Reimagining natural products: Tools and approaches to create new chemical entities for drug discovery

Natural products (NPs) remain a valuable source of bioactive scaffolds in drug discovery. Yet, the structural complexity of NPs frequently limits their direct clinical translation. This review provides a critical, strategy-organized synthesis of the chemical toolkit used to reengineer natural product scaffolds into new chemical entities. The major strategies suggested are ring distortion, late-stage C-H functionalization, cross-coupling, and click chemistry. To map the current state of the field, we analyzed approximately 300 natural product reengineering studies published between 2015 and 2025 and found that terpenoids and alkaloids account for most reported efforts. It was also clear that late-stage functionalization substantially outnumbers scaffold-level modification across nearly all natural product classes surveyed, highlighting where future methodological development is most needed. Two documented examples illustrate the outcome of these strategies. Diels-Alder cycloaddition of a pleuromutilin-derived intermediate gave ferroptocide 3, lowering the IC₅₀ from 6.7 to 1.6 μM. Likewise, late-stage esterification of yohimbic acid gave a yohimbine-derived α2A-adrenergic receptor antagonist with 6-fold and 24-fold improved selectivity indices. We conclude with two original, prospective case studies (geldanamycin and anthracimycin) in which we apply the reviewed strategies to propose structural diversification routes for these pharmacologically significant but comparatively underexploited scaffolds. These proposed transformations have not been experimentally validated. They are presented as a strategic roadmap to illustrate the applicability of the reviewed toolkit. Together, this review offers synthetic and medicinal chemists a practical, transferable framework for natural product diversification, and identifies concrete, underexplored opportunities for future investigation.