Bicyclic Pyrrolidine Inhibitors of Phenylalanine t-RNA Synthetase with Antiparasitic Potency In Vitro and Brain Exposure.

Previous studies have shown that bicyclic azetidines are potent and selective inhibitors of apicomplexan phenylalanine tRNA synthetase (PheRS), leading to parasite growth inhibition in vitro and in vivo, including in models of infection. Despite these useful properties, additional optimization is required for the development of efficacious treatments of toxoplasmosis from this inhibitor series, in particular, to achieve optimal exposure in the brain. Here, we describe a series of PheRS inhibitors built on a new bicyclic pyrrolidine core scaffold designed to retain the exit-vector geometry of the isomeric bicyclic azetidine core scaffold while offering avenues to sample diverse chemical space.

SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes.

We report the detailed background for the discovery and development of the synthesis of homopropargylic azides by the azido-alkynylation of alkenes. Initially, a strategy involving SOMOphilic alkynes was adopted, but only resulted in a 29% yield of the desired product. By switching to a radical-polar crossover approach and after optimization, a high yield (72%) of the homopropargylic azide was reached.

Bicyclic pyrrolidine inhibitors of phenylalanine t-RNA synthetase with antiparasitic potency and brain exposure.

Previous studies have shown that bicyclic azetidines are potent and selective inhibitors of apicomplexan phenylalanine tRNA synthetase (PheRS), leading to parasite growth inhibition and , including in models of infection. Despite these useful properties, additional optimization is required for the development of efficacious treatments of toxoplasmosis from this inhibitor series, in particular to achieve sufficient exposure in the brain. Here, we describe a series of PheRS inhibitors built on a new bicyclic pyrrolidine core scaffold designed to retain the exit-vector geometry of the isomeric bicyclic azetidine core scaffold while offering avenues to sample diverse chemical space.

Acyl-Ethynylbenziodoxolone (acyl-EBX): Access to Ketene Dithioarylacetals.

We report the synthesis of ketene dithioarylacetals in 40-97% yield using thiophenols and acyl-EBXs (ethynylbenziodoxolones) generated from a common hypervalent iodine precursor and alkynyl trifluoroborate salts. The products could be further modified to afford functionalized ketene dithioacetals and various -substituted heterocycles.

Azido-alkynylation of alkenes through radical-polar crossover.

We report an azido-alkynylation of alkenes allowing a straightforward access to homopropargylic azides by combining hypervalent iodine reagents and alkynyl-trifluoroborate salts. The design of a photocatalytic redox-neutral radical polar crossover process was key to develop this transformation. A variety of homopropargylic azides possessing electron-rich and -poor aryls, heterocycles or ether substituents could be accessed in 34-84% yield.

Copper-Catalyzed Alkynylation of Hydrazides: An Easy Access to Functionalized Azadipeptides.

We report a copper-catalyzed alkynylation of azadipeptides using ethynylbenziodoxolone (EBX) reagents. Nonsymmetrical ynehydrazides could be obtained in 25-97% yield using azaglycine derivatives as nucleophiles. The transformation is compatible with most functional groups naturally occurring on amino acid side chains and allows the transfer of silyl-, alkyl-, and aryl-substituted alkynes.

Tosyloxybenziodoxolone: A Platform for Performing the Umpolung of Alkynes in One-Pot Transformations.

Ethynylbenziodoxolones (EBXs) are commonly encountered reagents for the electrophilic alkynylation of nucleophiles. Herein, we report a one-pot, two-step process for EBX generation and their direct application in substrate functionalization. Our approach enables us to bypass the originally mandatory isolation and purification of the reagents, resulting in a more efficient synthesis.

Composition of Carbon Clusters in Implanted Silicon Using Atom Probe Tomography.

Atom probe tomography was employed to observe and derive the composition of carbon clusters in implanted silicon. This value, which is of interest to the microelectronic industry when considering ion implantation defects, was estimated not to exceed 2 at%. This measurement has been done by fitting the distribution of first nearest neighbor distances between monoatomic carbon ions (C+ and C2+).

Bicyclic azetidines kill the diarrheal pathogen in mice by inhibiting parasite phenylalanyl-tRNA synthetase.

is a protozoan parasite and a leading cause of diarrheal disease and mortality in young children. Currently, there are no fully effective treatments available to cure infection with this diarrheal pathogen. In this study, we report a broad drug repositioning effort that led to the identification of bicyclic azetidines as a new anticryptosporidial series.

Copper-Catalyzed Oxyalkynylation of C-S Bonds in Thiiranes and Thiethanes with Hypervalent Iodine Reagents.

We report the oxyalkynylation of thiiranes and thietanes using ethynylbenziodoxolone reagents (EBXs) to readily access functionalized building blocks bearing an alkynyl, a benzoate, and an iodide group. The reaction proceeds with high atom efficiency most likely through an alkynyl-episulfonium intermediate. The transformation is copper-catalyzed and compatible with a large array of thiiranes and thietanes.