macrocyclizations

Macrocyclizations are chemical reactions that assemble macrocyclic rings, typically defined as rings containing more than about 12 atoms. They play a central role in the synthesis of natural products, cyclic peptides, macrocyclic lactones, and related materials. Common modalities include macrolactamization (amide bond formation to form lactams) and macrolactonization (lactones), as well as carbon–carbon bond forming routes such as ring-closing metathesis (RCM) used to close large rings.

A defining challenge is the entropic cost of bringing the chain ends together in solution, which can lead to oligomerization. Solutions include carrying out reactions at high dilution to favor intramolecular cyclization, using templates or preorganized precursors, temporary tethers, and reaction design that increases effective molarity. Choice of solvent, temperature, and catalyst also influence efficiency and selectivity.

Macrolactamization and macrolactonization are classical approaches in total synthesis. Ring-closing metathesis provides a flexible alternative for forming diverse macrocycles from dienyl or enynyl precursors. Dynamic covalent macrocyclizations exploit reversible bonds to equilibrate toward the most stable ring. In many cases, the ring size and conformational rigidity are tuned to balance cyclization efficiency with post-cyclization functionalization requirements.

Macrocyclic motifs are widespread in biology and medicine, including antibiotics and peptide therapeutics, where the constrained geometry enhances potency and metabolic stability. In biosynthesis, macrocyclization is mediated by specialized enzymes in nonribosomal peptide synthetases or ribosomally synthesized and post-translationally modified peptide pathways, producing a broad array of macrocyclic natural products.