Construction of C(sp3)-C(sp3) attached ring motifs in natural product synthesis.

Abstract

Covering the literature until 2025C(sp³)-C(sp³) attached ring systems represent some of the most structurally intriguing and synthetically challenging polycyclic motifs found in natural products. Methods for their concise construction remain underdeveloped due to steric congestion and limited stereocontrol arising from the absence of inherent topological bias at fully saturated bridgehead carbons. In this review, we survey the different strategies and mechanistic frameworks that have been applied to assemble C(sp³)-C(sp³) attached rings. We first highlight selected examples of indirect approaches-including tethering and rearrangements-which continue to offer powerful solutions when direct coupling reactions are infeasible. We then place particular emphasis on fragment couplings, as well as derived cascade processes, that enable direct formation of saturated attached ring motifs, since such transformations can provide highly convergent access to complex target structures. Against the backdrop of natural product examples that illustrate both current successes and remaining limitations, we conclude by discussing emerging methods that may drive future advances toward making predictive, stereocontrolled construction of saturated attached rings a routine element of complex molecule synthesis and medicinal chemistry design.