Total Synthesis of Macrocyclic Natural Products

The total synthesis of macrocyclic natural products encompasses the design and execution of multistep sequences to construct large ring systems that occur in biologically active molecules. These targets often feature rings of twelve or more atoms bearing diverse functional groups and stereochemical complexity, which makes their assembly a formidable challenge. Key strategies include macrolactonization and macrolactamization to form ester or amide bonds, ring‐closing metathesis to forge carbon–carbon linkages, transition‐metal‐catalysed cross‐coupling for site‐selective bond formation, and ring‐expansion tactics that convert smaller cyclic precursors into medium‐sized and macrocyclic frameworks. Advances in chemoselective C–H bond activation and cascade reactions have further increased the efficiency and scope of these approaches. Success in this field not only provides access to scarce natural scaffolds for biological evaluation but also drives innovation in method development, with broad implications for drug discovery, agrochemicals and materials science.

Research from Nature Portfolio

Recent studies have introduced a general strategy combining site‐selective C–H oxidation with ring‐expansion chemistry to generate medium‐sized rings within polycyclic steroidal frameworks. This approach enables the rapid preparation of structurally diverse libraries by selectively oxidising unactivated C–H bonds followed by insertion of oxygen or nitrogen units to expand rigid small rings into larger macrocyclic architectures. The resulting compounds occupy unique regions of chemical space, extending beyond those accessible by traditional derivatisation and offering new small‐molecule probes for complex biological pathways.

Total Synthesis of Macrocyclic Natural Products publication trend

The graph below shows the total number of articles in total synthesis of macrocyclic natural products across all publications each year (not limited to Nature Index journals).

Technical terms

Macrocycle: A large ring structure typically containing twelve or more atoms, often associated with complex natural products.

Total synthesis: The complete construction of a complex target molecule from simple, commercially available precursors.

Ring expansion: A transformation that increases the size of an existing cyclic system by inserting additional atoms or molecular fragments.

Macrolactonization: A cyclization reaction forming a macrocyclic lactone (ester) bond, commonly used in the synthesis of natural products.

CRE cascade: Cyclization/ring‐expansion cascade, a tandem sequence in which an initial ring closure is directly followed by ring enlargement in one operation.

References

1. A Modular Strategy for the Synthesis of Macrocycles and Medium-Sized Rings via Cyclization/Ring Expansion Cascade Reactions. Journal of the American Chemical Society (2024).
2. Macrocyclization Reactions at High Concentration (≥0.2M): The Role of Catalysis. ACS Catalysis (2023).
3. A cheap metal catalyzed ring expansion/cross-coupling cascade: a new route to functionalized medium-sized and macrolactones. Chemical Science (2023).
4. A general strategy for diversifying complex natural products to polycyclic scaffolds with medium-sized rings. Nature Communications (2019).