Taming the 1,5-sigmatropic shift across protonated spirocyclic 4-pyrazoles.

The condensation of 1,3-diketones with hydrazine to access 4-pyrazoles is a well-established synthetic route that travels through a 4-pyrazol-1-ium intermediate. In the route to a 3,5-diphenyl-4-pyrazole containing a cyclobutane spirocycle, density functional theory calculations predict and experiments show that the protonated intermediate undergoes a rapid 1,5-sigmatropic shift to form a tetrahydrocyclopenta[]pyrazole. Replacing the 3,5-diphenyl groups with 2-furanyl groups decreases the calculated rate of the 1,5-sigmatropic shift by 6.

Click Organocatalysis: Acceleration of Azide-Alkyne Cycloadditions with Mutually Orthogonal Click Reactions.

"Click organocatalysis" uses mutually orthogonal click reactions to organocatalyze a click reaction. We report the development of an isobenzofuran organocatalyst that increases the rate and regioselectivity of an azide-alkyne cycloaddition. The organocatalytic cycle consists of (1) a Diels-Alder reaction of an alkyne with a diarylisobenzofuran to form a benzooxanorbornadiene, (2) a 1,3-dipolar cycloaddition with an azide to form a 4,5-dihydro-1,2,3-triazole, and (3) a retro-Diels-Alder reaction that releases the triazole product and regenerates the diarylisobenzofuran organocatalyst.

Computational study of an oxetane 4-pyrazole as a Diels-Alder diene.

We combine the effects of spirocyclization and hyperconjugation to increase the Diels-Alder reactivity of the 4-pyrazole scaffold. A density functional theory (DFT) investigation predicts that 4-pyrazoles containing an oxetane functionality at the saturated center are extremely reactive despite having a relatively high-lying lowest unoccupied molecular orbital (LUMO) energy.

Bioorthogonal 4-pyrazole "click" reagents.

4-Pyrazoles are emerging as useful click reagents. Fluorinating the saturated center enables 4-pyrazoles to react rapidly as Diels-Alder dienes without a catalyst but compromises the stability of these dienes under physiological conditions. To identify more stable 4-pyrazoles for bioorthogonal chemistry applications, we investigated the Diels-Alder reactivity and biological stability of three 4-oxo-substituted 4-pyrazoles.

Inhibition of HIV-1 Protease by a Boronic Acid with High Oxidative Stability.

HIV-1 protease is an important target for pharmaceutical intervention in HIV infection. Extensive structure-based drug design led to darunavir becoming a key chemotherapeutic agent. We replaced the aniline group of darunavir with a benzoxaborolone to form BOL-darunavir.

Emergent Organoboron Acid Catalysts.

Organoboron acids are stable, organic-soluble Lewis acids with potential application as catalysts for a wide variety of chemical reactions. In this review, we summarize the utility of boronic and borinic acids, as well as boric acid, as catalysts for organic transformations. Typically, the catalytic processes exploit the Lewis acidity of trivalent boron, enabling the reversible formation of a covalent bond with oxygen.

Boronic acid with high oxidative stability and utility in biological contexts.

Despite their desirable attributes, boronic acids have had a minimal impact in biological contexts. A significant problem has been their oxidative instability. At physiological pH, phenylboronic acid and its boronate esters are oxidized by reactive oxygen species at rates comparable to those of thiols.

The iron-regulated iupABC operon is required for saprophytic growth of the intracellular pathogen Rhodococcus equi at low iron concentrations.

Rhodococcus equi is a facultative intracellular pathogen which proliferates rapidly in both manure-enriched soil and alveolar macrophages. Although both environments are characterized by extremely low concentrations of free iron, very little is known regarding the strategies employed by R. equi to thrive under these conditions.