Copper-Catalyzed Intramolecular Alkene Carboetherification: Synthesis of Fused-Ring and Bridged-Ring Tetrahydrofurans

Fused-ring and bridged-ring tetrahydrofuran scaffolds
are found
in a number of natural products and biologically active compounds.
A new copper-catalyzed intramolecular carboetherification of alkenes
for the synthesis of bicyclic tetrahydrofurans is reported herein.
The reaction involves Cu-catalyzed intramolecular addition of alcohols
to unactivated alkenes and subsequent aryl C–H functionalization
provides the C–C bond. Mechanistic studies indicate a primary
carbon radical intermediate is involved and radical addition to the
aryl ring is the likely C–C bond-forming mechanism. Preliminary
catalytic enantioselective reactions are promising (up to 75% ee)
and provide evidence that copper is involved in the alkene addition
step, likely through a cis-oxycupration mechanism.
Catalytic enantioselective alkene carboetherification reactions are
rare and future development of this new method into a highly enantioselective
process is promising. During the course of the mechanistic studies
a protocol for alkene hydroetherification was also developed.