Polycyclizations

Polycyclizations are reactions in which multiple ring closures occur in a single synthetic operation, transforming a single substrate with multiple unsaturations into two or more fused or bridged rings. They are often described as cascade, domino, or tandem cyclizations and are valued for rapidly generating complex polycyclic frameworks with high degrees of skeleton complexity and potential stereochemical richness.

Several mechanistic classes are employed. Cationic polycyclizations initiate with protonation or coordination by a Lewis acid to generate carbocation intermediates that sequentially cyclize and rearrange. Radical polycyclizations depend on radical generation and intramolecular additions to multiple double bonds. Pericyclic cascades, including tandem cycloadditions and electrocyclizations, proceed concertedly to forge several rings in one step.

In nature, polycyclizations underpin the assembly of many terpenoids. Terpene cyclases convert linear prenyl diphosphates into polycyclic skeletons; for example, oxidosqualene cyclase transforms 2,3-epoxysqualene into lanosterol, establishing the steroid framework, and taxadiene synthase constructs the taxane skeleton from geranylgeranyl pyrophosphate in the biosynthesis of taxol.

In organic synthesis, cascade polycyclizations enable rapid construction of polycyclic cores and are exploited to access complex natural product-like targets. They pose challenges in controlling regio- and stereochemistry and often require carefully designed substrates and catalysts. Advances in catalyst design, protecting-group strategies, and reaction conditions continue to expand the scope and selectivity of polycyclizations.