Assembly of Strained Tri- and Tetracyclic Skeletons by Gold(I)-Catalyzed Cascade Reactions of 1,6-Diynyl Cycloheptatrienes

Abstract

Complex cage-like molecules possess three-dimensional architectures and attractive biological properties, making them appealing targets in drug discovery. However, their synthesis requires lengthy multistep sequences and harsh reaction conditions, resulting in low overall yields. Herein, we report a highly efficient gold(I)-catalyzed strategy for the construction of complex cage-like molecules under mild conditions. Gold(I)-catalyzed cyclization of 1,6-diynyl cycloheptatrienes in the presence of O- and C-nucleophiles affords tetracyclic cage-like compounds with high chemoselectivity. Alternatively, performing the reaction under an atmosphere of molecular oxygen leads instead to tricyclic cage-like diketones via oxidative cleavage of a highly strained alkene intermediate. The methodology exhibits broad functional-group tolerance and is compatible with the late-stage functionalization of natural products and drug molecules, highlighting its potential utility in medicinal chemistry. Density functional theory (DFT) calculations indicate that activation of the alkynylcycloheptatriene by gold(I) generates a barbaralyl gold(I) cation, which undergoes cyclization with the second alkyne to furnish a tetracyclic cage-like intermediate containing a highly strained alkene. Subsequent Brønsted acid-promoted, stepwise syn-addition of the nucleophile accounts for the formation of the observed products.