Formal synthesis of ferruginol methyl ether via an acid-catalysed intramolecular Diels–Alder cycloaddition

Abstract

Aromatic abietane diterpenoids, known for their wide range of biological and pharmaceutical activities, have attracted considerable interest from synthetic and medicinal chemists. Although some aromatic abietane diterpenoids are naturally abundant, many are only available in limited quantities, constraining their use in detailed biological investigations. We initiated a project to synthesize these compounds, and as our first approach, we describe the formal synthesis of ferruginol methyl ether. Starting from tiglic aldehyde (6) and 2-bromo-5-methoxybenzoic acid (11), we synthesized the triene (3) in nine steps. The key transformation involved an acid-catalysed intramolecular Diels-Alder (IMDA) cyclisation of triene (3), leading to the formation of 12-methoxy-19-norpodocarpa-4(18),8,11,13-tetraene (14) as the primary product, with an overall yield of 17.3 % across ten steps. While the yield is modest, this approach provides a novel pathway for synthesizing abietane-type compounds. We are actively exploring strategies to improve the overall yield and developing an asymmetric synthesis variant.