Facile Formation of Methylenebis(chalcone)s through Unprecedented Methylenation Reaction. Application to Antiparasitic and Natural Product Synthesis

Abstract

The formation of methylenebis(chalcone)s has been discovered during deprotection with methoxymethyl groups from trihydroxychalcones. Studies on this methylenation reaction led to a mechanism hypothesis that was extended to other chalcones and to dihydrochalcone, acetophenone, benzophenone and flavone derivatives. This new method was applied to the rapid synthesis of natural product piperanduncin C. These original methylenebis compounds were also evaluated for their antiparasitic activity.

Mallotojaponins B and C: Total Synthesis, Antiparasitic Evaluation, and Preliminary SAR Studies

“…Since the target compounds are dimeric, two strategies could be envisioned: functionalization followed by dimerization or vice versa. Based on our previous experience with the dimerization of phloroglucinol derivatives, the latter route was initially deemed more convergent, especially toward homodimeric adducts. Thus, phloroacetophenone 3 was first treated with trimethylsilyldiazomethane leading predominantly to the desired para- O -methylated product 4a (77% yield based on recovered starting material–brsm), along with minor amounts of o - O - and O,O ′-dimethylated compounds 4b and 4c , respectively (Scheme ).…”

“…The first set of mallotojaponin analogues was obtained by subjecting all three acetophenones 4a – c to methylenation conditions using MOMCl (generated in situ from dimethoxymethane) followed by heating with hydrochloric acid (Scheme ). The corresponding bridged dimers 5a – c were all obtained with excellent yields; however, further elaboration of these substrates to mallotojaponins, especially C -prenylation, proved extremely laborious…”

First Total Synthesis of Original Chalcone–Flavone Dimers as Cissampeloflavone Analogues

“…Compounds 4 , 21 , and 14 showed micromolar inhibitory activities against T. brucei (IC 50 = 28 ± 6.9 µ m , 3.8 ± 0.5 µ m, and 1.6 ± 0.1 µ m respectively). Note that the trypanocidal activities are very similar if we compare flavone 4 with chrysin (IC 50 = 14.4 ± 2.0 µ m ), and compound 14 with cissampeloflavone (IC 50 = 1 µ m ) . Both flavones ( 4 and chrysin) were found to be inactive against P. falciparum (IC 50 > 50 µ m ), whereas compounds 21 and 14 showed moderate antiplasmodial activity (IC 50 = 3.1 ± 0.1 µ m and 24.9 ± 1.9 µ m , respectively).…”

Antiparasitic Ovalicin Derivatives from Pseudallescheria boydii, a Mutualistic Fungus of French Guiana Termites

“…In all experiments, log-phage cell cultures were harvested by centrifugation at 3000× g and immediately used. Drug assays were based on the conversion of a redox-sensitive dye (resazurin) to a fluorescent product by viable cells and were performed according to the manufacturer recommendations (AlamarBlue ® Assay, Invitrogen Corporation, Carlsbad, CA, USA) [59,60]. Drug stock solutions were prepared in pure DMSO.…”