Cascade Cyclizations of Acyclic and Macrocyclic Alkynones: Studies toward the Synthesis of Phomactin A

A study
of the reactivity and diastereoselectivity of the Lewis
acid promoted cascade cyclizations of both acyclic and macrocyclic
alkynones is described. In these reactions, a β-iodoallenolate
intermediate is generated via conjugate addition of iodide to an alkynone
followed by an intramolecular aldol reaction with a tethered aldehyde
to afford a cyclohexenyl alcohol. The Lewis acid magnesium iodide
(MgI2) was found to promote irreversible ring closure,
while cyclizations using BF3·OEt2 as promoter
occurred reversibly. For both acyclic and macrocyclic alkynones, high
diastereoselectivity was observed in the intramolecular aldol reaction.
The MgI2 protocol for cyclization was applied to the synthesis
of advanced intermediates relevant to the synthesis of phomactin natural
products, during which a novel transannular cation–olefin cyclization
was observed. DFT calculations were conducted to analyze the mechanism
of this unusual MgI2-promoted process.