N-O tethered carbenoid cyclopropanation facilitates the synthesis of a functionalized cyclopropyl-fused pyrrolidine.

We report a facile approach to a cyclopropyl-fused pyrrolidine, which contains four stereogenic centers, by employing the N-O tethered carbenoid methodology. The synthesis was facilitated by the development of a direct Mitsunobu reaction of alcohols with N-alkyl-N-hydroxyl amides to give diazo precursors, which upon intramolecular cyclopropanation yielded a library of N-O containing cyclopropyl-fused bicyclic intermediates. Elaboration of the N-O moiety of one member of this library resulted in the formation of the desired pyrrolidine ring demonstrating the potential of this methodology for making cyclopropyl-fused heterocycles.

Nucleotide, c-di-GMP, c-di-AMP, cGMP, cAMP, (p)ppGpp signaling in bacteria and implications in pathogenesis.

For an organism to survive, it must be able to sense its environment and regulate physiological processes accordingly. Understanding how bacteria integrate signals from various environmental factors and quorum sensing autoinducers to regulate the metabolism of various nucleotide second messengers c-di-GMP, c-di-AMP, cGMP, cAMP and ppGpp, which control several key processes required for adaptation is key for efforts to develop agents to curb bacterial infections. In this review, we provide an update of nucleotide signaling in bacteria and show how these signals intersect or integrate to regulate the bacterial phenotype. The intracellular concentrations of nucleotide second messengers in bacteria are regulated by synthases and phosphodiesterases and a significant number of these metabolism enzymes had been biochemically characterized but it is only in the last few years that the effector proteins and RNA riboswitches, which regulate bacterial physiology upon binding to nucleotides, have been identified and characterized by biochemical and structural methods. C-di-GMP, in particular, has attracted immense interest because it is found in many bacteria and regulate both biofilm formation and virulence factors production. In this review, we discuss how the activities of various c-di-GMP effector proteins and riboswitches are modulated upon c-di-GMP binding. Using V. cholerae, E. coli and B. subtilis as models, we discuss how both environmental factors and quorum sensing autoinducers regulate the metabolism and/or processing of nucleotide second messengers. The chemical syntheses of the various nucleotide second messengers and the use of analogs thereof as antibiofilm or immune modulators are also discussed.

The Rhodium(II) Carbenoid Cyclization-Cycloaddition Cascade of alpha-Diazo Dihydroindolinones for the Synthesis of Novel Azapolycyclic Ring Systems.

Tandem carbonyl ylide formation-1,3-dipolar cycloaddition of alpha-diazo N-acetyl-tetrahydro-beta-carbolin-1-one derivatives occur efficiently in the presence of a dirhodium catalyst to afford bimolecular cycloadducts in high yield. The Rh(II)-catalyzed reaction also takes place intramolecularly to give products derived from trapping of the carbonyl ylide dipole with a tethered alkene. The power of the intramolecular cascade sequence is that it rapidly assembles a pentacyclic ring system containing three new stereocenters and two adjacent quaternary centers stereospecifically in a single step and in high yield.

Substitution and cyclization reactions involving the quasi-antiaromatic 2H-indol-2-one ring system.

The quasi-antiaromatic 2H-indol-2-one ring system is readily generated by treating a 3-hydroxy-substituted 1,3-dihydroindol-2-one with a Lewis acid. Stepwise addition of various pi-nucleophiles to the highly reactive 2H-indol-2-one system occurs smoothly to afford substituted oxindoles. The cyclization was also carried out in an intramolecular fashion to give spiro-substituted oxindoles in good yield.