Radical Retrosynthesis of Natural Products Enabled by Iron‐Based Reductive Olefin Coupling

ABSTRACT Metal‐hydride hydrogen atom transfer (MHAT) has opened new avenues for olefin hydrofunctionalization in organic synthesis, enabling mild, selective radical transformations. This review highlights iron‐catalyzed reductive olefin coupling (ROC)—a versatile MHAT‐driven strategy for C─C bond formation—as a key tool in the radical retrosynthesis for natural products. Initiated by the 2014 disclosure of Fe‐catalyzed inter‐ and intramolecular olefin–olefin coupling, ROC combines Mukaiyama's hydrofunctionalization with Giese's radical additions, offering kinetic control, broad scope, and operational simplicity. Emphasizing strategic disconnections, the review surveys dozens of total syntheses across terpenoids, alkaloids, and polyketides, showcasing ROC variants (e.g., olefin–nitrile, olefin–carbonyl couplings; cascades with aldol or Dowd–Beckwith rearrangements). The many creative applications of ROC highlight its power to forge strained rings, quaternary centers, and stereocenters from olefins, often supplanting 2e − tactics. Troubleshooting guides and retrosynthetic blueprints are included to aid future applications in complex molecule assembly.