Expanding Chemical Frontiers: Approaches for Generating Diverse and Bioactive Natural Product‐Like Compounds Libraries from Extracts

The realms of natural products and synthetic compounds exhibit distinct chemical spaces that not only differ but also complement each other. While the convergence of these two domains has been explored through semisynthesis and conventional pharmacomodulation endeavours applied to natural frameworks, a recent and innovative approach has emerged that involves the combinatorial generation of libraries of ‘natural product‐like compounds’ (NPLCs) through the direct synthetic derivatization of natural extracts. This has led to the production of numerous NPLCs that incorporate structural elements from both their natural (multiple saturated rings, oxygen content, chiral centres) and synthetic (aromatic rings, nitrogen and halogen content, drug‐like properties) precursors. Through careful selection of extracts and reagents, specific bioactivities have been achieved, and this strategy has been deployed in various ways, showing great promise without reaching its full potential to date. This review seeks to provide an overview of reported examples involving the chemical engineering of extracts, showcasing a spectrum of natural product alterations spanning from simple substitutions to complete scaffold remodelling. It also includes an analysis of the accomplishments, perspectives and technical challenges within this field. Combining natural and synthetic chemical spaces is achievable through the generation of ‘natural product‐like compounds’ that incorporate structural elements from natural and synthetic precursors, by directly chemically modifying natural extracts. The review provides insights into this approach, covering alterations from simple substitutions to complete scaffold remodelling, and highlighting achievements, promises and technical challenges in the field.