Planar Chirality Directs Enantiospecific Diastereoselectivity in Isocyanide-Based Multicomponent Reactions.

Stereochemical control in isocyanide-based multicomponent reactions (IMCRs) remains a fundamental challenge, particularly in substrate-controlled variants. Here we show that planar chirality embedded within [2.2]-paracyclophane scaffolds enables predictable enantiospecific stereochemical transfer across the Passerini three-component reaction as well as the Ugi four-component and Ugi-tetrazole manifolds. Each enantiomer of the planar-chiral substrate stereospecifically transfers its configuration to the product, establishing a deterministic relationship between substrate and product stereochemistry. Across more than 65 reactions, this strategy provides consistent diastereocontrol without external chiral catalysts. These findings establish planar chirality as a general substrate-encoded principle for stereochemical control in IMCRs and expand the scope of enantiospecific multicomponent synthesis beyond classical point chirality.