An Efficient First Synthesis of Licochalcone G

Abstract

Chalcones (1,3-diarylpropenones) constitute one of the major classes of flavonoids with widespread distribution in plant kingdom. Prehistoric therapeutic applications of these small and nonchiralmolecules can be associatedwith the 1000-yearold use of plants and herbs for the treatment of different medical disorders. Chalcones have a conjugated double bond and an entirely delocalized π-electron system on both benzene rings which attributes nonlinear optical properties to them. Several natural and nonnatural chalcones have been investigated as anti-inflammatory, anti-oxidant, antimicrobial, antiprotozoal (antileishmanial and antitrypanosomal), anticancer, antibacterial, antiviral, antihyperglycemic, antiplatelet, anti-ulcerative, antitubercular, antiangiogenic, and antiplasmodial agents. They have also shown inhibitory effects on several enzymes. Chalcones are important precursors in the biosynthesis of flavones and flavanones. The chemistry and therapeutic applications of chalcones have triggered extensive and enduring efforts toward the syntheses of these important compounds throughout the world. Licochalcone G (7, Figure 1) was isolated from the acetone extract of Glycyrrhiza inflata. G. inflata is the main species in licorice, contains numerous retrochalcones and showed various biological properties. Licorice has been used by human beings for over 4000 years and it appears as a component herb in about 60% of traditional Chinese medicine prescriptions. LicochalconeG (7) showed anti-influenza (H1N1 swine influenza) activity. To date, synthesis of this important chalcone was not reported in the literature. Previously, we have reported the synthesis of licochalcones A–E (1–5). In continuation of our work on the synthesis of these bioactive natural products and their derivatives, herein we wish to describe the first synthesis of licochalcone G (7) using water-accelerated [3,3]-sigmatropic rearrangement and Claisen–Schmidt condensation as key steps. Retrosynthetic approach for licochalcone G (7) synthesis is depicted in Scheme 1. We envisaged that the target molecules could be achieved from intermediate 8 by deprotection. Compound 8 could easily be prepared from compounds 9 and 10 by means of Claisen–Schmidt condensation. Compound 9 could be obtained from 2,4,-dihydroxyacetophenone (11) whereas compound 10 could be prepared from 4-hydroxy-2-methoxy benzaldehyde (12). Accordingly, we commenced the synthesis from 2,4,dihydroxyacetophenon (11). As shown in Scheme 2, allyl protection of compound 11 using K2CO3/NaI system in DMF at 60 C afforded the diallyl protected 2,4dihydroxyacetophenone 9 in 98% yield. Next, treatment of 4-hydroxy-2-methoxy benzaldehyde (12) with 1-bromo-3methyl-2-butene (prenyl bromide) in the presence of K2CO3 in acetone under reflux condition gave compound 13 in 97% yield. The aryl prenyl ether 13 was then subjected to water-accelerated [3,3]-sigmatropic rearrangement reaction using EtOH/H2O (v/v = 4/1) in pressure tube afforded the product 14 in 53% yield. The phenolic OH group of compound 14 was protected as ethoxymethyl aryl ether (EOM O Ar). The choice of protecting group is quite important in the chalcone synthesis in many aspects such as yield, migration, deprotection, etc. Treatment of compound 14 with chloromethyl ethyl ether (EOM Cl) using K2CO3 in DMF at room temperature resulted the compound 10 in 81% yield. Claisen–Schmidt condensation of compound 9 and10using ethanolicKOHat room temperature in 15 hproduced the protected chalcone 8 in 52% yield. The transconfiguration was confirmed with coupling constant (J = 16.2 Hz) between the two doublet signals at δ 7.98 and 7.56, a presentative coupling pattern for the protons in the conjugated alkene system. Treatment of compound 8withDowex resin in anhydrous methanol at room temperature gave the EOM-free chalcone in 60% yield. Finally, allyl group deprotection was achieved using K2CO3 and catalytic amount of Pd(PPh3)4 (2 mol %) in anhydrous MeOH at 60 C to furnish the desired natural chalcone licochalcone G in 85% yield. In conclusion, we have developed an efficient approach for the first synthesis of licochalcone G. Water-accelerated [3,3]sigmatropic rearrangement and Claisen–Schmidt condensation are the key transformations of the present method. We feel, the present synthetic route may find application for the construction of different natural and nonnatural chalcones of this kind.