Synthesis of Spirolactones and Functionalized Benzofurans via Addition of 3-Sulfonylphthalides to 2-Formylaryl Triflates and Conversion to Benzofuroisocoumarins.

A convenient protocol for the synthesis of spirobenzofuran-isobenzofurans and substituted benzofurans via a modified Hauser-Kraus reaction of 3-sulfonylphthalide with 2-formylaryl triflates is reported here. The initial reaction involved 1,2-addition of phthalide to the formyl group and intramolecular cyclization via substitution of triflate followed by a cascade of rearrangements leading to spirolactone or benzofuran derivatives. The electronic nature of substituents on aryl triflates affected the course and outcome of the reaction. The mechanism was supported by successful characterization of one of the intermediates by mass spectrometry. A medicinally relevant influenza virus type B inhibitor, benzofuroisocoumarin, was synthesized in a single step from the spiro compound, thus demonstrating the synthetic utility of our methodology.

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.

Fluconazole-COX Inhibitor Hybrids: A Dual-Acting Class of Antifungal Azoles.

When used in combination with azole antifungal drugs, cyclooxygenase (COX) inhibitors such as ibuprofen improve antifungal efficacy. We report the conjugation of a chiral antifungal azole pharmacophore to COX inhibitors and the evaluation of activity of 24 hybrids. Hybrids derived from ibuprofen and flurbiprofen were considerably more potent than fluconazole and comparable to voriconazole against a panel of Candida species. The potencies of hybrids composed of an S-configured azole pharmacophore were higher than those with an R-configured pharmacophore. Tolerance, defined as the ability of a subpopulation of cells to grow in the presence of the drug, to the hybrids was lower than to fluconazole and voriconazole. The hybrids were active against a mutant lacking CYP51, the target of azole drugs, indicating that these agents act via a dual mode of action. This study established that azole-COX inhibitor hybrids are a novel class of potent antifungals with clinical potential.

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.

Supramolecular Assembly of Gold Nanoparticles on Carbon Nanotubes: Application to the Catalytic Oxidation of Hydroxylamines.

A supramolecular heterogeneous catalyst was developed by assembly and stabilization of gold nanoparticles on the surface of carbon nanotubes. A layer-by-layer assembly strategy was used and the resulting nanohybrid was involved in the catalytic oxidation of hydroxylamines under mild conditions. The nanohybrid demonstrated high efficiency and selectivity on hydroxylamine substrates.