Stereoselective Synthesis of Polyketide Motifs via Nickel-Catalyzed Multicomponent Coupling of Aldehydes, Dienes, and Boronic Acids: Reaction Development and Mechanistic Insights

Polyketides are renowned for their structural complexity and potent biological activity, yet efficient and stereocontrolled synthesis of their densely functionalized motifs remains a formidable challenge. Here, we report a nickel-catalyzed, stereoselective multicomponent coupling that assembles polyketide-like architectures from an aldehyde, a diene, and an organoboronic acid in a single operation. This transformation forges two carbon-carbon bonds, establishes defined olefin geometry, and generates two contiguous sp3 stereocenters with high diastereo- and enantioselectivity across a broad substrate scope. Central to this selectivity is a chiral spiro phosphine-oxazoline ligand, which imparts precise chemo-, regio-, and stereocontrol through dual CH-π interactions. This strategy streamlines synthesis by enabling a convergent three-component assembly, dramatically reducing step count and complexity. Moreover, the method provides general access to all stereoisomers of polyketide motifs, representing a significant advance in asymmetric catalysis.