon or there may be many variations as shown in the following tables. 

In summary, water appears as an extremely unsuitable solvent for coordination of hard Lewis acids to hard Lewis bases, as it strongly solvates both species and hinders their interaction. Hence, catalysis of Diels-Alder reactions in water is expected to be difficult due to the relative inefficiency of the interactions between the Diels-Alder reactants and the Lewis acid catalyst. On the other hand, the high stereoselectivities and yields observed in biosyntheses, with water as the solvent, indicate that these rationalizations cannot entirely be true. As a matter of fact, we will demonstrate in the following that Lewis acid catalysis in water is not only possible, but also allows for effective as well as environmentally friendly reaction conditions. 

Another total synthesis of pamamycin-607 (lb) was reported in 2001 by our own group [6] at about the same time as the Lee synthesis. Here, the approach was based on the stereoselective intramolecular Diels-Alder reaction of vinyl-sulfonates and novel methods for elaboration of the resulting sultones [13,14]. 

Diels-Alder reactions have been conducted on solid phase, with either the dieno-phile or the diene linked to the support [156]. The reaction conditions and the regio-and stereoselectivities observed are similar to those in solution [58,157,158]. Illustrative examples of Diels-Alder reactions leading to support-bound cyclohexenes are listed in Table 5.10. Further examples include the cycloaddition of polystyrene-bound 2-sulfonyl-l,3-butadiene and V-phenylmaIcimidc [51], the high-pressure cycloaddition of 1,3-butadienes to resin-bound 1 -nitroacrylates [95], and the intramolecular Diels-Alder reaction of styrenes with acrylates [159]. 

Stereoselective intramolecular Diels-Alder reactions The reaction of Meldrum s acid (1) with (R)-citronellal (2) in the presence of ethylenediammonium acetate (EDDA)2 at 15-20° results in the tricyclic dihydropyran 3 as the major product with an optical purity of >98%. The product evidently results from an intramolecular hetero-Diels-Alder addition. It can be converted by acid into the optically pure a-methoxycarbonyllactone 4. 

Fig. 15.14. Evidence for stereoselectivity and stereospecificity with regard to the butadiene moiety in a pair of Diels-Alder reactions. The cis,trans-l,4-disubstituted 1,3-butadiene forms cyclohexene with a trans arrangement of the methyl groups. The trans,trans-1,4-disubstituted 1,3-butadiene forms cyclohexene with ris-methyl groups.

The stereoselective intramolecular Diels-Alder reaction of 3-alkenyl(oxy)-2(l//)-pyrazinones leading to tricyclic ring systems was investigated <02TL447>. A one-pot 7-alkoxylation of 6-arylpyrazino[2,3-c][l,2,6]thiadiazine 2,2-dioxides 169 was accomplished by using N-halosuccinimides <02EJ02109>, and the nitration of 2-(5-methyl-2-furyl)quinoxaline was shown... 

A similar approach to the synthesis of tetracyclic indole alkaloid derivatives has been described [182], and the use of reactive chiral iminium ions allows the realisation of stereoselective aza Diels-Alder reactions even in aqueous solution [183,184]. Nevertheless it should be noted that reactions of electron-rich dienes with imines e. g. derived from amino acids do not necessarily proceed via a Diels-Alder mechanism. They may as well undergo a domino-Mannich-Michael sequence which also efficiently leads to useful nitrogen heterocycles [185-188]. 

Numerous further chiral imines activated by electron-withdrawing substituents have been investigated in order to carry out stereoselective aza Diels-Alder reactions. In these studies, Bailey et al. have recently introduced the use of two inducing stereocenters in the imine. This approach proved to yield excellent diastereoselectivities thus, imine 3-12 bearing a (,R)-8-phenylmenthyl auxiliary gave the essentially pure cycloadduct 3-13 upon hetero Diels-Alder reaction with cyclopentadiene (Fig. 3-4) [194-196]. 

As a current example of a stereoselective intramolecular Diels-Alder reaction using nitroso dienophiles, Kibayashi s studies aimed at the enantioselective total sysnthesis of (-)-pumiliotoxin C 4-31 shall be discussed here [356, 357]. The chiral nitroso compound 4-30 derived from L-malic acid was generated in situ... 

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