No abstract

The amide functional group is one of Nature’s key functional and structural elements, most notably within peptides. Amides are also key intermediates in the preparation of a diverse range of therapeutic small molecules. Its construction using available methods focuses principally upon dehydrative approaches, although oxidative and radical-based methods are representative alternatives. During the carbon-nitrogen bond forming step in most every example, the carbon and nitrogen bear electrophilic and nucleophilic character, respectively. Here we show that activation of amines and nitroalkanes with an electrophilic iodine source in wet THF can lead directly to amide products. Preliminary observations support a mechanistic construct in which reactant polarity is reversed (umpolung) during C-N bond formation relative to traditional approaches. The use of nitroalkanes as acyl anion equivalents provides a conceptually innovative approach to amide and peptide synthesis, and one that might ultimately provide for efficient peptide synthesis that is fully reliant on enantioselective methods.

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.

Despite Nature's longstanding ability to use a proton, the most prevalent Lewis acid, to both activate and orient a substrate during an enantioselective reaction, this work represents the first example of this phenomenon outside of a protein. A chiral, nonracemic BisAMidine (BAM) ligand was designed, synthesized, and complexed to the proton of a Brønsted acid. The resulting coordination compound catalyzed the production of enantioenriched product from the combination of a Schiff base and nitroalkane (the aza-Henry reaction). This particular reaction is also considered a model for many analogous carbon-carbon bond-forming reactions catalyzed by enzymes (e.g., the Mannich reaction). This discovery suggests the use of ionic hydrogen bonds in asymmetric catalysis may not only be more general than previously thought, but also a viable "green" approach to single-enantiomer organic compounds.