An efficient approach to angular tricyclic molecular architecture via Nazarov-like cyclization and double ring-expansion cascade

Abstract

A modular and efficient method for constructing angular tri-carbocyclic architectures containing quaternary carbon center(s) from 1,3-dicycloalkylidenyl ketones is established, which involves an unconventional synergistic cascade of a Nazarov cyclization and two ring expansions. It features high selectivity, mild conditions and convenient operation, wide scope and easy availability of substrate. Substitution with R¹ and R² at the 4πe-system with electron-donating group favors this reaction, while that with electron-withdrawing group or proton disfavors. The electron-donating group as R¹ directs the initial ring expansion at its own site, while the p-π- or n-π- associated substituent as R² favors selectively the later ring expansion near its location because of the beneficial maintenance of an original conjugated system. The stereoselectivity has proved to be governed by either the steric effect of R³ and R⁴ at the expanded rings, or the migration ability of the migrating atom. Density Functional Theory calculation suggests the initial Nazarov cyclization would be the rate-determining step. A racemic total synthesis of the natural (±)-waihoensene is realized in 18 steps by use of this methodology.

Effective methods for accessing polycarbocycles are scarcely reported and generally involve complex, multistep transformations, thus restricting practical utility. Here, the authors construct tri-to-penta- cyclic frameworks containing at least two quaternary carbon centers via a tandem Nazarov-like cyclization / double cycloexpansion of simple 1,3-dicyclobutylidene ketone substrates.