Short and Efficient Synthesis of Licochalcone B and D Through Acid-Mediated Claisen-Schmidt Condensation

Abstract

Licochalcones A-E and echinatin were isolated and characterized from the roots of licorice (Glycyrrhiza inflata). 1-3These retrochalcones are an unusual phenolic compound family and are distinguished from ordinary chalcones by the absence of an oxygen functionality at the C-2' and C-6' positions.1 They have various biological activities including anti-cancer, 4,5 anti-parasitic, 6 anti-bacterial, 7 superoxidescavenging 7 and anti-oxidant activities. 8 Among the reported retrochalcones, licochalcone B and D (Fig. 1) strongly inhibited superoxide anion production in the xanthine/ xanthine oxidase system, and displayed potent scavenging activity on 2,2-diphenyl-1-picrylhydrazyl 1,1-diphenyl-2-picrylhydrazyl radicals.7,8 Licochalcone B and D have also been linked with potent anti-inflammatory activity involving the inhibition of lipopolysaccharide-induced phosphorylation at serine 276 and transcriptional activation of nuclear factor-kappa B.6 A recent study reported that licochalcone D inhibits mast cell degranulation by inhibiting extracellular Ca 2+ influx and activation of the MEK-ERK pathway. 7Chemical synthesis of licochalcone B and D was initiated due to low isolation yield from natural sources and high demand for diverse pharmacological activity studies.2 Though the first total synthesis of licochalcone D has been published recently, this synthetic method suffers from limitations including the need for multiple steps, high temperature, and requirement for a special bomb reactor device.9 Herein, we report a short, efficient and practical synthesis of licochalcone B and D with excellent overall yields.The synthesis of licochalcone B and D was accomplished by the procedures shown in Scheme 1. As detailed in earlier studies, 3-and 4-hydroxyl groups in 2,3,4-trihydroxybenzaldehyde (3) was selectively protected as methoxymethyl (MOM) ether to give compound 4 in 71% yield.10 Due to the intramolecular hydrogen bond between the 2-hydroxyl group and the neighboring aldehyde group and/or steric hindrance of 2-hydroxyl group, 3-OH and 4-OH in compound 3 are selectively protected. Subsequent methylation on 2-hydroxyl group in 4 was carried out using methyl iodide and NaH in N,N-dimethylforamide (DMF) to give compound 5 in 95% yield. With the key intermediate 5 in hand, we turned our attention to the preparation of 6b from 6a to complete the synthesis of licochalcone B and D.As shown in Scheme 2, attempts to prepare 6b from 6a by Friedel-Crafts reaction in the presence of BaO-Al 2 O 3 in dichloromethane did not give a satisfactory result (Method

Microbial Transformation of Licochalcones

“…And starting from 2,4dihydroxybenzaldehyde, licochalcone C (2) and its regio-isomer licochalcone H (4) were synthesized by acid-mediated Claisen-Schmidt condensation [24]. The 1 H-NMR data of licochlacones B (1), C (2), D (3), and H (4) agreed with data in the literature data [24,32]. The purity of each substrate was determined to be above 95% by HPLC analysis.…”

“…Licochalcones B (1) and D (3) were synthesized through acid-mediated Claisen-Schmidt condensation using 4-hydroxyacetophenone as a starting material [32]. And starting from 2,4-dihydroxybenzaldehyde, licochalcone C (2) and its regio-isomer licochalcone H (4) were synthesized by acid-mediated Claisen-Schmidt condensation [24].…”

Licochalcone D Induces ROS-Dependent Apoptosis in Gefitinib-Sensitive or Resistant Lung Cancer Cells by Targeting EGFR and MET

“…LCD was prepared by Professor Goo Yoon according to previous reports [1]. Roswell Park Memorial Institute (RPMI)-1640 medium, phosphate-buffered saline (PBS), fetal bovine serum (FBS), penicillin/streptomycin, and trypsin were purchased from Hyclone (Logan, UT, USA).…”

“…Flavonoids are the most effective and variable biologically active compounds in plants. Licochalcone D (LCD) is an active flavonoid isolated from the Chinese medicinal herb Glycyrrhiza inflata [1]. LCD is present in the roots and rhizomes of G. inflata.…”

Licochalcone B induces apoptosis of human oral squamous cell carcinoma through the extrinsic- and intrinsic-signaling pathways

“…Reagents and antibodies. We prepared Lico B with 95% purity according to the method previously reported (18). Dulbecco's modified Eagle's medium (DMEM), fetal bovine serum (FBS), trypsin, penicillin and streptomycin (P/S) and phosphatebuffered saline (PBS) were purchased from Thermo Scientific (Logan, UT, USA).…”