Quest for the Molecular Basis of Improved Selective Toxicity of All-Trans Isomers of Aromatic Heptaene Macrolide Antifungal Antibiotics

Three aromatic heptaene macrolide antifungal antibiotics, Candicidin D, Partricin A (Gedamycin) and Partricin B (Vacidin) were subjected to controlled cis-trans ® all trans photochemical isomerization. The obtained all-trans isomers demonstrated substantially improved in vitro selective toxicity in the Candida albicans cells: human erythrocytes model. This effect was mainly due to the diminished hemotoxicity. The molecular modeling studies on interactions between original antibiotics and their photoisomers with ergosterol and cholesterol revealed some difference in free energy profiles of formation of binary antibiotic/sterol complexes in respective membrane environments. Moreover, different geometries of heptaene: sterol complexes and variations in polyene macrolide molecule alignment in cholesterol-and ergosterol-containing membranes were found. None of these effects are of the crucial importance for the observed improvement of selective toxicity of aromatic heptaene antifungals but each seems to provide a partial contribution.

The photochemical Isomerization of Hexatomic Heterocyclic Compounds

: The photochemical isomerization of hexatomic heterocyclic compounds has been discussed. The attention was focused on the mono- and dinitrogen hexatomic heterocycles. To justify the photochemical isomerization of pyridines, Dewar isomers, azaprismane, and azaprefulvene derivatives have been proposed. The photoisomerization of pyridinium salts requires a ring reduction with the formation of arizines. Pryridium ylides gave photoisomerization reaction trough the formation of the corresponding azirines, while pyridinium N-oxide required to react the formation of the corresponding oxaziridines. The photochemical isomerization of pyrazine derivatives, Dewar isomers, diazaprismane, and benzvalene intermediates have been proposed to justify the observed reactivity. Finally, in the case of pyridazine and pyrimidine derivatives, Dewar isomers were used to explain the obtained reaction products. In the discussion of the results, the presence of different mechanistic hypotheses has been evidenced.

Hydrogen atom transfer in the photochemical isomerization of hydrazones of 1,2,4-oxadiazole derivatives

DFT calculations on the photoisomerization of hydrazones of 1,2,4-oxadiazole derivatives to 1,2,5-triazoles have been performed showing that the reaction occurred through the first excited singlet state. The Z isomer gave the reaction through a hydrogen atom transfer of the hydrazonic nitrogen atom to the nitrogen atom in four position on the oxadiazole ring. In this case, the isomerization was a concerted reaction. The E isomer could undergo the same reaction. However, it could not be a concerted reaction but required the presence of a ring opening intermediate.

Role of the Perfluoro Effect in the Selective Photochemical Isomerization of Hexafluorobenzene

Hexafluorobenzene and many of its derivatives exhibit a chemoselective photochemical isomerization, resulting in highly-strained, Dewar-type bicyclohexenes. While the changes in absorption and emission associated with benzene hexafluorination have been attributed to the socalled “perfluoro effect,” the resulting electronic structure and photochemical reactivity of hexafluorobenzene are still unclear. We now use a combination of ultrafast time-resolved spectroscopy, multiconfigurational computations, and non-adiabatic dynamics simulations to develop a holistic description of the absorption, emission, and photochemical dynamics of the 4πelectrocyclic ring-closing of hexafluorobenzene and the fluorination effect along the reaction coordinate. Our calculations suggest that the electron-withdrawing fluorine substituents induce a vibronic coupling between the lowest-energy 1B2u (ππ*) and 1E1g (πσ*) excited states by selectively stabilizing the σ-type states. The vibronic coupling occurs along vibrational modes of e2u symmetry which distorts the excited-state minimum geometry resulting in the experimentally broad, featureless absorption bands, and a ~100 nm Stokes shift in fluorescence– in stark contrast to benzene. Finally, the vibronic coupling is shown to simultaneously destabilize the reaction pathway towards hexafluoro-benzvalene and promote molecular vibrations along the 4π ring-closing pathway, resulting in the chemoselectivity for hexafluoro-Dewar-benzene.

Role of the Perfluoro Effect in the Selective Photochemical Isomerization of Hexafluorobenzene

Hexafluorobenzene and many of its derivatives exhibit a chemoselective photochemical isomerization, resulting in highly-strained, Dewar-type bicyclohexenes. While the changes in absorption and emission associated with benzene hexafluorination have been attributed to the socalled “perfluoro effect,” the resulting electronic structure and photochemical reactivity of hexafluorobenzene are still unclear. We now use a combination of ultrafast time-resolved spectroscopy, multiconfigurational computations, and non-adiabatic dynamics simulations to develop a holistic description of the absorption, emission, and photochemical dynamics of the 4πelectrocyclic ring-closing of hexafluorobenzene and the fluorination effect along the reaction coordinate. Our calculations suggest that the electron-withdrawing fluorine substituents induce a vibronic coupling between the lowest-energy 1B2u (ππ*) and 1E1g (πσ*) excited states by selectively stabilizing the σ-type states. The vibronic coupling occurs along vibrational modes of e2u symmetry which distorts the excited-state minimum geometry resulting in the experimentally broad, featureless absorption bands, and a ~100 nm Stokes shift in fluorescence– in stark contrast to benzene. Finally, the vibronic coupling is shown to simultaneously destabilize the reaction pathway towards hexafluoro-benzvalene and promote molecular vibrations along the 4π ring-closing pathway, resulting in the chemoselectivity for hexafluoro-Dewar-benzene.

Role of the Perfluoro Effect in the Selective Photochemical Isomerization of Hexafluorobenzene

Hexafluorobenzene and many of its derivatives exhibit a chemoselective photochemical isomerization, resulting in highly-strained, Dewar-type bicyclohexenes. While the changes in absorption and emission associated with benzene hexafluorination have been attributed to the socalled “perfluoro effect,” the resulting electronic structure and photochemical reactivity of hexafluorobenzene are still unclear. We now use a combination of ultrafast time-resolved spectroscopy, multiconfigurational computations, and non-adiabatic dynamics simulations to develop a holistic description of the absorption, emission, and photochemical dynamics of the 4πelectrocyclic ring-closing of hexafluorobenzene and the fluorination effect along the reaction coordinate. Our calculations suggest that the electron-withdrawing fluorine substituents induce a vibronic coupling between the lowest-energy 1B2u (ππ*) and 1E1g (πσ*) excited states by selectively stabilizing the σ-type states. The vibronic coupling occurs along vibrational modes of e2u symmetry which distorts the excited-state minimum geometry resulting in the experimentally broad, featureless absorption bands, and a ~100 nm Stokes shift in fluorescence– in stark contrast to benzene. Finally, the vibronic coupling is shown to simultaneously destabilize the reaction pathway towards hexafluoro-benzvalene and promote molecular vibrations along the 4π ring-closing pathway, resulting in the chemoselectivity for hexafluoro-Dewar-benzene.

Role of the Perfluoro Effect in the Selective Photochemical Isomerization of Hexafluorobenzene

Hexafluorobenzene and many of its derivatives exhibit a chemoselective photochemical isomerization, resulting in highly-strained, Dewar-type bicyclohexenes. While the changes in absorption and emission associated with benzene hexafluorination have been attributed to the socalled “perfluoro effect,” the resulting electronic structure and photochemical reactivity of hexafluorobenzene are still unclear. We now use a combination of ultrafast time-resolved spectroscopy, multiconfigurational computations, and non-adiabatic dynamics simulations to develop a holistic description of the absorption, emission, and photochemical dynamics of the 4πelectrocyclic ring-closing of hexafluorobenzene and the fluorination effect along the reaction coordinate. Our calculations suggest that the electron-withdrawing fluorine substituents induce a vibronic coupling between the lowest-energy 1B2u (ππ*) and 1E1g (πσ*) excited states by selectively stabilizing the σ-type states. The vibronic coupling occurs along vibrational modes of e2u symmetry which distorts the excited-state minimum geometry resulting in the experimentally broad, featureless absorption bands, and a ~100 nm Stokes shift in fluorescence– in stark contrast to benzene. Finally, the vibronic coupling is shown to simultaneously destabilize the reaction pathway towards hexafluoro-benzvalene and promote molecular vibrations along the 4π ring-closing pathway, resulting in the chemoselectivity for hexafluoro-Dewar-benzene.

Stereoretentive Olefin Metathesis: A New Avenue for the Synthesis of All-cis Poly(p-phenylene vinylene)s and Stereo­defined Polyalkenamers

Olefin metathesis has tremendously impacted all fields of synthetic chemistry. However, the control of the olefin stereochemistry during this process remains a grand challenge. Recent innovations in catalyst design have permitted control of the stereochemistry of the olefin product. Here, we discuss the development of stereoretentive olefin metathesis, with an emphasis on the synthesis of stereodefined polyalkenamers through ring-opening metathesis polymerization (ROMP). We then present our application of this unique reaction manifold to the preparation of all-cis poly(p-phenylene vinylene)s (PPVs). A dithiolate Ru catalyst was found to deliver perfect cis selectivity for the polymerization of a paracyclophane diene monomer. By using optimized conditions, all-cis PPVs with narrow dispersities and predictable molar masses were obtained by varying the ratio of monomer to catalyst. The high chain fidelity of the stereoretentive ROMP with a paracyclophane diene monomer enabled the preparation of well-defined diblock copolymers with a norbornene co-monomer. Photochemical isomerization of all-cis to all-trans PPVs was effected with both homopolymers and diblock copolymers. This process was shown to be selective for the PPV block, and resulted in changes in optical properties, polymer size, and solubility. Stereoretentive ROMP provides a promising platform for synthesizing polymers with unique properties, including photoresponsive all-cis PPVs with living characteristics.1 Introduction2 Synthetic Applications of Stereoretentive Olefin Metathesis3 Stereocontrol of Polyalkenamers through Stereoretentive ROMP4 Stereoretentive ROMP To Access All-cis Poly(p-phenylene vinylene)s5 Conclusion