Diels-Alder reaction simple diastereoselectivity

As with regioselectivity, the issue of endo- versus exo-selectivity in aqueous Diels-Alder reactions (simple diastereoselectivity) is also under FMO control. However, the unique solvent properties of water lead to an enhancement of endo-selectivity that goes beyond well-known solvent polarity effects. For example, Breslow s group looked at the endo/exo product ratios for the reaction of cyclopentadiene and several dienophiles (Table 1.5) [39,... 

Fig. 15.29. Regioselectivity and simple diastereoselectivity of a Diels-Alder reaction with a 1-substituted diene selectivity increase by way of addition of a Lewis acid.

Here we are primarily concerned with the fact that this ortho -adduct may occur in the form of two diastereomers. The diastereomers are formed as a 57 43 cis/trans-mixtme in the absence of A1C13, but a 95 5 cis/trans-mixture is obtained in the presence of A1C13. In the latter case, thus, one is dealing with a Diels-Alder reaction that exhibits a substantial simple diastereoselectivity (see Section 11.1.3 for a definition of the term). Here, the simple diastereoselectivity is due to kinetic rather than thermodynamic control, since the preferentially formed ds-disubstituted cyclohexene is less stable than its irans-isomer. 

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). 

The high simple diastereoselectivities seen in Figures 15.29 and 15.30 are due to the same preferred orientation of the ester group in the transition states. The stereostructure of the cycloadduct shows unequivocally that the ester group points underneath the diene plane in each of the transition states of both cycloadditions and not away from that plane. Figure 15.31 exemplifies this situation for two transition states of simple Diels-Alder reactions of 1,3-butadiene A shows a perspective drawing of the transition state of the acrylic acid ester addition, and B provides a side view of the addition of ethene, which will serve as an aid in the following discussion. Both structures were determined by computational chemistry. 

The most likely multistep mechanism of this type is shown in the lower part of Figure 12.17. It is a two-step mechanism where the diastereomeric diradicals F and G are the two intermediates that allow for rotation about the configuration-determining C—C bond. Each of the two radical centers is part of a well-stabilized allyl radical (cf. Section 1.2.1). It is unknown whether the formation of biradical F is subject to simple diastereoselectivity in comparison to G (for the occurrence of simple diastereoselec-tivity in one-step Diels-Alder reactions, see Section 12.3.4). Biradicals F and G cyclize without diastereocontrol to deliver the [4+2]-cycloadducts biradical F forms a mixture of1 2trans,cis-[D]2-C and 1,2trans, trans [D]2-C, since a rotation about the C2—C3 bond is possible but not necessary. For the same reason, biradical G forms a mixture of 1 2cis,cis- I) 2-C and 1,2cis,trans [D]2-C. 

A high asymmetric induction in intramolecular hetero Diels-Alder reactions was found using chiral 1-oxa-1,3-butadienes with a stereogenic center in the tether [54]. Such compounds can easily be obtained by a Knoevenagel condensation of a 1,3-dicarbonyl compound such as iV,N-dimethylbarbituric acid with a chiral aldehyde bearing a dienophile moiety [169 a] (Scheme 2-3). With the stereogenic center in a-position relative to the oxadiene or dienophile moiety an excellent induced diastereoselectivity is obtained for the nearly exclusively formed trans-cycloadduct (simple diastereoselectivity = 97.9 2.1 and 98.3 1.7,... 

The advanced state of the art in carbohydrate synthesis basing on hetero Diels-Alder reactions of 1-oxa-l,3-butadienes has opened an access to enan-tiopure sugar derivatives. Thus, our group found the cycloaddition of the chiral heterodiene 7-1 and the electron-rich alkene 7-2 under the influence of Me2AlCl to give the dihydropyran 7-3 in excellent endo selectivity (endo/exo >50 1) and as well excellent induced diastereoselectivity (54 1) [478]. A short sequence involving one simple recrystallisation then led to the ethyl-/)-D-mannopyrano-side 7-4 in enantiomerically pure form (Fig. 7-1). 

Three types of cycloaddition products are generally obtained from the photochemical reaction between aromatic compounds and alkenes (Scheme 31). While [2 + 2] (ortho) and [3 + 2] (meta) cycloaddition are frequently described, the [4 + 2] (para or photo-Diels-Alder reaction) pathway is rarely observed [81-83]. Starting from rather simple compounds, polycyclic products of high functionality are obtained in one step. With dissymmetric alkenes, several asymmetric carbons are created during the cycloaddition process. Since many of the resulting products are interesting intermediates for organic syntheses, it is particularly attractive to perform these reactions in a diastereoselective way. 

Control of the stereochemistry of the Diels-Alder reaction by means of a chiral center in the substrate is a versatile means of synthesizing cychc systems stereoselec-tively [347]. For preparation of ring systems with multi-stereogenic centers, in particular, the diastereoselective Diels-Alder reaction is, apparently, one of the most dependable methods. The cyclization of optically active substrates has enabled asymmetric synthesis. Equation (147) shows a simple and very efficient asymmetric Diels-Alder reaction, starting from commercially available pantolactone [364,365], in which one chlorine atom sticking out in front efficiently blocks one side of the enone plane. A fumarate with two chiral auxiliaries afforded virtually complete stereocontrol in a titanium-promoted Diels-Alder reaction to give an optically active cyclohexane derivative (Eq. 148) [366,367]. A variety of diastereoselective Diels-Alder reactions mediated by a titanium salt are summarized in Table 13. 

Tietze, L. F., Geissler, H., Fennen, J., Brumby, T., Brand, S., Schulz, G. Intra- and intermolecular hetero-Diels-Alder reactions. 45. Simple and induced diastereoselectivity in intramolecular hetero-Diels-Alder reactions of 1-oxa-1,3-butadienes. Experimental data and calculations. 

Dihydropyrans are useful intermediates in the total synthesis of monosaccharides and have been prepared by hetero-Diels-Alder reaction of simple alkyl- and arylaldehydes 48 with electron-rich ( )-l-methoxy-l,3-butadiene (49) in reasonable to good yield. As expected e do-diastereoselectivity is predominant because, as usual, pressure strongly favours e do-addition (Scheme 7.12). 

In the discussion of the influence of high pressure on the diastereoselectivity of chemical transformations wc will first look at simple diastereoselectivity and later at induced diastereoselectivity. Most of the work concerning the influence of high pressure on diastereoselectivity has been carried out on Diels-Alder reactions. For an understanding of the effect of pressure on these reactions, a careful analysis of the different pathways must be undertaken. It is usually accepted that in most cases Diels-Alder reactions are concerted, they can, however, also proceed via biradicals or zwitterions depending on the solvents and substrates (Scheme 8.15). 

To assess the diastereoselectivity and the intrinsic reactivity of prosolanapyrones, Diels-Alder reactions were examined under various conditions." In less polar solvents, heating was required for the effective cycloaddition of 136—138. Increase in the oxidation levels of the three substituents in the prosolanapyrones enhances rate acceleration. This can be rationalized in terms of the LUMO energy of the dienophile moiety in the pyrone precursors. Wo-/cxo-selectivities with 136—138 were essentially the same in various organic solvents, while the wt /o-selectivity was increased with increasing solvent polarity. The slight preference for f zfo-selectivity in less polar solvents suggests that there is little steric congestion in both endo- and cxo-transition states as reported in the reactions of simple decatriene systems." ... 

The chiral alcohols are mainly employed as esters or enol ethers. Esters with carboxylic acids can be obtained by any convenient esterification technique. Dienol ethers were obtained by transetherification with the ethyl enol ether of a 1,3-diketone, followed by Wittig reaction8 silyldienol ethers were obtained by the method of Danishefsky11-12 and simple enol ethers by mercury-catalyzed transetherification13. Esters and enol ethers have been used as chiral dienophiles or dienes in diastereoselective Diels-Alder reactions (Section D. 1.6.1.1.1.1.). (R)-l-Phenylethanol [(R)-4] has been used for enantioselective protonation (Section C.) and the (S)-enantiomer as chiral leaving group in phenol ethers for the synthesis of binaphthols (Section B.2.) the phenol ethers are prepared as described for menthol in the preceding section. (S)-2-Octanol [(S)-2] has found applications in the synthesis of chiral allenes (Section B.I.). 

Subsequent work has shown that simple, unactivated enantiomerically pure vinyl sulfoxides such as p-tolyl vinyl sulfoxide, without further substitution on the double bond, are not effective dienophiles for inducing diastereoselectivity in asymmetric Diels-Alder reactions. In the majority of cases, further substitution of the double bond by electron-withdrawing groups is necessary to achieve high stereoselectivity under mild conditions. However, a recent report by Ronan and Kagan [157,158] has shown that (5)-p-tolyl vinyl sulfoxide (26b) can be efficiently activated toward Diels-Alder cycloaddition by transformation into a sulfoxonium... 

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]. 

A readily available 9-NH2 cinchona alkaloid has proved to efficiently catalyse the asymmetric Diels-Alder reaction of simple a,p-unsaturated ketones with 2-pyrones. In the presence of TFA as an additive, the reaction afforded the exo-cycloadduct as the major product in good enantiomeric excess of up to 99% ee in almost all cases of substrates, as shown in Scheme 6.3. Moderate to excellent diastereoselectivities of 50-94% de were obtained, but it is important to note that both the diastereoselectivity and the enantioselectivity of the reaction did not fluctuate significantly when the aromatic substituent of the a,p-unsaturated ketone was changed to an aliphatic substituent. 

Simple stereoinduction in the Diels-Alder reaction typically follows a number of general guidelines. Two of these are well known to the student of organic chemistry, namely the notable preference for endo selectivity, as a consequence of secondary orbital overlap, and regioselectivity consistent with the optimal interactions of the frontier molecular orbitals [38]. Additional stereochemical preferences may also be observed for chiral reacting partners. In a study by Overman with cyclic dienes such as 30, cycloaddition was observed to occur on the olefin face anti to the allylic substituent in 30 (Scheme 17.7) [39]. The superimposition of the basic stereochemical features of the Diels-Alder reaction (i.e., endo selectivity cf 32) on the steric differentiation of the olefin faces leads to the preferential formation of 33-35 with increasing diastereoselectivity as a function of the size of the substituent X. 

---