Synthesis of Highly Functionalized Decalins via Metallacycle-Mediated Cross-Coupling

Bridged
bicyclic metallacyclopentenes generated from the [4 + 2]
cycloaddition of metallacyclopentadienes with alkenes have been proposed
as reactive intermediates in the course of [2 + 2 + 2] annulation
reactions. Recently a collection of alkoxide-directed Ti-mediated
[2 + 2 + 2] annulation reactions have been discovered for the synthesis
of densely functionalized hydrindanes, where the bridged bicyclic
metallacyclopentenes from intramolecular [4 + 2] were treated as fleeting
intermediates en route to cyclohexadiene products formed by formal
cheletropic extrusion of Ti­(Oi-Pr)2. In
studies aimed at understanding the course of these organometallic
cascade reactions it was later discovered that these bridged bicyclic
intermediates can be trapped by various elimination processes. Here,
we have realized metallacycle-mediated annulation reactions for the
assembly of angularly substituted decalinsstructural motifs
that are ubiquitous in natural products and molecules of pharmaceutical
relevance. In addition to defining the basic annulation reaction we
have discovered a surprising stability associated with the complex
organometallic intermediates generated in the course of this coupling
process and document here the ability to control the fate of such
species. Ligand-induced cheletropic extrusion of the titanium center
delivers cyclohexadiene-containing products, while several distinct
protonation events have been identified to realize polycyclic products
that contain three new stereocenters (one of which is the angular
quaternary center that is a hallmark of alkoxide-directed titanium-mediated
[2 + 2 + 2] annulation reactions). Examples of this metallacycle-mediated
annulation reaction are provided to demonstrate that a range of stereodefined
fused bicyclo­[4.4.0]­decanes are accessible, including
those that contain aromatic and aliphatic substituents, and an empirical
model is presented to accompany the observations made.