One Pot Synthesis of the C-3 Complex (Curcumin, Demethoxycurcumin, and Bis-Demethoxycurcumin): Their Joint and Independent Biological Actions

TL;DR

This paper describes a new method to synthesize a mixture of curcuminoids found in turmeric, allowing control over their proportions for potential health benefits.

Contribution

A novel synthesis method for the C-3 complex curcuminoids that mimics natural proportions and allows selective enrichment of specific compounds.

Findings

The synthesis method successfully mimics natural proportions of CUR, DMC, and BDMC.

DFT calculations show di-condensation is more favorable than mono-condensation.

Adjusting aldehyde mixtures allows preferential production of DMC.

Abstract

Curcumin (CUR) is the primary metabolite isolated from the Curcuma longa L. rhizome. Most synthetic and biological studies have focused mainly on the curcumin molecule due to its essential biological activity as an antioxidant, anti-cancer, and anti-Alzheimer’s disease agent. However, the natural extract of turmeric also contains two essential curcuminoids (demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC)), which altogether comprise the so-called C-3 complex. They are present in commercial compositions for treating biliary or digestive ailments. The vegetal rhizome’s extraction typically leads to a mixture of the three main curcuminoids, CUR, DMC, and BDMC, in variable proportions, and each of these metabolites has reported specific synthetic routes. Herein, we have performed the synthesis and isolation of the three major curcuminoids using the method called scrambling of aldehydes followed by aldol di-condensation reactions. A density functional theory (DFT) approach supported the experimental results by inspecting the predicted energies for the aldol condensation. Thus, the di-condensation reaction is substantially favoured (ΔG° = −2685.9 kJ/mol) over the mono-condensation reaction (ΔG° = −1393.753 kJ/mol). Our approach allows us to mimic closely the proportions of these curcuminoids found in extracts from natural sources that follow the order CUR > DMC > BDMC, respectively. The proportion of aldehydes can be modified in the scrambling reaction with an adequate mixture of aldehydes to render the order DMC > CUR > BDMC. This is an advantageous way to increase the amount of the unsymmetric DMC metabolite.

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