Ring-opening reactions provide an effective platform for converting readily accessible, widely available chiral hetero- and carbocycles into hard-to-attain stereodefined linear carbon chains. While Nature relies on enzymes to build complex enantiopure heterocyclic natural products, synthetic chemists can count on an ever-growing, wide-ranging suite of transformations to access chiral cyclic scaffolds, often with excellent control over multiple stereocentres formed in a single step. Conversely, the synthesis of linear frameworks featuring multiple stereocentres is considerably more challenging, especially when the stereochemical information is located away from reactive functionalities (amines or carbonyls). Yet such linear motifs are prevalent in lead compounds and blockbuster drugs, embedded in aliphatic chains and macrocycles. Our target is to leverage the enhanced complexity-generating ability and stereocontrol provided by the formation and functionalisation of cyclic systems to access highly decorated, stereodefined linear architectures via electrochemically driven ring-opening fragmentation reactions.
To realise this, we developed a practical, general and selective strategy for the regio- and stereoselective functionalisation of C=C bonds, named “sew & cut”.¹ This hinges on the design of novel reagents − consisting of a 1,3-dipole precursor equipped with a sulfonyl redox handle. These can selectively di-functionalise alkenes via “click” 1,3-dipolar cycloadditions, and then facilitate the telescoped SET reduction and radical fragmentation of the resulting heterocyclic intermediate, furnishing stereodefined building blocks. More recently, we extended this concept to more challenging C(sp³)–N bond cleavage reactions in saturated N-heterocycles.² Here, we leveraged electrochemical conditions to facilitate the two-electron cathodic reduction of N-carbonyl protecting groups, generating umpoled α-amino–α-oxy-carbanion species that promote the heterolytic ring-opening of a broad array of unstrained cyclic amines (including pyrrolidines, piperidines, azepines, azocanes, and N-macrocycles), protected as N-amides, thioamides, carbamates or ureas. Our electroreductive protocol is readily scalable and amenable to miniaturisation for high-throughput experimentation, and it efficiently converts stereochemically rich N-heterocycles into highly decorated, stereodefined linear amides.
1 a) Wanderley, T. A. S.; Buscemi, R.; Conboy, Ó.; Knight, B.; Crisenza, G. E. M. J. Am. Chem. Soc. 2024, 146, 32848−32858; b) Wanderley, T. A. S.; Crisenza, G. E. M. Synlett 2025, 37, 287–297.
2. Buscemi, R.; Martínez-Balart, P.; Bura, D.; Díaz-Ruiz, M.; Moreno-González, J.; Douglas, J. J.; Trujillo, C.; Crisenza, G. E. M. J. Am. Chem. Soc. 2026, 148, 11925–11938.
