N-Alkyl Carbamoylimidazoles as Isocyanate Equivalents: Exploration of the Reaction Scope for the Synthesis of Ureas, Hydantoins, Carbamates, Thiocarbamates, and Oxazolidinones.

The reaction of the HCl or trifluoroacetic acid salts of primary amines with carbonyldiimidazole (CDI) is shown to be a preparatively useful method for forming monosubstituted carbamoylimidazoles (28 examples) without the formation of symmetrical urea side products. The utility of these air- and water-stable crystalline carbamoylimidazole reagents was demonstrated by their reactions as blocked or masked isocyanate equivalents. Reaction with various classes of nucleophiles provides access to useful functional groups including ureas, carbamates, thiocarbamates, hydantoins, and oxazolidinones. A parallel synthesis library of 30 ureas was generated by the reaction of 6× carbamoylimidazole intermediates with 5× amines and triethylamine. The unsymmetrical urea-containing natural products macaurea A and pygmaniline A were also prepared in good yields (95% over four steps and 79% over three steps, respectively) using this approach. The reaction of carbamoylimidazoles with amino acid methyl esters followed by microwave irradiation in aqueous media gives hydantoins in high yields, further demonstrating the ability of carbamoylimidazoles as isocyanate surrogates. Three hydantoin-containing natural products including macahydantoin D and meyeniihydantoin A were prepared in nearly quantitative yields from proline methyl ester and carbamoylimidazoles. The reaction of carbamoylimidazoles with alcohols and thiols under basic conditions affords carbamates and thiocarbamates, respectively, in good yields. Lastly, a method for the preparation of chiral oxazolidinone heterocycles from chiral epoxy alcohols is demonstrated using a double displacement approach. The reactions occur with high regio- and stereoselectivity (dr ≥ 15:1 by 1H NMR) via a domino attack of the corresponding alkoxides with carbamoylimidazoles followed by an intramolecular attack of the in situ generated urea anion at the proximal position of the epoxide group.

Development of Antibiotics That Dysregulate the Neisserial ClpP Protease.

Evolving antimicrobial resistance has motivated the search for novel targets and alternative therapies. Caseinolytic protease (ClpP) has emerged as an enticing new target since its function is conserved and essential for bacterial fitness, and because its inhibition or dysregulation leads to bacterial cell death. ClpP protease function controls global protein homeostasis and is, therefore, crucial for the maintenance of the bacterial proteome during growth and infection. Previously, acyldepsipeptides (ADEPs) were discovered to dysregulate ClpP, leading to bactericidal activity against both actively growing and dormant Gram-positive pathogens. Unfortunately, these compounds had very low efficacy against Gram-negative bacteria. Hence, we sought to develop non-ADEP ClpP-targeting compounds with activity against Gram-negative species and called these activators of self-compartmentalizing proteases (ACPs). These ACPs bind and dysregulate ClpP in a manner similar to ADEPs, effectively digesting bacteria from the inside out. Here, we performed further ACP derivatization and testing to improve the efficacy and breadth of coverage of selected ACPs against Gram-negative bacteria. We observed that a diverse collection of Neisseria meningitidis and Neisseria gonorrhoeae clinical isolates were exquisitely sensitive to these ACP analogues. Furthermore, based on the ACP-ClpP cocrystal structure solved here, we demonstrate that ACPs could be designed to be species specific. This validates the feasibility of drug-based targeting of ClpP in Gram-negative bacteria.

Mild double allylboration reactions of nitriles and acid anhydrides using potassium allyltrifluoroborate.

The double allylboration of nitriles and acid anhydrides to form bis-allyl amines and esters, respectively, can be achieved through the use of potassium allyltrifluoroborate in the presence of boron trifluoride etherate at room temperature. The method described is relatively mild, exhibits chemoselectivity to other electrophiles present, avoids the use of metals, and features the use of an operationally stable and robust potassium organotrifluoroborate reagent.