Experimental and Computational Study on the Intramolecular Hydrogen Atom Transfer Reactions of Maleimide-Based Enediynes After Cycloaromatization.

ABSTRACT

The follow-up reaction pathways of the diradical species formed from cycloaromatization of enediynes or enyne-allenes determine their ability of H-abstraction from DNA, significantly affecting their biological activity performance. To gain a deeper understanding of subsequent reaction pathways of the diradical intermediates formed from acyclic enediynes based on maleimide-assisted rearrangement and cycloaromatization (MARACA), a maleimide-based enediyne featuring methylene groups adjacent to the propargyl sites of the terminal alkynes was synthesized through the Sonogashira coupling reaction. Three thermal cyclization products after intramolecular hydrogen atom transfer (HAT) were obtained from the thermolysis experiment and their structures were confirmed by 1D and 2D nuclear magnetic resonance spectroscopic analysis. Density functional theory was employed to analyze the important elementary steps including rearrangement, cycloaromatization, and intramolecular HAT processes toward the formation of the cyclized products, where the low-energy barriers of HAT pathways relative to the formation of diradicals from cycloaromatization were successfully identified. Overall, the HAT processes to consume diradicals intramolecularly have become competitive with that of intermolecular H-abstraction, implying that the DNA-cleavage ability of enediynes can be further boosted once the HAT processes are halted. This study offers a promising direction for designing novel and potent acyclic enediynes for antitumor applications.