Efficient and metal catalyst-free approach towards highly-substituted N-sulfonylpiperidine-/mono-spiro-1,2,4,5-tetraoxanes for potential applications in chemotherapy

Abstract

Abstract A highly efficient metal and catalyst-free approach for the preparation of synthetically challenged tri -OMe-aryl-substituted heterocyclic, di -/ tri -OMe-aryl-based cyclic and acyclic 1,2,4,5-tetraoxanes ( 5a–l and 6a–k ) is presented herein. Under green-chemistry conditions, the reactions occur in two key steps. The first one involves azeotropic activation of hydrogen peroxide for N -sulfonylpiperidone ( 2a–f ), substituted cyclic and acyclic ketones ( 2a 1 –a 4 ) oxidation, whereas the second one was H + [BF 4 ]ˉ (50–55% solun; 25 mol%)-catalyzed cyclization of the highly reactive gem -dihydroperoxide ( 3a–f and 3a 1 –a 4 ) intermediates in an SN 1 -type manner with secondary keto compounds ( 4a–d ). Both reactions furnished a diverse array of heterocyclic, cyclic, and open-chain 1,2,4,5-tetraoxane analogues ( 5a–l and 6a–k ; 19–83%) in attainable yields. The outcomes of the control and competition experiment strongly indicate that the electronic effects of the EWGs group and the strong steric influence of the bulky tri -OMe-aryl group directly impacted reaction advancement. These effects were clearly observed in the reactivity of the substituted N -sulfonylpiperidones ( 2a–f ) and gem -dihydroperoxides ( 3a–f and 3a 1 –a 4 ), and finally, also in the construction of the final products ( 5a–l and 6a–k ). In addition, this metal-free approach is also suitable for the ‘one pot’ synthesis of structurally complex, highly substituted, pharmaceutically privileged di -/ tri -OMe-aryl-based cyclic and acyclic 1,2,4,5-tetraoxanes ( 6a–h and 6k ), offering significant potential for synthetic advancements in malaria and cancer chemotherapy. Furthermore, in preliminary biological evaluations, the in vitro antiplasmodial and cytotoxic potentials of novel tri -OMe-aryl-substituted N -sulfonylpiperidine-spiro-1,2,4,5-tetraoxanes ( 5a–l ) were established against the chloroquine-resistant FcB1 strain of Plasmodium falciparum and human cancer cell lines, including HeLa and A2780 cells.