Strategic Applications of Single-Atom Skeletal Editing in Natural Product Synthesis

Skeletal editing is rapidly reshaping synthetic chemistry by enabling precise, atom-level modifications to complex molecular frameworks. Despite recent advances in methodology development, skeletal editing has yet to realize its full impact on complex molecule synthesis. In this Perspective, we highlight the power of single-atom skeletal editing transformations in enabling efficient syntheses of various complex natural products and advocate for the development of new methods and novel applications. We present guidelines rooted in historical precedent along with modern case studies that highlight when skeletal edits enable efficient synthesis, and where reactivity gaps still limit broader adoption. By analyzing the existing literature, we aim to inspire novel retrosynthetic disconnections, and steer new method development, which, collectively, will advance the fields of total synthesis and skeletal editing.