Exploring Cuneanes as Potential Benzene Isosteres and Energetic Materials: Scope and Mechanistic Investigations into Regioselective Rearrangements from Cubanes.

Cuneane is a strained hydrocarbon that can be accessed via metal-catalyzed isomerization of cubane. The carbon atoms of cuneane define a polyhedron of the C2v point group with six faces─two triangular, two quadrilateral, and two pentagonal. The rigidity, strain, and unique exit vectors of the cuneane skeleton make it a potential scaffold of interest for the synthesis of functional small molecules and materials. However, the limited previous synthetic efforts toward cuneanes have focused on monosubstituted or redundantly substituted systems such as permethylated, perfluorinated, and bis(hydroxymethylated) cuneanes. Such compounds, particularly rotationally symmetric redundantly substituted cuneanes, have limited potential as building blocks for the synthesis of complex molecules. Reliable, predictable, and selective syntheses of polysubstituted cuneanes bearing more complex substitution patterns would facilitate the study of this ring system in myriad applications. Herein, we report the regioselective, AgI-catalyzed isomerization of asymmetrically 1,4-disubstituted cubanes to cuneanes. In-depth DFT calculations provide a charge-controlled regioselectivity model, and direct dynamics simulations indicate that the nonclassical carbocation invoked is short-lived and dynamic effects augment the charge model.

Formal Cycloadditions Driven by the Homolytic Opening of Strained, Saturated Ring Systems.

The field of strain-driven, radical formal cycloadditions is experiencing a surge in activity motivated by a renaissance in free radical chemistry and growing demand for sp3 -rich ring systems. The former has been driven in large part by the rise of photoredox catalysis, and the latter by adoption of the "Escape from Flatland" concept in medicinal chemistry. In the years since these broader trends emerged, dozens of formal cycloadditions, including catalytic, asymmetric variants, have been developed that operate via radical mechanisms. While cyclopropanes have been studied most extensively, a variety of strained ring systems are amenable to the design of analogous reactions. Many of these processes generate lucrative, functionally decorated sp3 -rich ring systems that are difficult to access by other means. Herein, we summarize recent efforts in this area and analyze the state of the field.

Photochemical Formal (4 + 2)-Cycloaddition of Imine-Substituted Bicyclo[1.1.1]pentanes and Alkenes.

Amines containing bridged bicyclic carbon skeletons are desirable building blocks for medicinal chemistry. Herein, we report the conversion of bicyclo[1.1.1]pentan-1-amines to a wide range of polysubstituted bicyclo[3.1.1]heptan-1-amines through a photochemical, formal (4 + 2)-cycloaddition of an intermediate imine diradical. To our knowledge, this is the first reported method to convert the bicyclo[1.1.1]pentane skeleton to the bicyclo[3.1.1]heptane skeleton. Hydrolysis of the imine products gives complex, sp3-rich primary amine building blocks.

TMPRSS2 Inhibitor Discovery Facilitated through an In Silico and Biochemical Screening Platform.

The COVID-19 pandemic has highlighted the need for new antiviral approaches because many of the currently approved drugs have proven ineffective against mitigating SARS-CoV-2 infections. The host transmembrane serine protease TMPRSS2 is a promising antiviral target because it plays a role in priming the spike protein before viral entry occurs for the most virulent variants. Further, TMPRSS2 has no established physiological role, thereby increasing its attractiveness as a target for antiviral agents. Here, we utilize virtual screening to curate large libraries into a focused collection of potential inhibitors. Optimization of a recombinant expression and purification protocol for the TMPRSS2 peptidase domain facilitates subsequent biochemical screening and characterization of selected compounds from the curated collection in a kinetic assay. In doing so, we identify new noncovalent TMPRSS2 inhibitors that block SARS-CoV-2 infectivity in a cellular model. One such inhibitor, debrisoquine, has high ligand efficiency, and an initial structure-activity relationship study demonstrates that debrisoquine is a tractable hit compound for TMPRSS2.