Synthesis and photoswitching properties of bioinspired dissymmetric 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

“…We observed consistently a common behavior as it was also reported in the case of the modeling of the absorption spectrum as reported in our previous contribution. 19 Even though B3LYP provides an absorption spectrum whose shape is closer to the experimental results, its use to study the rotation coordinate was dismissed due to the appearance of intruder states that makes impossible the right representation of the PES along this coordinate. This is mostly due to the well-known overstabilization of charge-transfer states, that is an issue plaguing hybrid functionals, and for that reason the long-range corrected CAM-B3LYP was chosen instead.…”

“…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 p-p* nature and involving the pyrone CQC which is coupled to the main chromophore because of the extended conjugation could also be considered. However, all the computational methodologies used agree in Fig.…”

“…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.…”

“…15 With all these motivations in mind, we recently reported the design and synthesized a biomimetic analogue based on natural CC showing improved non-linear absorption properties, especially concerning significantly increased TPA cross-section, while keeping the main photoswitchable characteristics of the natural CC. 19 As a matter of fact, the combination of a biomimetic strategy using synthetic and molecular design has emerged as a clearly advantageous procedure in the improvement of the photoswitching capabilities. 20,21 Indeed, we reported the first bioinspired photoswitch derived from cyclocurcumin (CC) showing that trans-cis photo-isomerization is possible and rather solvent independent.…”