Diels-Alder Reaction in Molecular Cavities

The transition state of concerted Diels-Alder reactions has stringent regio- and stereochemical requirements and can assume settled configurations if the reaction is carried out in a molecular cavity. Cyclodextrins, porphyrin derivatives and cyclophanes are the supramolecular systems that have been most investigated. 

As an approach to biomimetic catalysis, Sanders and colleagues [67] synthesized a series of 1,1,2-linked cyclic porphyrin trimers that allow the stereo- and regiochemistry of the Diels-Alder reaction of 84 and 85 within the molecular cavity to be controlled, thereby producing prevalently or exclusively the endo 86 or the exo 87 adduct. Two examples are illustrated in Scheme 4.18. At 30 °C and in the absence of 88, the reaction furnishes a mixture of diastereoisomers, while the addition of one equivalent of trimer 88 accelerates the reaction 1000-fold and the thermodynamically more stable exo adduct 87 is the sole detectable product. 

An example of a cyclophane-type cavity is the azacyclophane CP66 supra-molecular system which provides a lipophilic cavity with an internal width of approximately 6.5 A, as well as positive charges which accelerate and increase the selectivity of the process. The Diels-Alder reaction of cyclopentadiene with diethylfumarate at 20 °C in 10% and 50 To dioxane-water is accelerated by the presence of CP66 by 2.9 and 1.5 times, respectively [65c] (Equation 4.12). 

In striking contrast with these two previous examples of 1,3-dipolar cycloaddition catalyzed by encapsulation, the EMs calculated for particular examples of Diels-Alder reactions catalyzed by Rebek s softball [25] or by Sanders [26] cyclophane, which was selected from a dynamic combinatorial library (DCL), are lower than the actual reactant concentration calculated from the volumes of the molecular cavities. Probably, the Diels-Alder reactions have more stringent orientational requirements than the 1,3-dipolar cycloaddition. The reactants of the Diels-Alder reactions, when encapsulated or included, spend a significant amount of time in ternary complexes displaying a non-productive mutual orientation. 

---