ABSTRACT
Carbon dioxide exhibits many of the qualities of an ideal reagent: it is nontoxic, plentiful, and inexpensive. Unlike other gaseous reagents, however, it has found limited use in enantioselective synthesis. Moreover, unprecedented is a tool that merges one of the simplest biological approaches to catalysis-Brønsted acid/base activation-with this abundant reagent. We describe a metal-free small molecule catalyst that achieves the three component reaction between a homoallylic alcohol, carbon dioxide, and an electrophilic source of iodine. Cyclic carbonates are formed enantioselectively.
Subject(s)
Acids/chemistry , Alkalies/chemistry , Carbon Dioxide/chemistry , Ethylenediamines/chemistry , Organometallic Compounds/chemistry , Small Molecule Libraries/chemical synthesis , Catalysis , Molecular Structure , Small Molecule Libraries/chemistry , StereoisomerismABSTRACT
Chagas disease is a deadly infection caused by the protozoan parasite Trypanosoma cruzi. Afflicting approximately 8 million people in Latin America, Chagas disease is now becoming a serious global health problem proliferating beyond the traditional geographical borders, mainly because of human and vector migration. Because the disease is endemic in low-resource areas, industrial drug development has been lethargic. The chronic form remains incurable, there are no vaccines, and 2 existing drugs for the acute form are toxic and have low efficacy. Here we report the efficacy of a small molecule, VNI, including evidence of its effectiveness against chronic Chagas disease. VNI is a potent experimental inhibitor of T. cruzi sterol 14α-demethylase. Nontoxic and highly selective, VNI displays promising pharmacokinetics and administered orally to mice at 25 mg/kg for 30 days cures, with 100% cure rate and 100% survival, the acute and chronic T. cruzi infection.
Subject(s)
Chagas Disease/drug therapy , Enzyme Inhibitors/administration & dosage , Imidazoles/administration & dosage , Oxadiazoles/administration & dosage , Administration, Oral , Animals , Chronic Disease , Disease Models, Animal , Enzyme Inhibitors/pharmacokinetics , Female , Imidazoles/pharmacokinetics , Mice , Mice, Inbred BALB C , Oxadiazoles/pharmacokinetics , Survival Analysis , Treatment OutcomeABSTRACT
VNI is a potent inhibitor of CYP51 and was recently shown to achieve a parasitological cure of mice infected with T. cruzi in both acute and chronic stages of infection. T. cruzi is the causative parasite of Chagas disease, a neglected tropical disease. The first enantioselective chemical synthesis of VNI (at a materials cost of less than $0.10/mg) is described. Furthermore, the key enantioselective step is performed at the 10 g scale.
Subject(s)
Chagas Disease/drug therapy , Cytochrome P-450 Enzyme Inhibitors , Imidazoles/chemical synthesis , Imidazoles/therapeutic use , Oxadiazoles/chemical synthesis , Oxadiazoles/therapeutic use , Trypanosoma cruzi/drug effects , Animals , Chagas Disease/parasitology , Cytochrome P-450 Enzyme System , Imidazoles/chemistry , Mice , Molecular Structure , Neglected Diseases , Oxadiazoles/chemistry , Triazoles/chemistry , Triazoles/therapeutic use , Tropical MedicineABSTRACT
Highly enantioselective halolactonizations have been developed that employ a chiral proton catalyst-N-iodosuccinimide (NIS) reagent system in which the Brønsted acid is used at catalyst loadings as low as 1 mol %. An approach that modulates the achiral counterion (equimolar to the neutral chiral ligand-proton complex present at low catalyst loadings) to optimize the enantioselection is documented for the first time in this transformation. In this way, unsaturated carboxylic acids are converted to γ-lactones in high yields (up to 98% ee) using commercially available NIS.
Subject(s)
Ions , Carboxylic Acids/chemistry , Catalysis , Halogens , Hexanes/chemistry , Hydrogen Bonding , Ligands , Models, Chemical , Stereoisomerism , Succinimides/chemistry , TemperatureABSTRACT
A Brønsted base-catalyzed reaction of nitroalkanes with alkyl electrophiles provides indole heterocycles substituted at C3 bearing a sec-alkyl group with good enantioselectivity (up to 90% ee). Denitration by hydrogenolysis provides a product with equally high ee. An indolenine intermediate is implicated in the addition step, and surprisingly, water cosolvent was found to have a beneficial effect in this step, leading to a one-pot protocol for elimination/enantioselective addition using PBAM, a bis(amidine) chiral nonracemic base.
