Piperidine dispiro-1,2,4-trioxane analogues

Dispiro N-Boc-protected 1,2,4-trioxane 2 was synthesised via Mo(acac)2 catalysed perhydrolysis of N-Boc spirooxirane followed by condensation of the resulting β-hydroperoxy alcohol 10 with 2-adamantanone. N-Boc 1,2,4-trioxane 2 was converted to the amine 1,2,4-trioxane hydrochloride salt 3 which was subsequently used to prepare derivatives (4–7). Several of these novel 1,2,4-trioxanes had nanomolar antimalarial activity versus the 3D7 strain of Plasmodium falciparum. Amine intermediate 3 represents a versatile derivative for the preparation of achiral arrays of trioxane analogues with antimalarial activity.

Graphical abstractDispiro N-Boc-protected 1,2,4-trioxanes were synthesised via Mo(acac)2 catalaysed perhydrolysis of N-Boc spirooxirane followed by condensation of the resulting β-hydroperoxy alcohol with 2-adamantanone. N-Boc 1,2,4-trioxane was converted to the 1,2,4-trioxane hydrochloride salt which was subsequently used to prepare piperidine dispiro-1,2,4-trioxane analogues which were assayed versus Plasmodium falciparum in vitro.Figure optionsDownload full-size imageDownload as PowerPoint slide