Synthesis of novel 6,7-dihydro-5h-oxepin-2-one derivatives

Abstract

In last decades, biologically active natural compound (R)-goniothalamin and its derivatives received great attention from researchers. The reason for this interest is the wide range of biological properties of goniothalamin; including anti-microbial, antiprotozoan, anti-inflammatory, cytotoxic and anti-proliferative activities. The present study sets out the asymmetric large scale synthesis of α,β- unsaturated lactone derivative (R)-(+)-6-(2-Methylnaphthalen-1-yl)-5,6-dihydro-2Hpyran- 2-one. In recent studies, this linker modified analog of goniothalamin was shown to be cytotoxic against PC-3 (prostate cancer) and MCF-7 (human breast cancer) cell lines with half maximal inhibitory concentration values of 0.13 μM and 2.6 μM, respectively. The preparation of the target compound consists of three steps. First, asymmetric synthesis of homoallylic alcohol using (R)-Tol-BINAP AgF catalyst complex was performed with allyltrimethoysilane. After that, treating the chiral homoallylic alcohol with acryloylchloride in the presence of triethylamine followed by ring closing metathesis of acrylate ester using 1st generation Grubbs' catalyst finally yielded the lead compound. The large scale preparation of (R)-(+)-6-(2- Methylnaphthalen-1-yl)-5,6-dihydro-2H-pyran-2-one was achieved in order to evaluate its in-vivo anti-cancer activity in mice, and to study its mechanism of action in the cell. Additionally, synthesis of three new 7-membered β-ï § unsaturated lactone derivatives was carried out. Allylation reaction of corresponding aldehydes with allyltrimethoxysilane using CuCl-TBAT gave the racemic homoallylic alcohols. Coupling reactions of this homoallylic alcohol with 3-butenoic acid in the presence of DCC/DMAP yilded the esters. Ring closing metathesis of the related esters was studied by using 2nd generation Grubbs' catalyst.