Synthesis of Chromen[4,3-b]pyrrolidines by Intramolecular 1,3-Dipolar Cycloadditions of Azomethine Ylides: An Experimental and Computational Assessment of the Origin of Stereocontrol

Azomethine ylides, generated from imine‐derived O‐cinnamyl or O‐crotonyl salicylaldeyde and α‐amino acids, undergo intramolecular 1,3‐dipolar cycloaddition, leading to chromene[4,3‐b]pyrrolidines. Two reaction conditions are used: (a) microwave‐assisted heating (200 W, 185 °C) of a neat mixture of reagents, and (b) conventional heating (170 °C) in PEG‐400 as solvent. In both cases, a mixture of two epimers at the α‐position of the nitrogen atom in the pyrrolidine nucleus was formed through the less energetic endo‐approach (B/C ring fusion). In many cases, the formation of the stereoisomer bearing a trans‐arrangement into the B/C ring fusion was observed in high proportions. Comprehensive computational and kinetic simulation studies are detailed. An analysis of the stability of transient 1,3‐dipoles, followed by an assessment of the intramolecular pathways and kinetics are also reported. The two‐component synthesis of chromene[4,3‐b]pyrrolidines has been achieved under two different conditions. The strategy was used to obtain N‐sulfonylated adducts with interesting biological activity. Calculations show that formation of W and S′ 1,3‐dipoles determines the stereochemical outcome of the reaction, which involves asynchronous transition structures.