Experimental and Theoretical Study on the Cycloreversion of a Nucleobase‐Derived Azetidine by Photoinduced Electron Transfer

Abstract

Azetidines are interesting compounds in medicine and chemistry as bioactive scaffolds and synthetic intermediates. However, photochemical processes involved in the generation and fate of azetidine-derived radical ions have scarcely been reported. In this context, the photoreduction of this four-membered heterocycle might be relevant in connection with the DNA (6-4) photoproduct obtained from photolyase. Herein, a stable azabipyrimidinic azetidine (AZT ), obtained from cycloaddition between thymine and 6-azauracil units, is considered to be an interesting model of the proposed azetidine-like intermediate. Hence, its photoreduction and photo-oxidation are thoroughly investigated through a multifaceted approach, including spectroscopic, analytical, and electrochemical studies, complemented by CASPT2 and DFT calculations. Both injection and removal of an electron result in the formation of radical ions, which evolve towards repaired thymine and azauracil units. Whereas photoreduction energetics are similar to those of the cyclobutane thymine dimers, photo-oxidation is clearly more favorable in the azetidine. Ring opening occurs with relatively low activation barriers (<13 kcal mol ) and the process is clearly exergonic for photoreduction. In general, a good correlation has been observed between the experimental results and theoretical calculations, which has allowed a synergic understanding of the phenomenon.

Synthesis of azetidines by aza Paternò–Büchi reactions

“…14). 36 Relying on either direct or acetone-sensitized excitation, the desired azetidine (44) was isolated in 80-85% yield. Notably, the imine 43 used in this report did not require any conjugating group for successful reactivity.…”

“…In a subsequent study, the Miranda group reported that the azetidine fragmentation could be achieved by both single-electron reduction and oxidation. 44 …”

Theoretical Study on the Photo-Oxidation and Photoreduction of an Azetidine Derivative as a Model of DNA Repair

“…The impact of the solvation and the influence of the temperature and entropic effects on the kinetics and thermodynamics of the ring-opening reactions can be assessed with the data compiled in Table 3 and Table 4 , referring to the electronic thermodynamics (ΔE), the electronic activation energy (ΔE ‡ ), their respective corrected values with the zero-point vibrational energy (ZPVE), i.e., ΔE 0 and ΔE 0 ‡ , and the Gibbs free energies (ΔG and ΔG ‡ ). Note that the DFT protocol used here was previously validated by comparing to data generated at the CASPT2 level [ 15 ]. Commented above, the ΔE values indicate that both isomers undergo a spontaneous ring-opening reaction in the anionic state, while the same process in the cationic state is clearly endergonic.…”

“…The instability of the formed four-membered ring oxetane/azetidine intermediates is an important limitation because it prevents not only their isolation and characterization but also their use as substrates to investigate the electron-induced cycloreversion. Several models have been designed to mimic this intermediate to follow the electron-transfer processes by spectroscopic techniques [ 14 , 15 ] and theoretical methods [ 6 , 15 ]. Understanding DNA repair processes is crucial to comprehend not only life functioning and evolution on Earth, but also to develop applications that could contribute to the fight against the harmful biological consequences of unprotected exposure to solar radiation.…”

“…Viewing a previous work, a model system of the azetidine intermediate obtained by the cycloaddition of thymine and 6-azauracil was designed [ 3 ]. A systematic study was also performed on the photo-oxidation and photoreduction by several photosensitizers (Phs) combining spectroscopy, electrochemistry, analytical tools, and multiconfigurational theoretical methods, revealing that photo-oxidation is more efficient in repairing this model [ 15 ].…”