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

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 (2a1-a4) oxidation, whereas the second one was H+[BF4]- (50-55% solun; 25 mol%)-catalyzed cyclization of the highly reactive gem-dihydroperoxide (3a-f and 3a1-a4) intermediates in an SN1-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 3a1-a4), 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.