Rhodium-Phosphoramidite Catalyzed Alkene Hydroacylation: Mechanism and Octaketide Natural Product Synthesis

We describe a method that allows salicylaldehyde derivatives
to
be coupled with a wide range of unactivated alkenes at catalyst loadings
as low as 2 mol %. A chiral phosphoramidite ligand and the precise
stoichiometry of heterogeneous base are key for high catalytic activity
and linear regioselectivity. This protocol was applied in the atom-
and step-economical synthesis of eight biologically active octaketide
natural products, including anticancer drug candidate cytosporone
B. Mechanistic studies provide insight on parameters affecting decarbonylation,
a side reaction that limits the turnover number for catalytic hydroacylation.
Deuterium labeling studies show that branched hydride insertion is
fully reversible, whereas linear hydride insertion is largely irreversible
and turnover-limiting. We propose that ligand (Ra,R,R)-SIPHOS-PE
effectively suppresses decarbonylation, and helps favor a turnover-limiting
insertion, by lowering the barrier for reductive elimination in the
linear-selective pathway. Together, these factors enable high reactivity
and regioselectivity.