Enantioselective Sulfonimidamide Acylation via a Cinchona Alkaloid-Catalyzed Desymmetrization: Scope, Data Science, and Mechanistic Investigation.

Methods to access chiral sulfur(VI) pharmacophores are of interest in medicinal and synthetic chemistry. We report the desymmetrization of unprotected sulfonimidamides via asymmetric acylation with a cinchona-phosphinate catalyst. The desired products are formed in excellent yield and enantioselectivity with no observed bis-acylation. A data-science-driven approach to substrate scope evaluation was coupled to high throughput experimentation (HTE) to facilitate statistical modeling in order to inform mechanistic studies. Reaction kinetics, catalyst structural studies, and density functional theory (DFT) transition state analysis elucidated the turnover-limiting step to be the collapse of the tetrahedral intermediate and provided key insights into the catalyst-substrate structure-activity relationships responsible for the origin of the enantioselectivity. This study offers a reliable method for accessing enantioenriched sulfonimidamides to propel their application as pharmacophores and serves as an example of the mechanistic insight that can be gleaned from integrating data science and traditional physical organic techniques.

Catalytic Asymmetric Synthesis of Atropisomeric N-Aryl 1,2,4-Triazoles.

The atroposelective synthesis of N-aryl 1,2,4-triazoles was developed. A cyclodehydration reaction was rendered asymmetric with the use of a chiral phosphoric acid catalyst to afford atropisomeric N-aryl 1,2,4-triazoles in up to 91:9 er. Recrystallization of the isolated heterocycle further enriched the atropisomeric ratio of several analogs to 99:1 er or greater. A divergent and substrate-dependent reaction pathway yielding a different heterocyclic product is also disclosed.

Replication-dependent size reduction precedes differentiation in Chlamydia trachomatis.

Chlamydia trachomatis is the most common cause of bacterial sexually transmitted infection. It produces an unusual intracellular infection in which a vegetative form, called the reticulate body (RB), replicates and then converts into an elementary body (EB), which is the infectious form. Here we use quantitative three-dimensional electron microscopy (3D EM) to show that C. trachomatis RBs divide by binary fission and undergo a sixfold reduction in size as the population expands. Conversion only occurs after at least six rounds of replication, and correlates with smaller RB size. These results suggest that RBs only convert into EBs below a size threshold, reached by repeatedly dividing before doubling in size. A stochastic mathematical model shows how replication-dependent RB size reduction produces delayed and asynchronous conversion, which are hallmarks of the Chlamydia developmental cycle. Our findings support a model in which RB size controls the timing of RB-to-EB conversion without the need for an external signal.