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

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.