Intramolecular Diels-Alder reaction endo rule

Indeed, it seems that intramolecular Diels-Alder reactions are governed more by normal steric considerations than by the endo rule. 

A comparison of the relevant transition states of the intramolecular Diels-Alder reaction can explain the observed configuration of the products 76 and 77. In the case of 76 (n = 0), the diene moiety is more likely to approach from underneath the enal face in an "endo manner (the Alder rule) because of a steric interaction with the phenyl group. The other structures 77 that contain a longer side chain (n = 1) allow the approach from both beneath and above the enal face, but NOE analyses of the isolated products 77 revealed that the diene approaches the dienophile from the top. Thus, in both systems, the trans-fused endo-configuration is preferred because of steric interactions with the phenyl substituents and the nitro group (Enders et al. 2007b). 

When the diene and the dienophile are already part of the same molecule it is not so important for them to be held together by bonding interactions across space and the exo product is often preferred. Indeed, many intramolecular Diels-Alder reactions are governed more by normal steric considerations than by the endo rule. 

Since its discovery over sixty years ago [1] the Diels-Alder reaction has lost none of its attraction. [2, 3] It enables, in a one-step inter- or intramolecular reaction, the rapid preparation of cyclic compounds having a six-membered ring. During the course of the [4 -I- 2] cycloaddition four new stereocenters can be introduced directly, and their stereo-control is a topic of major interest in modem synthetic chemistry. [4-6] In addition, in intermolecular reactions, the relative positions of the reaction partners (regiochemistry) must be taken into account. If a concerted reaction is assumed, both a cis addition (suprafacial mode) and a preferred endo orientation (Alder rules) can be expected. But how can the absolute configuration of the desired product be controlled There are three basic possibilities the use of a chirally modified diene, a chirally modified dienophile, or a chiral catalyst. Although the first successes resulted from the attractive, hut difficult, catalytic route, [4b, 7] the majority of the investigators are concerned with the stoichiometric... 

The diastereoselectivity inherent to the Diels-Alder reaction can be seen in most of the examples in preceding reactions. The reaction is not, however, enantioselective since there is no facial control for intermolecular reactions (some facial control is available for intramolecular reactions). The ortho rule, the endo rule (secondary orbital interactions), and steric interactions provide some orientational control but facial control is also required for enantioselectivity. When ethyl acrylate reacts with 2-methyl-1,3-pentadiene, it can approach from the bottom as in 247A or from the top as in 247B. Clearly, the two products (248A and 248B) are mirror images and enantiomers. This lack of facial selectivity leads to racemic mixtures in all Diels-Alder cyclizations discussed to this point. 

In intermolecular Diels-Alder reactions, the combination of these effects, particularly with cyclic dienophiles, often leads to a preference for the endo adduct in the kinetically controlled reaction. In intramolecular reactions, the endo rule can be a good guide to the stereochemistry of the product, but as described in the next section, geometrical constraints may outweigh other factors and the exo product may predominate. 

The endo rule, formulated for the intermolecular Diels-Alder reaction, is not rigorously followed even in the intermolecular case (33). For intramolecular cyclizations, geometric factors (vide infra) tend to be more important. With highly activated dienophiles, and especially under acid catalysis, endo cyclization can predominate (34) [28, 29]. In the second example, the role of the acidic reaction medium in overcoming the geometric preference for an exo (chair-like) transition state is apparent. Other examples of improved endo selection on acid catalysis have been reported (7, 38). 

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