Synthetic Framework Evolution: A Scaffold-Centric Perspective on Iterative Chemical Space Expansion.

Abstract

ConspectusThe efficient exploration of natural product-like chemical space remains a central challenge in synthetic chemistry and chemical biology. Despite major advances, many synthetic strategies remain organized around individual targets or predefined compound collections, which can limit the continuity and cumulative expansion of chemical space exploration across successive synthetic campaigns. Developing approaches that enable sustained, scalable, and unbiased expansion of biologically relevant molecular diversity is therefore a key objective for modern synthesis.Here, we formalize Synthetic Framework Evolution (SFE) as a scaffold-centric conceptual framework that organizes synthetic planning in terms of persistence, connectivity, and growth. Building upon emerging concepts in bioinspired chemical divergence and scaffold evolution, SFE directs retrosynthetic analysis toward the identification of information-rich intermediates that function as reusable nodes within an evolving synthetic network. Rather than converging on isolated end points, synthesis is organized around persistent scaffolds that enable iterative divergence and cumulative expansion of interconnected molecular architectures.We demonstrate the implementation of SFE in sesquiterpenoid synthesis, a natural product family whose biosynthetic diversity provides an ideal platform for framework-based design. Central to this approach is the hierarchical organization of conformationally flexible, low-oxidation-state scaffolds that encode latent reactivity and stereochemical information. These intermediates enable access to multiple carbocyclic frameworks through controlled rearrangements, cyclizations, and functional group interconversions, allowing structurally distinct natural product families to emerge from unified and continuously expandable synthetic pathways.Beyond scaffold-level divergence, SFE incorporates oxidative transformations as a second, amplifying dimension of chemical space generation. In this context, oxidation is not treated as a terminal functionalization step, but as a generative process that unlocks new topologies through rearrangements, cascade reactions, and bond reorganization, closely reflecting biosynthetic oxidative phases. In this sense, SFE places oxidative diversification alongside scaffold rearrangement as a complementary and generative driver of chemical space expansion. The integration of these two layers, scaffold persistence and oxidative amplification, enables the efficient construction of structurally complex and densely connected regions of chemical space from a limited set of intermediates.Cheminformatic analysis reveals that SFE-derived compounds occupy broad and biologically relevant regions of chemical space, exhibiting high natural product-likeness, shape diversity, and molecular complexity relative to their size. In contrast to established paradigms such as BIOS, DOS, and CtD, which often focus on the generation of discrete collections or predefined diversification campaigns, SFE emphasizes the cumulative expansion of a unified synthetic framework, enabling diversity to emerge as a function of system evolution rather than target enumeration.By shifting the focus of synthesis from molecule production to framework evolution, SFE establishes a conceptual bridge between synthetic chemistry and biosynthetic organization. This perspective enables a more dynamic and scalable approach to chemical space exploration and provides a general framework for the discovery of new molecular architectures and functions.