Cycloaromatization Of Enediynes Research Articles

Nucleophilic Addition to Diradicals Derived From Cycloaromatization of Maleimide‐Based Enediynes

AbstractDiradical chemistry, typified by the cycloaromatization of enediynes or enyne‐allenes, have been extensively explored due to the involved intriguing biological activity and unique mechanistic actions. Because of the essential Myers‐Saito cycloaromatization involved in the maleimide‐assisted rearrangement and cycloaromatization (MARACA) mechanism disclosed in our recent work, the important object of diradical/zwitterion dichotomy and the reactivity of thermally induced σ,π‐diradicals were investigated in this work through the combination of experimental and computational studies. Deuterium incorporation experiments demonstrated that the polar product was afforded from the MARACA strategy, in which the diradical and zwitterion reactivities from the cycloaromatization step could both lead to the closed‐shell product via the subsequent nucleophilic addition reaction and protonation. Using the density functional theory calculations, the unusual reactivity of the heterosymmetric diradicals to closed‐shell zwitterions was examined, and the addition of carbonyl moiety to α,3‐dehydrotoluene was allowed to occur via a nonplanar cyclic allene transition structure with a small barrier of 9.1 kcal/mol. The observed nonplanar geometry is essential for the necessarily symmetry‐breaking action, resulted in the continuous transformation from open‐shell diradical to closed‐shell zwitterion species during the addition process.

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

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.