Synthesis of functionalised pyrrolidinone scaffolds via smiles-truce cascade Thomas Sephton 1 , Jonathan M. Large 2 , Sam Butterworth 3 *, Michael F. Greaney 1 * 1 Dept. of Chemistry, University of Manchester, UK, 2 LifeArc, Accelerator Building, Open Innovation Campus, UK, 3 Division of Pharmacy and Optometry, University of Manchester, UK The pyrrolidinone heterocycle is present throughout chemistry and the natural world, featuring as a privileged pharmacophore in numerous biologically active compounds. 1 As such, there exists a plethora of methods for their synthesis and functionalisation, often requiring multiple steps to arrive at the highly functionalised target. Much less common are single-step procedures which afford densely functionalised pyrrolidinone scaffolds from available starting materials. Inspired by previous work in the group exploiting the rich aminoarylation chemistry of sulfonamides, we proposed to develop such a transformation. 2 We have thus developed a metal-free, domino method for the synthesis of highly functionalised pyrrolidinone scaffolds, starting from widely commercially available starting materials and utilising operationally simple reaction conditions. 3 The substrate scope of the transformation encompasses various electron-deficient arenes, alongside substitution on both the sulfonamide and cyclopropane starting materials. The functionalised pyrrolidinones afforded can be readily derivatised, providing rapid access to spirooxindole scaffolds, present as the backbones of many pharmacologically active compounds and natural products. 4 This chemistry uniquely showcases the post- functionality of arylsulfonamides, building on their rich amphiphilic history.
References 1. Shorvon, S. Pyrrolidone derivatives. The Lancet , 2001 , 358 , 1885–1892. Whalley, D. M.; Greaney, M. F. Recent Advances in The Smiles Rearrangement: New Opportunities for Arylation. Synthesis , 2022 , 54 , 1908−1918. 2. Sephton, T.; Large, J. M.; Butterworth, S.; Greaney, F. Synthesis of Functionalized Pyrrolidinone Scaffolds via Smiles-Truce Cascade. Org. Lett ., 2023, 25 , 6736–6740. 3. Galliford, C. V.; Scheidt, K. A. Pyrrolidinyl-Spirooxindole Natural Products as Inspirations for the Development of Potential Therapeutic Agents. Chem., Int. Ed., 2007 , 46 , 8748−8758.
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