The total synthesis of Kapakahines E and F: the evolution of the discovery of a unique reaction upon bromopyrroloindolines

The C(3)-quaternary substituted pyrroloindoline is a motif that is found in many natural products; therefore, a suitable methodology that can construct such a motif and has broad range and versatility is highly valuable. Discussed herein is the development of a novel method of the construction of C(3)-quaternary substituted pyrroloindolines and the application of the methodology to natural product synthesis. A ring contraction of C(3)-bromo pyrroloindolines to form a highly strained cyclopropane intermediate allows for the direct addition of a wide range of nucleophiles to form valuable C(3)-quaternary substituted pyrroloindolines including C(3)-N(1') heterodimeric indolines. The heterodimeric indolines synthesized using this method were then used in the total syntheses of Kapakahines E and F and toward a total synthesis of chetomin.