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The ability to construct molecules with potential applications in biomedicine via efficient and selective molecular design and syntheses hinges on a thorough understanding of underlying reaction mechanisms. The biological importance of steroids and related heterocyclic compounds are well known but theoretical studies aimed at delineating reaction mechanisms to complement efforts of experimentalists are lacking. Herein, we report an extensive theoretical study on the regio‐, stereo‐, and enantio‐selectivity of the tandem sequential intramolecular (4 + 2)/intermolecular (3 + 2) cycloaddition reaction of (E)‐3‐(2‐[furan‐2‐ylmethoxy]phenyl)acrylate derivatives (R1) and azides (R3 and R3′) as well as nitrones (R2) for the formation of steroids. In the reaction of R1 and the azide derivatives R3 and R3′, the intramolecular (4 + 2) cycloaddition of R1 is the rate‐determining step (rds). The reaction is also found to be very selective. Reaction of electron‐withdrawing groups‐substituted R1 with R3 is found to generally increase the barrier of the rds except bromine whiles electron‐donating groups are found to generally decrease the activation energies of the rds. Subsequently, we report a novel reaction of R1 with cyclic nitrone (R2), which compares favorably with the azide reaction. Results from the global reactivity descriptors are in good agreement with the activation barrier trends. All the considered reactions in this study are found to be kinetically driven.

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The synthesis of isoxazolidine and isoxazole derivatives, versatile building blocks for the construction of a wide range of complex heterocyclic architectures in synthetic organic and medicinal chemistry, is efficiently achieved via the 1,3‐dipolar cycloaddition reaction (1,3‐DC). Herein, we report an extensive theoretical study on the peri‐, regio‐, stereo, and enantio‐selectivities of 1,3‐DC of 7‐isopropylidenebenzonorbornadiene with nitrile oxide and cyclic nitrone derivatives using density functional theory calculations. Acetophenone‐substituted nitrile oxide periselectively adds across the endocyclic olefinic bond of the dipolarophile to furnish the exo‐cycloadduct as the major product, a reaction that has a rate constant of 1.88 × 109 s−1. The endo approach of this periselective path is the closest competing pathway with a rate constant of 4.59 × 107 s−1. Different substituents on the nitrile oxide do not affect the peri‐ and stereo‐selectivity of the reaction. Diethyl ether solvation has no substantial effect on the energetic patterns observed in the gas phase computation. Also, we report a novel 1,3‐DC between cyclic nitrone derivatives and 7‐isopropylidenebenzonorbornadiene as an efficient way to generate isoxazolidine derivatives. Even though the reactions of the cyclic nitrone derivatives have slightly higher activation barriers than the acyclic nitrile oxide derivatives, the former is more enantioselective than the latter. Whereas electron‐donating groups (EDGs) on the cyclic nitrone favor the formation of the exo‐cycloadduct, electron‐withdrawing groups (EWGs) favor the formation of the endo‐cycloadduct. Both 1,3‐dipoles add across the dipolarophile via a concerted asynchronous mechanism.

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