Gold(I)-catalyzed divergent and diastereoselective synthesis of azepines by ammoniumation/ring-expansion reactions

Abstract

Gold(I) catalysts enable the chemoselective addition of tailor-made N-sulfonylated azetidine derivatives onto alkynes, affording bicyclic vinyl-ammonium gold intermediates. Intramolecularly intercepted by an adequately positioned nucleophilic carbonate or ester function, these ammoniums efficiently lead to ring-expanded azepine products, which are important pharmacophore fragments. Depending on the substitution pattern of the starting material, divergent deauration pathways occur, stereoselectively producing monomeric or original dimeric nitrogenated seven-membered rings in good to excellent yields, such as cis -tetrahydroazepin-4,5-diol carbonate, ( E )-alkylidene tetrahydroazepin-4-yl ester, and cis -bis(azepinyl)cyclobutane derivatives. One of the synthetic methods was extended to the formation of dihydrobenzazepines of high pharmaceutical value. A mechanistic study including kinetics and labeling experiments allowed us to fully understand the origin of the high chemo- and diastereoselectivity of these rearrangements. Overall, this work demonstrates the underlying synthetic potential of the ammoniumation catalyzed by gold for the future development of reaction cascades and preparation of bioactive compounds. • Gold-catalyzed ammoniumation of alkynes gives biologically relevant azepines • Functional groups on the starting material define the mechanistic pathway • NMR labeling and kinetic studies explain the chemo- and stereoselectivities observed • A dimeric bis(azepinyl)cyclobutane original scaffold is reported In the family of nitrogen heterocyclic drugs, azepine and its derivatives are very important pharmacophore fragments present in several pharmaceutical and a few agrochemical products. Currently, synthetic access to (hydro)azepine systems starting from simple and robust building blocks remains challenging, especially when targeting densely functionalized motifs. From tailor-made azetidine derivatives, we developed three diastereoselective methods to reach azepines with broad flexibility in good to excellent yields by using the unmatched ability of gold, a quasi-nontoxic metal, to promote nucleophilic additions onto unsaturated carbon-carbon bonds. The work described herein could offer efficient and modular routes to the preparation of useful intermediates in drug development. Azepines are fragments found in natural products possessing relevant biological activities. Our method provides access to multiple azepine derivatives from simple azetidine derivatives in the presence of a gold catalyst. Small variations on the starting material conduct to different reaction cascades whose mechanisms have been thoroughly studied to explain and control the observed selectivity. This journey led to the discovery of original azepine scaffolds along the way, whose biological activity remains to be studied.