Challenges in the complexity-to-diversity strategy for natural product-like compound synthesis: two sides of the same coin.

Abstract

Covering: up to the end of 2025Natural products have long served as valuable therapeutic agents owing to their high structural complexity, rich stereochemistry, and three-dimensional architecture. Nevertheless, the difficulty of isolating novel natural products in substantial quantities has shifted drug-discovery efforts over the past two decades toward simpler synthetic libraries, often at the expense of biologically relevant chemical space. The complexity-to-diversity (CtD) strategy offers a compelling alternative: by distorting and reorganizing natural-product scaffolds, CtD efficiently generates structurally diverse, highly complex small molecules capable of engaging challenging biological targets. Recent advances have demonstrated the power of this approach, enabling concise, scalable syntheses of diverse libraries through strategic skeletal rearrangements. This viewpoint highlights the unique potential of CtD predominantly derived from alkaloidal and terpenoidal nuclei, examines representative synthetic examples, and discusses the opportunities and challenges inherent to scaling both structural complexity and molecular diversity. This perspective aims to underscore the relevance of CtD for natural product, synthetic, and medicinal chemists seeking new avenues for innovative lead discovery.