Advancing Total Synthesis Through Skeletal Editing

ConspectusTotal synthesis has long been a proving ground for advancing chemical thought, pushing chemists to develop strategies that not only replicate nature's complexity but often surpass it. The pursuit of efficiency, practicality, and elegance continues to challenge and reshape the guiding principles of total synthesis. In recent years, skeletal editing has emerged as a powerful strategy for reconfiguring skeletal frameworks in ways that were previously difficult to imagine. Unlike conventional chemical synthesis approaches, which primarily rely on the logic of bond construction reactions and functional group manipulations, skeletal editing introduces elements that allow for atom insertion, deletion, and exchange and skeletal rearrangement/reorganization by harnessing the potential energy and reactivity of certain structural motifs and morphing them into new electronic and spatial configurations. The logic of modern skeletal editing has been fueling the development of new editing methods and advancing the fields of total synthesis, medicinal chemistry, materials science, and others.In this Account, we detail our program using skeletal editing-based retrosynthetic logic to facilitate natural product synthesis. We first highlight two one-carbon insertion editing strategies utilizing the Ciamician-Dennstedt rearrangement and the Büchner-Curtius-Schlotterbeck ring expansion to streamline the total syntheses of complanadine and phleghenrine Lycopodium alkaloids. We next present our synthesis of crinipellin and gibberellin diterpenes by leveraging the facile synthesis and intrinsic strain of cyclobutanes as precursors to challenging cyclopentanes via cut-and-insert editing (crinipellins) or C-C bond migratory ring expansion (GA₁₈). Toward the end, we describe our early efforts in orchestrating structural rearrangement and functional group pairing reactions to access seven monoterpene indole alkaloids and highlight the divergent potential of skeletal editing. Each of the five examples follows a build-edit-decorate workflow, inspired by Schreiber's build-couple-pair in diversity-oriented synthesis. In the build stage, key scaffolds are efficiently assembled from starting materials with matched reactivity. The edit stage morphs these scaffolds to the desired but more challenging ones encoded by the target molecules, reminiscent of Corey's application of rearrangement transforms as a topological strategy. The decorate stage introduces additional functional groups and adjusts oxidation states to complete the total synthesis, similar to the oxidase phase of Baran's two-phase synthesis. The essence of skeletal editing-based retrosynthetic analysis is to identify latent structural relationships between the readily assembled key scaffolds constructed in the build stage and the desired ones encoded by the target molecules as well as proper editing methods to transform the former into the latter with precision. The build-edit-decorate approach parallels the dynamism of biosynthesis, enabling rapid building of complexity with great efficiency and step economy, as analyzed by the spacial scores (SPS) of each case. Drawing on these principles, chemists can adopt skeletal editing-based retrosynthetic logic by identifying latent intermediates and employing and developing strategic editing methods to overcome synthetic bottlenecks.