Total synthesis of welwitindolinone A isonitrile

An efficient and highly stereoselective total synthesis of the alkaloid natural product (+/-)-welwitindolinone A isonitrile ( 1) is presented herein. The bicyclo[4.2.0]octane core of 1 was established by a regio- and diastereoselective [2+2] ketene cycloaddition reaction. The C12 quaternary center and vicinal stereogenic chlorine were installed in a single operation with complete stereocontrol utilizing a chloronium-ion mediated semi-pinacol rearrangement. In the key step, the natural product (1) was produced from an isocyano-isocyanate precursor using a novel anionic cyclization that simultaneously constructed the spiro-oxindole and vinyl isonitrile moieties. This total synthesis also resulted in the discovery of a SmI2/LiCl-mediated reductive cyclization of tethered alpha,beta-unsaturated ketones and aryl isocyanates to give spiro-oxindoles. While this method was not utilized in the successful total synthesis of 1, it was used to synthesize a variety of functionalized spiro-cyclobutane oxindoles in good yields under mild conditions.