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We recently developed a novel chiral catalyst‐directed dynamic kinetic diastereoselective acylation of hemiacetals for the synthesis of carbohydrates. In this update, we describe a catalytic method for the dynamic kinetic enantioselective acylation of 2‐chromanols using benzotetramisole derived catalysts. High yields and enantiomeric excesses were obtained for a broad range of acylated 2‐chromanols, which are important intermediates for the synthesis of various bioactive pharmaceuticals. We hypothesize that the high stereoselectivity of the reaction originates from a novel cation‐n interaction between the chromanol substrate and the acylated catalyst.magnified image

To identify novel inhibitors of the carbapenemase New Delhi metallo-β-lactamase (NDM) as possible therapeutic compounds, we conducted a high-throughput screen of a 43,358compound library. One of these compounds, a 2-quinazolinone linked through a diacylhydrazine to a phenyl ring (QDP-1) (IC 50 = 7.9 ± 0.5 μM), was characterized as a slow-binding reversible inhibitor (K i app = 4 ± 2 μM) with a noncompetitive mode of inhibition in which substrate and inhibitor enhance each other's binding affinity. These studies, along with differential scanning fluorimetry, zinc quantitation, and selectivity studies, support an allosteric mechanism of inhibition. Cotreatment with QDP-1 effectively lowers minimum inhibitory concentrations of carbapenems for a panel of resistant Escherichia coli and Klebsiella pneumoniae clinical isolates expressing NDM-1 but not for those expressing only serine carbapenemases. QDP-1 represents a novel allosteric approach for NDM drug development for potential use alone or with other NDM inhibitors to counter carbapenem resistance in enterobacterales.

Carbohydrates are the most prevalent class of naturally occurring biomolecules. They mediate cell signaling, bacterial virulence, and metabolism, among other functions. The site‐selective functionalization of carbohydrates has been a long‐standing problem in chemistry. Phosphoramidates are a particularly challenging functional group to install stereoselectively because of the chirality at the phosphorus center. As such, the site‐ and stereoselective phosphoramidation of carbohydrates has never been achieved. We have developed the first site‐ and stereoselective phosphoramidation reaction of carbohydrates using a chiral catalyst and a chiral electrophile. This method offers a convenient solution for the selective synthesis of phosphoramidated carbohydrate‐containing prodrugs and natural products.magnified image

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