Design, Development, Mechanistic Elucidation, and Rational Optimization of a Tandem Ireland Claisen/Cope Rearrangement Reaction for Rapid Access to the (Iso)Cyclocitrinol Core

An approach to the synthesis of the
(iso)­cyclocitrinol core structure
is described. The key step is a tandem Ireland Claisen/Cope rearrangement
sequence, wherein the Ireland Claisen rearrangement effects ring contraction
to a strained 10-membered ring, and that strain in turn drives the
Cope rearrangement under unusually mild thermal conditions. A major
side product was identified as resulting from an unexpected and remarkably
facile [1,3]-sigmatropic rearrangement, and a tactic to disfavor the
[1,3] pathway and increase the efficiency of the tandem reaction was
rationally devised.