Synthesis and Antiproliferative Activity of New Carnosic Acid Derivatives: 14-Acetyl and 14-Formyl from Methyl Carnosate

Four new derivatives of bioactive natural carnosic acid were obtained during a planned project of target synthesis starting from readily available natural products. In this work, we describe the synthesis of methyl 11,12-di-O-methyl-14-acetylcarnosate and methyl 11,12-di-O-methyl-14-formylcarnosate from methyl 11,12-di-O-methylcarnosate, which was obtained from commercial carnosic acid, by Friedel–Crafts acylation and formylation, respectively. Despite the low yield of the acylation reaction (17% (56% brsm) yield), alternative formylation worked well, which, followed by Grignard addition and oxidation, increased the overall yield of the 14-acetyl derivative to 53%. Subsequent selective 11-O-demethylation at low temperature afforded in high yield the corresponding hydroxy derivatives. The structure assignment of the newly synthesized compounds was established by 1H and 13C NMR, 2D NMR and mass spectrometry. The proximity of the acetyl group at C14 to the characteristic isopropyl group of abietane-type diterpenes at C13 resulted in unusual signals in the 1H and 13C NMR spectra. These four novel compounds were screened in a panel of tumor cell lines and basic structure-activity relationships were deduced. They showed improved antiproliferative activity in comparison with natural carnosic acid, even in the low micromolar range for certain cells.