An Improved And Practical Synthesis Route To Antiproliferative (+/-)-Shikonin And Its O-Acyl Derivatives

Shikonin and its O-acyl derivatives are attracting increasing levels of attention among medicinal chemists due to their potencies as highly selective cytotoxic agents against cancer cells. However, providing a large number of shikonin-related samples by organic synthesis remains challenging. In the present study, we developed an improved and practical synthesis route to shikonin derivatives by olefin metathesis that has enabled the gram-scale preparation of a prenylated tetramethylnaphthazaline, a key intermediate in the synthesis of shikonin. In addition, a method for the selective cleavage of the acyl protecting groups at the phenolic positions of tri-O-acylated shikonins has been developed that provides concise routes to diverse O-acylshikonin derivatives.