Photoinduced Reactivity in a Dispiro-1,2,4-trioxolane: Adamantane Ring Expansion and First Direct Observation of the Long-Lived Triplet Diradical Intermediates.

Elisa M Brás,Rui Fausto,Maria L S Cristiano,Manabu Abe,Lília I L Cabral,Patrícia S M Amado

doi:10.1021/acs.jpca.0c01974

Abstract

Dispiro-1,2,4-trioxolane, 1, an ozonide with efficient and broad antiparasitic activity, was synthesized and investigated using matrix isolation FTIR and EPR spectroscopies together with both B3LYP/6-311++G(3df,3dp) and M06-2X/6-311++G(3df,3dp) theoretical methods. Irradiations (λ ≥ 290 nm) of the matrix isolated 1 (Ar or N2) afforded exclusively 4-oxahomoadamantan-5-one, 4, and 1,4-cyclohexanedione, 5. These results suggested that the reaction proceeded via a dioxygen-centered diradical intermediate, formed upon homolytic cleavage of the labile peroxide bond, which regioselectively isomerized to form the more stable (secondary carbon-centered)/oxygen-centered diradical. In situ EPR measurements during the photolysis of 1 deposited in a MeTHF-matrix led to the detection of signals corresponding to two triplet species, one of which was short-lived while the other proved to be persistent at 10 K. These observations strongly support the proposed mechanism for the photogeneration of 4 and 5, which involves intramolecular rearrangement of the intermediate diradical species 2 to afford the triplet diradical 3.

Highlights

Organic dispiro-endoperoxides, in particular dispiro 1,2,4-trioxanes and 1,2,4-trioxolanes, have been attracting much attention since the discovery of artemisinin more than 40 years ago[1-3], which provided a completely new antimalarial structural prototype of pharmacophore
Adamantane-2-spiro-3’-8’-oxo-1’,2’,4’-trioxaspiro[4,5]decane 1, a reported potent antiparasitic dispiro-1,2,4-trioxolane, has been synthesized and studied from the view point of its molecular structure and monomeric photochemistry, using matrix isolation techniques coupled to Fourier transform infrared (FTIR) and EPR spectroscopy
The UV-induced reactivity of 1 was investigated in the two types of matrices (Ar, N2), using broadband (λ ≥ 290 nm) and narrowband (λ = 290 nm) irradiation, the results proving qualitatively identical in both matrices and for the two followed excitation procedures

Summary

Introduction

Organic dispiro-endoperoxides, in particular dispiro 1,2,4-trioxanes and 1,2,4-trioxolanes (ozonides), have been attracting much attention since the discovery of artemisinin more than 40 years ago[1-3], which provided a completely new antimalarial structural prototype of pharmacophore. The structural computed data obtained with the B3LYP and M06-2X functionals for 4 and 5 (graphical representation of the optimized minimum energy structures, and summary of calculated energy data), as well as the spectroscopic data obtained both theoretically and experimentally for these compounds (graphical comparison of the calculated and matrix isolation experimental infrared spectra of the compounds, and tables with calculated and experimental frequencies and intensities, those latter including the bands of 4 and 5 both in the photolysed matrices of 1 and as isolated species) are given in the Supporting Information (Tables S6-S14 and Figures S4 and S5).

Results

Conclusion