Reactions of Sulfonylphthalide with Diverse Activated Imines for the Synthesis of Enaminophthalides, Spiro-isoquinolinones, and Homalicine Natural Products.

The reactivity of the Hauser-Kraus (H-K) donor, 3-sulfonylphthalide, with various activated imines under basic conditions is demonstrated. The reaction of 3-sulfonylphthalide with Boc-protected aldimine provides a rapid access to 1,2-imine adducts and alkylidenephthalides depending upon the stoichiometry of the base. The alkylidenephthalides could be transformed to ketophthalides, a new class of phthalides, on acid hydrolysis, which upon reductive cyclization using Zn/AcOH afforded the natural product homalicine. On the contrary, the Boc-protected isatinimines undergo an efficient H-K annulation to provide spiro-isoquinolinone-oxindoles in excellent yields. However, the corresponding conjugated ketimines afforded Michael adducts, which were converted to the corresponding alkylidenephthalides under TBAF conditions.

Substrate-oriented selectivity in the Mg-mediated conjugate addition of bromoform to electron-deficient alkenes.

The Mg-mediated conjugate addition of bromoform to a variety of electron-deficient alkenes has been investigated. In the case of nitrodienes and dibenzylideneacetones, tribromomethylated products were isolated, whereas spiro-cyclopropanated products were obtained with cyclic dibenzylideneketones and 3-olefinic oxindoles. The spiro-cyclopropyl ketones derived from cyclic dibenzylideneketones were successfully transformed into fused furans via the Cloke-Wilson rearrangement.

Synthesis of indenofurans, benzofurans and spiro-lactones via Hauser-Kraus annulation involving 1,6-addition of phthalide to quinone methides.

An unprecedented reactivity of 3-sulfonylphthalide with 2-hydroxyaryl-p-quinone methides (HQMs) is reported here. A cascade of reactions starting with 1,6-addition and Dieckmann cyclization produced a diverse array of indenofurans and benzofurans in high yields, depending on the amount of base used, presumably via a common 8-membered ketolactone intermediate. The indenofurans could be transformed to benzofurans in the presence of excess base via a key spiro-lactone intermediate, which could be characterized via in situ oxidation to a stable spirolactone linked quinone methide, providing crucial evidence for the mechanism of the reaction. The three diverse oxygen heterocycles synthesized by our methodology constitute the core structure of several bioactive compounds including natural products.

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.

Stereoselective synthesis of hydrazinodihydrofurans via cascade Michael addition-substitution involving the reaction of curcumin and other ß-dicarbonyls with α-hydrazinonitroalkenes.

Highly diastereoselective synthesis of 2-hydrazinated 2,3-dihydrofurans in good to excellent yields involving an interrupted Feist-Bénary type reaction by treating a wide variety of 1,3-dicarbonyl compounds, including curcumins, with α-hydrazinated nitroalkenes is reported here. The first ever enantioselective reaction of α-hydrazinonitroalkenes has also been carried out with two selected 1,3-dicarbonyls, dimedone and cyclohexanone by employing an l-t-leucine derived squaramide as the chiral organocatalyst to afford the enantio-enriched 2-hydrazinodihydrofurans as single diastereomers in good yields and with good enantioselectivities.

Synthesis of fused cyanopyrroles and spirocyclopropanes via addition of N-ylides to chalconimines.

Addition of N-ylides derived from DABCO to chalconimines takes place through a Michael addition-cyclization pathway to afford fused cyanopyrroles and/or spirocyclopropanes. The product profile depends heavily on the nature of chalconimines. While 6-membered cyclic chalconimines provide a mixture of pyrrole and spirocyclopropane, 5-membered chalconimines furnish exclusively spirocyclopropane. Cyclopropane was the only product in the case of a representative open chain chalconimine as well. On the other hand, chalcones provide only spirocyclopropanes which is in contrast to the previously reported reactivity of enones. The complementary nature of the reactivity of the tetralone derived chalcone and its corresponding imine in providing spirocyclopropane and pyrrole, respectively, has also been demonstrated.

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.