Design and Synthesis of Aculeatin Oxo-Analogues and Aculeatin Natural Products Enabled by Oxo-Carbenium Ion Cyclization

Abstract

Aculeatin natural products have garnered significant attention for their exceptional biological activities, such as antimalarial, antiprotozoal, and cytotoxic properties, prompting extensive total synthesis studies and the development of unnatural analogs. We have established a novel cascade methodology to synthesize skeletally modified aculeatin analogs. This method involves PIDA-mediated oxidative dearomatization of phenol derivatives in the in situ formation of a highly reactive bifunctional electrophilic spiroacetal oxo-carbenium ion intermediate, which on double nucleophilic addition reaction with diols produces a range of aculeatin oxo-analogs. Comprehensive mechanistic investigations, including control experiments and computational studies, confirm the involvement of the spiroacetal oxo-carbenium ion intermediate in this transformation.Malaria, a widespread parasitic disease in tropical and subtropical regions, continues to rise, infecting millions each year. 1 The primary cause of this severe illness is blood protozoan parasites belonging to the Apicomplexa phylum, namely the Plasmodium genus, 2 in which the most lethal species of these parasites is Plasmodium falciparum. 3 The rise in the malaria death toll is primarily owing to the spread of resistance to all currently used antimalarial medications, 4 with artemisinin derivatives remaining an exception. 5 As a result, the quest for finding novel antimalarial compounds is ongoing. Approaches with unique modes of action and molecules structurally distinct from currently used antimalarial drugs are given more importance. 6 Amomum aculeatum is a plant that has long been used in Papua New Guinean folk medicine to cure malaria and fever. 7 Heilmann and co-workers have isolated b) All-oxygen spirocyclic orthoester motif in bioactive natural products