Strategies towards potent trypanocidal drugs: Application of Rh-catalyzed [2 + 2 + 2] cycloadditions, sulfonyl phthalide annulation and nitroalkene reactions for the synthesis of substituted quinones and their evaluation against Trypanosoma cruzi.

Rhodium-catalyzed [2 + 2 + 2] cycloadditions, sulfonyl phthalide annulations and nitroalkene reactions have been employed for the synthesis of 56 quinone-based compounds. These were evaluated against Trypanosoma cruzi, the parasite that causes Chagas disease. The reactions described here are part of a program that aims to utilize modern, versatile and efficient synthetic methods for the one or two step preparation of trypanocidal compounds. We have identified 9 compounds with potent activity against the parasite; 3 of these were 30-fold more potent than benznidazole (Bz), a drug used for the treatment of Chagas disease. This article provides a comprehensive outline of reactions involving over 120 compounds aimed at the discovery of new quinone-based frameworks with activity against T. cruzi.

Enantioselective Synthesis of Quaternary α-Amino Acids via l-tert-Leucine-Derived Squaramide-Catalyzed Conjugate Addition of α-Nitrocarboxylates to Enones.

Enantioselective Michael addition of tertiary α-nitroesters to ß-unsubstituted vinyl ketones has been carried out in the presence of an l-tert-leucine-derived squaramide as organocatalyst. The products, quaternary α-nitroesters, were formed in excellent yield and moderate to good ee's in most cases. Scale-up of the reaction and synthetic applications of the products, including transformation to representative quaternary α-amino acids, have also been demonstrated.