Exo transition state

Preference for endo or exo transition state depends on the substitution of the diene, dieneophile and connecting chain. 

Theoretical work by the groups directed by Sustmann and, very recently, Mattay attributes the preference for the formation of endo cycloadduct in solution to the polarity of the solvent Their calculations indicate that in the gas phase the exo transition state has a lower energy than the endo counterpart and it is only upon introduction of the solvent that this situation reverses, due to the difference in polarity of both transition states (Figure 1.2). Mattay" stresses the importance of the dienophile transoid-dsoid conformational equilibrium in determining the endo-exo selectivity. The transoid conformation is favoured in solution and is shown to lead to endo product, whereas the cisoid conformation, that is favoured in the gas phase, produces the exo adduct This view is in conflict with ab initio calculations by Houk, indicating an enhanced secondary orbital interaction in the cisoid endo transition state . 

Two approaches to convergent steroid syntheses are based on the thermal opening of benzocyclobutenes to the o-quinodimethane derivatives (see p. 80 W. Oppolzer, 1978 A) and their stereoselective intramolecular Diels-Alder cyclizations. T, Kametani (1977 B, 1978) obtained (+ )-estradiol in a six-step synthesis. The final Diels-Alder reaction occurred regio- and stereoselectively in almost quantitative yield, presumably because the exo transition state given below is highly favored over the endo state in which rings A and D would stcrically inter-... 

Another stereochemical feature of the Diels-Alder reaction is addressed by the Alder rule. The empirical observation is that if two isomeric adducts are possible, the one that has an unsaturated substituent(s) on the alkene oriented toward the newly formed cyclohexene double bond is the preferred product. The two alternative transition states are referred to as the endo and exo transition states ... 

In general, stereochemical predictions based on the Alder rule can be made by aligning the diene and dienophile in such a way that the unsaturated substituent on the dienophile overlaps the diene n system. The stereoselectivity predicted by the Alder rule is independent of the requirement for suprafacial-suprafacial cycloaddition, since both the endo and exo transition states meet this requirement. 

Compare energies of endo transition state and exo transition state. Which of the two has the lower energy Were the reaction under kinetic control, which would be the major product and what would be the ratio of major to minor products Use equation (2). 

Another application of catalyst 8 is to the reaction of acetylenic aldehydes [10c] (Scheme 1.18, Table 1.6). Two acetylenic dienophiles have been reacted with cyclo-pentadiene or cyclohexadiene to give bicyclo[2.2.1]heptadiene or bicyclo[2.2.2]octa-diene derivatives in high optical purity. A theoretical study suggests that this reaction proceeds via an exo transition state. 

The four different transition states in Fig. 8.10 were considered with BF3 as a model for the BLA catalyst in the theoretical calculations. It was found that the lowest transition-state energy for the BF3-catalyzed reactions was calculated to be 21.3 kcal mol for anti-exo transition state, while only 1.5 kcal mol higher in energy the syn-exo transition state, was found. The uncatalyzed reaction was calculation to proceed via an exo transition state having an energy of 37.0 kcal mol . The calculations indicated that the reaction proceeds predominantly by an exo transition-state structure and that it is enhanced by the coordination of the Lewis acid. 

Gratifyingly, when compound 24 is refluxed in a solution of toluene at 110°C, it undergoes quantitative [4+2] cycloaddition to polycyclic system 25. The indicated stereochemistry of 25 was anticipated on the basis of the trans,trans geometry of the phenyl-diene system in precursor 24 and the presumed preference for an exo transition state geometry. These assumptions were vindicated by the eventual conversion of 25 to endiandric acids A (1) and B (2). 

In contrast to these results, a preference for rearrangement through an exo-transition state has been detected in the rearrangement of several cyclic allylic sulfoxides. For example, while sulfoxide 36 rearranged to alcohol 37 with 60% ee, introduction of bulky substituents at the (i position of the ring enhanced the optical purity to 90%, as a result of further destabilization of the endo conformation (equation 21)82,84. 

Rearrangement of sulfoxides 38a, b exhibited the interplay of several conformational factors. Both diastereomers afford predominant axial (trans) alcohol, but with opposite absolute configuration. The (R, R)-diastereomer strongly prefers the exo-transition state, whereas the (R, S)-isomer prefers the endo conformation. Hoffmann interprets these results in terms of an approximately 3-fold preference for the exo-transition state but a 6-fold preference for formation of an axial bond, these effects reinforcing each other in one isomer but opposing each other in the second. 

Interestingly, the cycloaddition of 2-azadiene 44 with N-methylmaleimide in 2.5m LT-DE gave predominantly exo-adduct in contrast to the thermal cycloaddition that is mainly enJo-selective (Scheme 6.27). A similar but not so dramatic increase in cxo-selectivity was also observed [47] for the cycloaddition of 44 with N-phenylmaleimide. The reaction is kinetically controlled, but the origin of the high cxo-selectivity observed in LT-DE is unclear the polar medium probably favors the more polar exo transition state. 

Imines, on the contrary, proved particularly reactive under these conditions (Fig. 4.34). For example, Jones and Selenski report that the introduction of one equivalent of methyl magnesium bromide to benzaldehyde 5 stirring at —78 °C in the presence of one and half equivalents of the imine that is derived from the condensation of benzyl amine and benzaldehyde proceeds immediately to the aminal 65 in 94% yield.27 Only the trans isomer is observed from this low-temperature cycloaddition. While the relative stereochemistry appears to be result of an exo transition state, we suspect that initial cis adduct from and endo addition may epimerize under these conditions. 

Alcaide, Aknendros and coworkers developed a combination of a 3,3-sigmatropic rearrangement of the methanesulfonate of an a-allenic alcohol to give a 1,3-bu-tadiene which is intercepted by a dienophile present in the molecule to undergo an intramolecular Diels-Alder reaction [83]. Thus, on treatment of 4-236 with CH3S02C1, the methanesulfonate was first formed as intermediate, and at higher temperature this underwent a transposition to give 4-237 (Scheme 4.51). This then led directly to the cycloadduct 4-238 via an exo transition state. 

In these dimerisations one molecule acts as a diene and the other as the dienophile. The endo product is thermodynamically less stable and secondary interactions tend to reduce the activation energy. No such interactions are possible for the exo transition state. 

FIGURE 1. Endo and exo transition states of the Diels-Alder reaction... 

FIGURE 6. Model of the exo transition state to form 366 using 367d as the catalyst... 

Recently, Yamamoto and coworkers249 reported the first examples of chiral induction in the cycloadditions of cyclopentadiene to propargylic aldehydes 402 using catalysts 380c, 387 and 393 (equation 119). The cycloadditions were stated to proceed via exo transition states and were accelerated by coordination of the Lewis acid to the carbonyl group. 

Cycloaddition reactions using tropone or another cyclic triene as the 6ji partner have been abundantly described in the literature. It has been found that virtually all metal-free [6 + 4] cycloadditions of cyclic trienes afford predominantly exo adducts. This has been rationalized by consideration of the HOMO-LUMO interactions between the diene and triene partners. An unfavorable repulsive secondary orbital interaction between the remaining lobes of the diene HOMO and those of the triene LUMO develops during an endo approach. The exo transition state is devoid of this interaction (Figure 9). 

In contrast to Nicolaou s model system, the IMDA reaction of quinone 86 to adduct 85 proceeded through an exo transition state geometry. This difference is due to the two additional substitutes attached to the diene side chain of quinone 86. A more detailed analysis (molecular modeling) of the four theoretically possible transition states (Fig. 10) reveals that an enophilic endolexo... 

For an unsymmetrical dienophile, there are two possible stereochemical orientations with respect to the diene. The two possible orientations are called endo and exo, as illustrated in Fig. 6.3. In the endo transition state, the reference substituent on the dienophile is oriented toward the % orbitals of the diene. In the exo transition state, the substituent is oriented away from the % system. For many substituted butadiene derivatives, the two transition states lead to two different stereoisomeric products. The endo mode of addition is usually preferred when an electron-attracting substituent such as a carbonyl group is present on the dienophile. The empirical statement which describes 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 Diels-Alder reaction. The endo product is often the more sterically congested. The preference for the endo transition state... 

In entry 2, a similar triene that lacks the activating carbonyl group undergoes reaction, but a much higher temperature is required. In this case, the ring junction is trans. This corresponds to an exo transition state and presumably reflects the absence of an important secondary orbital interaction between the diene and dienophile. 

With some 1,3-dipoles, two possible stereoisomers can be formed by syn addition. These result from two differing orientations of the reacting molecules, which are analogous to the endo and exo transition states in Diels-Alder reactions. Diazoalkanes, for example, can add to unsymmetrical dipolarophiles to give two diastereomers. 

In an extensive study into the application of the decarboxylative approach to azomethine ylides, Giigg reported the construction of numerous, complex polycyclic systems via an intramolecular protocol. Thiazolidine-4-carboxylic acid (263) was shown to react with 264 in refluxing toluene to furnish a 2 1 mixture of 265 and 266 in 63% yield (81). The reaction is assumed to occur via condensation of the aldehyde and amino acid to generate the imine 267, followed by cyclization to 268. Subsequent thermal decarboxylation of the ester generates either a syn dipole leading to 265 from an exo transition state, or an anti dipole and endo transition state generating adduct 266 (Scheme 3.90). 

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