Macrocyclization

Macrocyclization is the chemical process by which a linear precursor forms a macrocycle through an intramolecular bond-forming event, typically yielding rings containing 12 or more atoms. It is a key step in the synthesis of macrolides, macrocyclic peptides, crown ethers, and related compounds. The reaction is entropically disfavored relative to intermolecular reactions, so strategies often emphasize dilution, preorganization, or templating to favor cyclization over polymerization.

Common approaches include macrolactamization (amide bond formation between a carboxyl group and an amine) and macrolactonization (ester formation between a carboxyl group and an alcohol), as well as ring-closing metathesis (RCM) to form carbon–carbon backbones. Other methods employ click-based intramolecular ligations, native chemical ligation, or other cyclization chemistries such as activated lactam or lactone formation. The choice of method depends on ring size, functional group compatibility, and the desired connectivity.

Factors influencing success include chain length, conformational bias, presence of competing reactive groups, and reaction concentration. Pseudo-dilution techniques, slow addition of dilute solutions, and the use of tethered or templated precursors can increase the effective molarity of the reactive ends and improve cyclization yields. Protecting groups and orthogonal chemistries are often employed to control selectivity.

Applications span natural product total synthesis, pharmaceutical agents, and supramolecular chemistry. Macrocycles serve as antibiotics and immunosuppressants, receptor ligands, and hosts in host–guest chemistry. The field continues to develop methods that enable efficient, scalable macrocyclizations with improved selectivity and functional group tolerance.