Xiaolei Liu, Mingliang Lou, Songlin Bai, Guoxin Sun,* and Xiangbing Qi*
The complex structures and important biological functions of Strychnos alkaloids have attracted a great deal of attention from synthetic chemists. Herein, we describe the concise asymmetric total syntheses of the Strychnos alkaloids, (−)-dehydrotubifoline, (−)-tubifoline, and (−)-tubifolidine, as well as the formal total synthesis of (−)-strychnine. Our strategy features the construction of the common tetracyclic pyrrolo[2,3- d]carbazole structure using regioselective Fischer indolization on unsymmetrical cyclic ketones and late-stage functionalization for divergent synthesis. We developed a stepwise Fischer indolization featuring selective formation of enol triflate to solve the challenging regioselectivity problem, leading to the common tetracyclic ring skeleton in these Strychnos alkaloids. The regioselectivity of Fischer indolization on unsymmetrical cyclic ketones was studied on the basis of different types of ring systems and supported by density functional theory calculations. Overall, our success in the construction of this tetracyclic ring secured the syntheses of Strychnos alkaloids and may provide a general method for the total syntheses of various alkaloids containing this skeleton.