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 macro cycles 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