Total Synthesis of Lavendamycin by a [2+2+2] Cycloaddition

The total synthesis of the bacterial-derived, pentacyclic, antitumor antibiotic lavendamycin has been achieved through a highly convergent strategy. The key step of this synthesis is a ruthenium-catalyzed [2+2+2] cycloaddition of an electron-deficient nitrile to an alkynyl-ynamide to prepare the carboline scaffold. The elaborate cycloaddition substrate is obtained in few steps by an N-ethynylation using alkynyliodonium salt chemistry and two palladium-catalyzed cross-coupling reactions. An efficient synthesis of a halogenated quinoline-5,8-dione building block starting from hydroquinone is presented.