The Synthesis of Structurally Diverse Macrocycles By Successive Ring Expansion

Structurally diverse macrocycles and medium‐sized rings (9–24 membered scaffolds, 22 examples) can be generated through a telescoped acylation/ring‐expansion sequence, leading to the insertion of linear fragments into cyclic β‐ketoesters without performing a discrete macrocyclization step. The key β‐ketoester motif is regenerated in the ring‐expanded product, meaning that the same sequence of steps can then be repeated (in theory indefinitely) with other linear fragments, allowing macrocycles with precise substitution patterns to be “grown” from smaller rings using the successive ring‐expansion (SuRE) method. Expanding the family: Macrocycles can be generated using a telescoped acylation/ring‐expansion sequence, leading to the insertion of linear fragments into cyclic β‐ketoesters without performing a discrete macrocyclization step. The β‐ketoester motif is regenerated in the ring‐expanded product, therefore the same sequence of steps can be repeated, allowing macrocycles with precise substitution patterns to be “grown” from smaller rings.