For example, hydrogen‐bonded solvents can activate ketones to undergo a DA reaction, or bifunctional hydrogen bond donor organocatalysts, such as differently substituted thioureas, are able to increase both the reaction rate as well as the endo/ exo‐selectivity of DA reactions between a diene and α, β‐unsaturated carbonyl compounds. In analogy with conventional Lewis acids, hydrogen‐bonded organocatalysts are also able to significantly modify both the reactivity and selectivity of the DA reaction. on the total synthesis of the tetrodotoxin. Interestingly, LAs can also reverse the regiochemical course of the DA reaction leading to products that otherwise would be impossible to synthesize: a pioneering example has been shown by Kishi et al. For example, Lewis acids (LAs) are able to greatly accelerate the DA via binding to the dienophile. A striking number of organocatalysts have been developed over the years to increase the reactivity and selectivity of the DA reaction. Since its discovery in 1928, it has paved the way for a convenient procedure to create six‐membered rings, with up to four stereocenters, becoming the gold standard for many applications ranging from the synthesis of natural products to the industrial production of relevant compounds in the pharmaceutical field.
The Diels‐Alder (DA) cycloaddition reaction is of paramount importance in synthetic organic chemistry. These findings again demonstrate the generality of the Pauli repulsion‐lowering catalysis concept.
Notably, the reactivity can be further enhanced on going from a Period 3 to a Period 5 LA, as these species amplify the asynchronicity of the Diels‐Alder reaction due to a stronger binding to the dienophile. Our detailed activation strain and Kohn‐Sham molecular orbital analyses reveal that these LAs lower the Diels‐Alder reaction barrier by increasing the asynchronicity of the reaction to relieve the otherwise destabilizing Pauli repulsion between the closed‐shell filled π‐orbitals of diene and dienophile. The reaction barriers systematically increase from halogen
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