Study of Aromatic Derivatization of Carnosic Acid: Synthesis and Antiproliferative Evaluation of Methyl 11,12-dimethoxy-14-acetyl Carnosate

Over the last decade, plant-derived diterpenes have attracted considerable attention as a rich source of structurally diverse bioactive compounds with significant potential for drug discovery. Among them, abietane-type diterpenes represent one of the most extensively investigated families due to their broad spectrum of biological activities, including antioxidant, antimicrobial, anti-inflammatory, neuroprotective, and antitumor effects. Their unique tricyclic scaffold, together with the possibility of selective chemical functionalization, makes them highly attractive platforms for the development of new bioactive molecules. The availability of the chiral natural (+)-carnosic acid at reasonable price from some providers encouraged us to use it as starting material.

In this communication, we report the synthesis of methyl 11,12-dimethoxy-14-acetyl carnosate, a novel derivative of the natural product carnosic acid. The target compound was prepared from methyl 11,12-dimethoxycarnosate through a key Friedel-Crafts acylation. The structural characterization was unambiguously established by extensive 1H, 13C, and 2D-NMR analysis. It is interesting to note that the proximity of the acetyl group at the C14 position to the characteristic isopropyl moiety at C13 of the abietane skeleton induced an atypical pattern of spectral signals in 1H and 13C NMR spectra. Preliminary biological evaluation in a panel of tumor cell lines revealed promising antiproliferative activity for this derivative, highlighting its potential as a scaffold for further medicinal chemistry optimization.