Structural Elucidation of Micro-Scale Natural Products through Analytical and Synthetic Approaches

Abstract

Natural products exhibit extraordinary structural diversity and play central roles in chemical ecology, biological interactions, and drug discovery. However, many natural products are available only in trace amounts, making structural elucidation a major analytical challenge. This review summarizes landmark studies and recent advances in the structural analysis of natural products available in microgram- to sub-milligram quantities. It focuses primarily on NMR-based structural elucidation, including the use of high-field instrumentation, cryogenic probes, and advanced pulse sequences, while also covering approaches based on comparison with synthetic standards, DFT-assisted structure validation, the crystalline sponge method, and MicroED. Representative examples, including natural toxins, biosynthetic intermediates, and microbial signaling molecules, illustrate how integrated analytical and synthetic approaches enable reliable structure determination from limited material. These methodologies provide an important foundation not only for natural product discovery but also for understanding biosynthesis, biological activity, and chemical ecology at the molecular level.