Curcumin isolated from natural sources has received significant attention in the scientific community due to its unique bioactive properties (e.g., anti-viral, anti-bacterial, and anti-carcinogenic). Despite pharmacological potential, the development of curcumin as a therapeutic agent is constrained by its low water solubility, low absorption, and high decomposition. Curcumin is a symmetric molecule that consists of three components, the central acetylacetone linker and two equivalent sidearms. Research demonstrates that modification of a central linker to more rigid cyclic linkers positively impacted biological properties. Herein we report our findings on the synthesis of asymmetric curcuminoids using an acetylcyclohexanone central linker and aldehydes with varied electronic and structural features. All reactions were performed with a microwave-assisted, solvent-free method using a Biotage® Initiator+ microwave reactor. Our research was complemented by computational modeling to probe factors leading to the desired asymmetric product formation. We explored the impact of functional group identities and locations in the side arms components on the relative reactivity of aldehydes used, as well as the thermodynamic preference of additions on the central linker. All calculations were conducted using GAMESS at the B3LYP/6-311++G** level of theory. To the best of our knowledge, this is the first example of a hybrid computational-synthetic methodology towards the solvent-free microwave synthesis of asymmetric curcuminoids using acetylcyclohexanone and various aldehydes.

Application of a solvent-free microwave synthesis towards asymmetric curcuminoids: synthetic findings and computational modeling

ACS Spring Meeting 2021

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