ABSTRACT
The cytotoxic natural product (-)-sclerophytin A was constructed in 13 steps from geranial. Highlights from the synthesis are a stereoselective Oshima-Utimoto reaction, a Shibata-Baba indium-promoted radical cyclization, and a novel stereoconvergent epoxide hydrolysis.
Subject(s)
Bridged-Ring Compounds/chemical synthesis , Epoxy Compounds/chemistry , Furans/chemical synthesis , Bridged-Ring Compounds/chemistry , Cyclization , Furans/chemistry , Hydrolysis , Indium/chemistry , Molecular Structure , StereoisomerismABSTRACT
Treatment of gamma,delta-unsaturated ketones with hydrogen peroxide and acid provides a rapid entry into the medicinally important 1,2,4-trioxane structure. Alkene substitution that stabilizes carbocationic intermediates proved to be important for the success of this transformation.
Subject(s)
Alkenes/chemistry , Heterocyclic Compounds/chemical synthesis , Ketones/chemistry , Catalysis , Cyclization , Heterocyclic Compounds/chemistry , Hydrogen Peroxide/chemistry , Molecular Structure , StereoisomerismABSTRACT
Artemisinin-derived compounds play an integral role in current malaria chemotherapy. Given the virtual certainty of emerging resistance, we have investigated spiro-1,2-dioxolanes as an alternative scaffold. The endoperoxide functionality was generated by the SnCl(4)-mediated annulation of a bis-silylperoxide and an alkene. The first set of eight analogs gave EC(50) values of 50-150 nM against Plasmodium falciparum 3D7 and Dd2 strains, except for the carboxylic acid analog. A second series, synthesized by coupling a spiro-1,2-dioxolane carboxylic acid to four separate amines, afforded the most potent compound (EC(50) approximately 5 nM).
