Synthesis of novel aryl-substituted acetylenic monoterpene analogues by Sonogashira coupling

Terpenes and terpenoids are naturally occurring secondary metabolites isolated from plants, which exhibit broad spectrum of biological activity and provide a large library of basic structures for medicinal chemistry. Among this class of substances, camphor and carvone have long been used as starting compounds for the synthesis of new drug candidates. Since natural compounds typically have a complex structure, differing in the hydrocarbon framework and/or the number and position of functional groups, the search for chemo-, stereo- and regioselective methods of transforming native molecules to obtain promising pharmacologically significant analogues is of great importance. To date, numerous derivatives of camphor and carvone have been synthesized, which showed various biological effects.

The present work is aimed at the synthesis of new aryl-substituted propynyl analogues of camphor and carvone as promising building blocks for medicine chemistry. First, alkylation of camphor and carvone with propargyl bromide in the presence of base KN(SiMe₃)₂–Et₃B in 1,2-dimethoxyethane (DME) at room temperature provides 2-propargyl- substituted camphor and carvone derivatives with a yield of 69% and 47%, respectively. Second, the synthesis of aryl-substituted acetylenic monoterpene derivatives with the yield of 70-82% was carried out by the Sonogashira reaction in the presence of PdCl₂(PPh₃)₂, СuI and Et₃N.