Synthesis and Photoswitching Properties of Bioinspired Dissymmetric 2,6-Gamma-Pyrone, Analogue of Cyclocurcumin

Abstract

Cyclocurcumin, a turmeric curcuminoid with potential therapeutic properties, is also a natural photoswitch that may undergo E/Z photoisomerization under UV light. In order to be further exploited in relevant biological applications, photoactivation under near infrared (NIR) irradiation is required. Such requirement can be met through opportune chemical modifications,and most notably by favoring two-photon absorption (TPA) probability. Herein, a general and efficient synthesis of a biomimetic 2,6-g-pyrone analogue of cyclocurcumin is described, motivated by the fact that molecular modeling previews an order of magnitude increase of the NIR TPA cross-section for the latter compared to the natural counterpart. Three retrosynthetic pathways have been identified (i) via an aryl-oxazole intermediate or via an aryl-diynone through (ii) a bottom-up or (iii) a top-down approach. While avoiding the passage through unstable synthons or low yield intermediate reactions, only the latest approach could conveniently afford the 2,6-g-pyrone analogue of cyclocurcumin, in ten steps and with an overall yield of 18%. The photophysical properties of our biomimetic analogue have also been characterized showing an improved photo-isomerization yield over the parent natural compound. The potentially improved non-linear optical properties, as well an enhanced stability, may be correlated to the enforcement of the planarity of the pyrone moiety leading to a quadrupolar D-p-A-p-D system.<br>

Trans-cis Photoisomerization of a Biomimetic Cyclocurcumin Analogue Rationalized by Molecular Modelling

“…It should be noted that this transition is stabilized when computed in solution and slightly red shifting when increasing the polarity of the used solvent. 19 Additionally, a third contribution of π-π* nature and involving the pyrone C=C which is coupled to the main chromophore because of the extended conjugation could also be considered. However, all the computational methodologies used agree in placing this transition at higher energies than the former along the entirety of the double-bond torsion coordinate, hence suggesting that its role on the photoisomerization is negligible.…”

“…However, all the computational methodologies used agree in placing this transition at higher energies than the former along the entirety of the double-bond torsion coordinate, hence suggesting that its role on the photoisomerization is negligible. 19 To validate the use of TD-DFT to include solvent effects in a more affordable manner, the energy levels of the two lowest energy states along the double-bond rotation coordinate have been benchmarked against wavefunction-based methods. This involved the use of a complete active space approach (CASSCF) and the multi state second order perturbation expansion (MS-CASPT2).…”

“…The presence of the two minima in excited state presenting similar energies is in good agreement with the stokes-shifted fluorescent emission found experimentally. 19 To begin with the exploration of the photoisomerization process, the two lower excited states were followed along the most relevant coordinate, which in a trans to cis isomerization is obviously the dihedral angle along the isomerizable bond. For that, a relaxed scan over the dihedral angle (θ), see Figure 1, was performed in vacuo with the geometry of the two states relaxed at CAS-SCF level, and the energy corrected by single point MS-CASPT2 to include the dynamic electron correlation.…”

Trans-cis Photoisomerization of a Biomimetic Cyclocurcumin Analogue Rationalized by Molecular Modelling

“…However, all the computational methodologies used agree in placing this transition at higher energies than the former along the entirety of the double-bond torsion coordinate, hence suggesting that its role on the photoisomerization is negligible. 19 To validate the use of DFT and to choose the best functional, the energy levels of the two lowest energy states along the double-bond rotation coordinate have been benchmarked against wavefunction-based methods. This involved the use of Figure 2.…”

Synthesis and photoswitching properties of bioinspired dissymmetric gamma-pyrone, analogue of cyclocurcumin

“…In summary, we designed and synthesized a 2,6-disubstituted-g-pyrone analogue of cyclocurcumin, a natural photoswitch in the UV-Vis region, in order to improve its photophysical properties and more particularly to increase the cross-section value of twophoton absorption. 42 Indeed, this feature is compulsory for further in vivo applications for which irradiation in the NIR region is needed. To do so, three retrosynthetic pathways were explored.…”