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. 1Introduction 2Insertion Reactions 2.1Transamidation/Transpeptidation 2.2Transesterification 2.3Transthioesterification 2.4Aminyl Radical Cascade 2.5Iterative Synthesis of Lactones 2.6Successive Ring Expansion of beta-Ketoesters and Lactams 3Pericyclic Reactions 3.1Sulfur-Mediated Rearrangements 3.2Nitrogen-Mediated Rearrangements 4Fragmentation Reactions 5Conclusions and Future Outlook