Synthesis of Fatty 1,2,4-Trioxanes by Peracetalization of β-Hydroxy Hydroperoxides

Abstract

The peracetalization of a β-hydroxy hydroperoxide derived from methyl oleate was studied using benzaldehyde as a model substrate to give the corresponding fatty 1,2,4-trioxane. The desired product was obtained as a mixture of regioisomers but only one diastereoisomer of each was formed. The nature of the acid catalyst was studied and both p-toluene sulfonic acid (PTSA) and Amberlyst A35 (A35) were found to be efficient homogeneous and heterogeneous catalysts, respectively. The nature of the solvent was also investigated and ethereal solvents such as 2-methyltetrahydrofuran (2-MeTHF), methyl tert-butyl ether (MTBE) and cyclopentyl methyl ether (CPME) gave the best NMR yield (85%) for the preparation of the fatty trioxane. The optimized conditions were applied to a range of aromatic and aliphatic aldehydes, and the corresponding 1,2,4-trioxanes were isolated with 30–91% yields (21 examples). The antimalarial activity of three trioxanes was studied against Plasmodium falciparum, however, no significant activity was detected (IC₅₀ >1600 nM).

Key words

β-hydroxy hydroperoxides - aldehydes - peracetalization - 1,2,4-trioxanes - fatty acids

Publication History

Received: 29 July 2021

Accepted after revision: 13 September 2021

Accepted Manuscript online:
13 September 2021

Article published online:
19 October 2021

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