Total Synthesis of Phenanthroquinolizidine Alkaloids Using a Building Block Strategy

Abstract

A concise and general strategy for the total synthesis of the phenanthroquinolizidine alkaloids has been developed. An iterative Suzuki-Miyaura coupling reaction between the requisite aryl boronic acid, 2-bromo-4,5-dimethoxyphenyl N-methyliminodiacetate (MIDA) boronate derived from boronic acid, and a suitable bromopyridine substrate bearing a homopropargyl alcohol at the 2-position generated the desired ortho-aza-terphenyl compounds. Hydrogenation of the triple bond followed by treatment with methanesulfonyl chloride afforded their corresponding tetrahydroquinolizinium ion intermediates, which were subsequently reacted with NaBH4 to provide the desired hexahydroquinolizine products. A final oxidative electrocyclization reaction gave the target phenanthroquinolizidine natural products. This synthetic approach only requires the use of three chromatographic separations throughout the entire synthesis.