Preparation of Antimalarial Endoperoxides by a Formal [2 + 2 + 2] Cycloaddition.
A formal [2 + 2 + 2] cycloaddition reaction between a 1,3-dione, an olefin, and molecular oxygen mediated by light is reported, which delivers endoperoxides in good yield through the formation of two C-O and one C-C bond in one step. The resulting 1,2-dioxanes are stable compounds and can be further derivatized at the hemiacetal position via alkylation or acetylation. All compounds have been evaluated against Plasmodium falciparum, and the best compound displayed an IC50-value of 180 nM. A potential mechanistic rationale for the formation of these compounds is presented.
Department of Chemistry, University of Basel , St. Johanns-Ring 19, CH-4056 Basel, Switzerland.|Department of Chemistry, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Christophe
C
Daeppen
Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute (Swiss TPH), Socinstrasse 57, CH-4002 Basel, Switzerland.
Marcel
M
Kaiser
Department of Chemistry, University of Basel , St. Johanns-Ring 19, CH-4056 Basel, Switzerland.
Markus
M
Neuburger
Department of Chemistry, University of Basel , St. Johanns-Ring 19, CH-4056 Basel, Switzerland.|Department of Chemistry, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Karl
K
Gademann
D000478:Alkylation; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D061565:Cycloaddition Reaction; D004146:Dioxanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010545:Peroxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000962:Antimalarials; D004146:Dioxanes; D010545:Peroxides