Consecutive Ring-Expansion Reactions for the Iterative Assembly of Medium-Sized Rings and Macrocycles

Macrocycles and medium-sized rings have important applications in several scientific fields but can be challenging to make using traditional end-to-end cyclization reactions. Ring-expansion methods represent a useful alternative and offer numerous practical benefits. In this Account, we discuss the current state of the art of ring-expansion strategies that have been applied consecutively. Such methods have the power to expedite the design and synthesis of functionalized macro­cycles via the selective, iterative insertion of smaller fragments into ring-enlarged products. 1 Introduction 2 Insertion Reactions 2.1 Transamidation/Transpeptidation 2.2 Transesterification 2.3 Transthioesterification 2.4 Aminyl Radical Cascade 2.5 Iterative Synthesis of Lactones 2.6 Successive Ring Expansion of β-Ketoesters and Lactams 3 Pericyclic Reactions 3.1 Sulfur-Mediated Rearrangements 3.2 Nitrogen-Mediated Rearrangements 4 Fragmentation Reactions 5 Conclusions and Future Outlook