Tamoxifen: A Synthetic Overview

Tamoxifen (TAM) comprises a triphenylethylene derivative with pronounced activity as Selective Estrogen Receptor Modulator (SERM) that acts on the Estrogen Receptor (ER)-positive breast cancer cells preventing the tumorigenesis in high risk women. TAM constitutes the most prescribed chemotherapeutic drug for the treatment of breast cancer, acting through its in vivo metabolites (Z)- 4-hydroxytamoxifen (Z-4-HTAM) and 4-hydroxy-N-desmethyl-tamoxifen (endoxifen). Literature search has indicated that the efficient construction of TAM backbone is achieved through three major routes. One concerns the formation of the appropriately phenylsubstituted double bond of TAM, a second includes the reductive coupling of two aromatic ketones and the third refers to the coupling of olefins with metallated aromatics in the presence of transition metal catalysts. A deconstruction of these pathways and a comprehensive picture of the synthetic strategies towards the efficient approach of TAM are presented in this review. Furthermore, novel synthetic routes that differentiate or act complementary to these general routes are also considered. Issues such as the reactions efficiency and stereoselectivity have also been addressed.