ABSTRACT A highly diastereoselective synthesis of tricyclic pyrrolizines was presently achieved through the intramolecular 1,3‐dipolar cycloaddition of 5‐formyl‐ N‐ allenylpyrroles substituted with alkyl acrylates or acrylonitrile as reactive dipolarophiles. The N‐ benzylhydroxylamine‐based Cope‐type hydroamination reaction with the N‐ allenylpyrrole moiety satisfactorily proceeded to the in situ generation of the respective nitrones, which underwent a highly diastereoselective intramolecular 1,3‐dipolar cycloaddition to the dipolarophile fragment to provide the corresponding isoxazolidine‐fused pyrrolizine adducts. An alternative non‐concerted mechanism has been proposed for nitrone formation to account for the low reactivity of formyl‐free N‐ allenylpyrroles. Bromination, olefination, and reduction reactions of the adducts led to selective functionalization. The replacement of the substituents in both the pyrrole ring and the dipolarophile modifies the reactivity and the outcome of the reaction, leading to the formation of indolizines. A theoretical study on the stereoselective 1,3‐dipolar reactions, carried out by calculating the transition states of the endo/exo and cis/trans ‐fused five‐membered bridgehead bicyclic rings, revealed that conformational restraints of the tether linking the dipole and dipolarophile govern the endo ‐cis preference.
Escalante et al. (Fri,) studied this question.