biostudies-literatureZalessky IGlaxoSmithKlineUniversity of YorkRoyal Society5702-5711https://www.ebi.ac.uk/biostudies/studies/S-EPMC10910531biostudies-literatureUnknown146(8)Macrocycles and medium-sized rings are important in many scientific fields and technologies but are hard to make using current methods, especially on a large scale. Outlined herein is a strategy by which functionalized macrocycles and medium-sized rings can be prepared using cyclization/ring expansion (CRE) cascade reactions, without resorting to high dilution conditions. CRE cascade reactions are designed to operate exclusively via kinetically favorable 5-7-membered ring cyclization steps; this means that the problems typically associated with classical end-to-end macrocyclization reactions are avoided. A modular synthetic approach has been developed to facilitate the simple assembly of the requisite linear precursors, which can then be converted into an extremely broad range of functionalized macrocycles and medium-sized rings using one of nine CRE protocols.Journal of the American Chemical SocietyA Modular Strategy for the Synthesis of Macrocycles and Medium-Sized Rings via Cyclization/Ring Expansion Cascade Reactions.PMC10910531INF\R1\221057Tam JKFKnapper BJGlover-Humphreys WCSpurling DEZalessky IDonald JRTanner TFNUnsworth WPMiah AHOrukotan WEWootton JMWhitwood ACDuff LCLynam JMfalseA Modular Strategy for the Synthesis of Macrocycles and Medium-Sized Rings via Cyclization/Ring Expansion Cascade Reactions.Macrocycles and medium-sized rings are important in many scientific fields and technologies but are hard to make using current methods, especially on a large scale. Outlined herein is a strategy by which functionalized macrocycles and medium-sized rings can be prepared using cyclization/ring expansion (CRE) cascade reactions, without resorting to high dilution conditions. CRE cascade reactions are designed to operate exclusively via kinetically favorable 5-7-membered ring cyclization steps; this means that the problems typically associated with classical end-to-end macrocyclization reactions are avoided. A modular synthetic approach has been developed to facilitate the simple assembly of the requisite linear precursors, which can then be converted into an extremely broad range of functionalized macrocycles and medium-sized rings using one of nine CRE protocols.2024-01-01T00:00:00Z2024 Feb2025-04-05T11:39:02.62Z2025-04-05T11:39:02.62ZS-EPMC109105313837265110.1021/jacs.4c00659