Stereochemistry of the Diels-Alder Reaction

The great synthetic usefulness of the Diel-Alder reaction depends not only on the fact that it provides easy access to a variety of six-membered ring compounds, but also on its remarkable stereoselechvity. This factor has contributed to its successful application in the synthesis of many complex natural products. It should be noted, however, that the high stereoselechvity appUes to the kinehcally controlled 

The stereochemistry of the adduct obtained in many Diels-Alder reactions can be selected on the basis of two empirical rules formulated by Alder and Stein in 1937. According to the cis principle , the relative stereochentistry of substituents in both the dienophile and the diene is retained in the adduct. That is, a dienophile with trans substituents will give an adduct in which the trans configuration of the substituents is retained, while a cis disubstituted dienophile will form an adduct in which the substituents are cis to each other. This aspect is often referred to as the stereospecific nature of the Diels-Alder reaction. For example, in the reaction of cyclopentadiene with dimethyl maleate, the cis adducts 74 and 75 are formed, while in the reaction with dimethyl fumarate, the trans configuration of the ester groups is retained in the adduct 76 (3.64). 

Similarly, with the diene component, the relative configuration of the substituents in the 1- and 4- positions is retained in the adduct trans, rra s-l,4-disubstituted dienes give rise to adducts in which the 1- and 4-subsfituents are cis to each other, and cis, rra 5-disubstituted dienes give adducts with trans substituents (3.65). 

The almost universal application of the cis principle provides strong evidence for a mechanism for the Diels-Alder reaction in which both new bonds between the diene and the dienophile are formed at the same time. This includes a mechanism in which the two new a-bonds are formed simultaneously but at different rates and it does not completely exclude a two-step mechanism, if the rate of formation of the second bond in the (diradical or zwitterionic) intermediate were faster than the rate of rotation about a carbon-carbon bond. 

To illustrate this aspect of stereoselectivity, the addition of maleic anhydride to cyclopentadiene gave almost exclusively the endo product 77 (3.66). The thermodynamically more stable exo compound is formed in yields of less than 2%. 

The [t 4j + t 2j] cycloaddition of alkenes and dienes is a very useful method for forming substituted cyclohexenes. This reaction is known as the Diels-Alder (abbreviated D-A in this chapter) reaction. The transition structure for a concerted reaction requires that the diene adopt the s-cis conformation. The diene and substituted alkene (called the dienophile) approach each other in approximately parallel planes. This reaction has been the object of extensive mechanistic and computational study, as well as synthetic application. For most systems, the reactivity pattern, regioselectivity, and stereoselectivity are consistent with a concerted process. In particular, the reaction is a stereospecific syn (suprafacial) addition with respect to both the alkene and the diene. This stereospecificity has been demonstrated with many substituted dienes and alkenes and also holds for the simplest possible example of the reaction, ethene with butadiene, as demonstrated by isotopic labeling.  

The issue of the concertedness of the D-A reaction has been studied and debated extensively. It has been argued that there might be an intermediate that is diradical in character. D-A reactions are almost always stereospecific, which implies that if an intermediate exists, it cannot have a lifetime sufficient to permit rotation or inversion. The prevailing opinion is that the majority of D-A reactions are concerted reactions and most theoretical analyses agree with this view. ° It is recognized that in reactions between unsymmetrical alkenes and dienes, bond formation might be more advanced at one pair of termini than at the other. This is deseribed as being an asynchronous 

Loss of stereospecificity is observed when ionic intermediates are involved. This occurs when the reactants are of very different electronic character, with one being strongly electrophilic and the other strongly nucleophilic. Usually more than one substituent of each type is required for the ionic mechanism to occur. 

For many substituted butadiene derivatives, the two TSs lead to two different stereoisomeric products. The endo mode of addition is usually preferred when an EWG substiment such as a carbonyl group is present on the dienophile. This preference is called the Alder rule. Frequently a mixture of both stereoisomers is formed and sometimes the exo product predominates, but the Alder rule is a useful initial guide to prediction of the stereochemistry of a D-A reaction. The endo product is often the more sterically congested. For example, the addition of dienophiles to cyclopentadiene usually favors the encto-stereoisomer, even though this is the sterically more congested product. 

The preference for the endo mode of addition is not restricted to cyclic dienes such as cyclopentadiene. By using deuterium labels it has been shown that in the addition of 1,3-butadiene and maleic anhydride, 85% of the product arises from the endo TS.  

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According to frontier molecular orbital theory (FMO), the reactivity, regio-chemistry and stereochemistry of the Diels-Alder reaction are controlled by the suprafacial in phase interaction of the highest occupied molecular orbital (HOMO) of one component and the lowest unoccupied molecular orbital (LUMO) of the other. [17e, 41-43, 64] These orbitals are the closest in energy Scheme 1.14 illustrates the two dominant orbital interactions of a symmetry-allowed Diels-Alder cycloaddition. 

The stereochemistry of the Diels-Alder reaction can be considered from several aspects ... 

Aromatic thioureas were more active than alkyl (octyl, cyclohexyl) derivatives. Thioureas with trilluoromethyl substituents were even more effective. The same group also showed that these organocatalysts can act as weak Lewis acids and are thus able to alter the stereochemistry of the Diels-Alder reaction between cyclopentadiene and chiral acrylamide derivatives (Scheme 49) [167]. 

In the synthesis of the tetracyclic intermediates for the synthesis of isoarborinol and its CDE-antipode femenol, the stereochemistry of the Diels-Alder reaction can be varied using various Lewis-acid catalysts in aqueous media (Eq. 12.36).97 Their results show that the hydrophobic effects play an important role in enhancing reaction rates and can control product distribution. Novel 2,4-dialkyl-1-alkylideneamino-3-(methoxycarbonylmethyl)azetidines were obtained from aldazines and... 

FMO theory can also be used for explaining the stereochemistry of the Diels-Alder reaction. Consider the reaction between 2-methyl butadiene and cyanoethylene. These may react to give two different products, the para and/or meta isomer. The MO coefficients for the p-orbitals on the isoprene HOMO and cyanoethylene LUMO (taken from AMI calculations) are given in Figure 15.6. The FMO sum for the para isomer is (0.594 0.682 -I- 0.517 0.552) = 0.477, while the sum for the meta isomer is... 

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. 

There are several aspects to the stereochemistry of the Diels-Alder reaction, (a) First, we have taken for granted—correctly—that the diene must be in the... 

Figure 29.19. Stereochemistry of the Diels-Alder reaction, illustrated for the reaction between two moles of 1,3-butadiene.

FMO theory can also be used for explaining the stereochemistry of the Diels-Alder reaction. Consider the reaction between 2 methyl butadiene and cyanoethylene. Tliese may react to give two different products, the para and/or meta isomer. The MO... 

Alder-Stein rules. Set of rules governing the stereochemistry of the Diels-Alder reaction. The most important are that (1) the stereochemical relationship of groups attached to the diene and the dienophile is maintained in the product (cis-addi-tion) and (2) the product resulting from maximum accumulation of unsaturated centers in the transition state is favored (endo rule). 

Cycloadditions with acyclic N-acylimiiles show reasonably good kinetic stereochemical control. In an important series of papers, Krow et cd. have thoroughly investigated the stereochemistry of the Diels-Alder reaction of 1,3-cyclohexadiene with a laiige numbef of C-substituted Af-acyliminium dienophiles (20) [Eq. (4)]. 

It has been recognized for many years that chloral will react with simple 1,3-dienes to afford reasonable yields of [4 + 2] adducts.6 7 The stereochemistry of the Diels-Alder reaction of cyclohexadiene and chloral7 has been reinvestigated and was unambiguously established to give the endo adduct [Eq. (2)].8... 

A further feature of the stereochemistry of the Diels-Alder reaction is also shown in the transition state (6.105). The EWG prefers to lie across the diene system during the reaction, as shown in Figure 6.23. In the case of isoprene and ocimene, this is of no consequence. However, in the case of cyclic dienes, it explains the preference for the -configuration of the EWG in the adduct. 

Relative position of the groups (present on diene and dienophile) in the product depends on the stereochemistry of the Diels—Alder reaction. The groups on the dienophile that are endo in the transition state will become cis... 

The frontier molecular orbital analysis led to the conclusion that butadiene will react with ethylene to give cyclohexene if both butadiene and ethylene collide in a suprafacial manner. However, ethylene will not react with ethylene in an analogous manner. We can extend these conclusions to the reaction of any conjugated diene with any alkene and to any alkene with another alkene. Presented below are several examples and practical considerations of the allowed 4 + 2 reaction (the Diels-Alder reaction). The suprafacial approach of both reactants has important consequences on the stereochemistry of the Diels-Alder reaction. 

The uncertain stereochemistry in this situation is illustrated by our results on the stereochemistry of the Diels-Alder reactions shown in Scheme 1, where N-phenylmaleimide reacts with the diene 3 in the sense 1 to give the anti adduct 4 as the major product, but reacts... 

The stereochemistry of the Diels-Alder reaction was investigated by the reactions of 3,4-di-tert-butylthiophene 1-oxide with cis- and lrans-3-hexenes. The reactions occur on heating 3,4-di-tert-butylthiophene 1-oxide and an excess of the alkene at 100°C in a sealed tube and demonstrated that Diels-Alder reactions take place exclusively at the sy -jr-face of 3,4-di-tert-butylthiophene 1-oxide (Scheme 20) [33]. 

The same is true when donor and acceptor are on alkene and diene, respectively. A donor on carbon 2 of a diene enlarges the HOMO coefficient at carbon 1, and an acceptor on carbon 2 enlarges the LUMO coefficient at carbon 1. This favors a 1,4-disubstituted cyclohexene product. The increase in regioselectivity brought about with Lewis acid catalysis is a result of coordination of the catalyst with a receptor substituent, making it a stronger receptor. The stereochemistry of the Diels-Alder reaction is discussed further in Section 8.6. 

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