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 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.

Tandem carbonyl ylide formation-1,3-dipolar cycloaddition of α-diazo N-acetyl-tetrahydro-β-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.

We have investigated 1,5-electrocyclic ring-closure reactions of conjugated esters with dimethyl diazoA C H T U N G T R E N N U N G malonate in the presence of [Cu(acac) 2 ] as catalyst. Our new protocol offers an easy entry to various polyfunctionalized g-lactones in high yields. Their subsequent derivatives may be used as valuable intermediates, especially in the synthesis of natural products and their analogues.

The [Cu(acac) 2 ]-catalyzed reactions of various a,b,g,d-unsaturated bis-ketones/bis-esters/bis-keto esters with dimethyl diazomalonate and ethyl diazoacetate were studied. Total steric/electronic convenience of the present reaction paths was investigated. Methoxy/nitro substituents in m-/p-positions on benzylidene biscarbonyls did not alter the general routes of the reactions, supporting concerted mechanism. Dihydrobenzoxepine/oxepine formation was sterically sensitive to the related pre-ring conformation, and dihydrofurans were effected by both charge control and steric factors.Helvetica Chimica Acta -Vol. 95 (2012) a ) Compound 15 was obtained as a 1 : 1 mixture of stereoisomers. b ) N/A: Not available.

The [Cu(acac) 2 ]-catalyzed reactions of a,b-unsaturated carboxamides with dimethyl diazomalonate yielded dihydrofuran derivatives by a 1,5-electrocyclic reaction at C(b), and butadiene derivatives by carbene addition reaction at C(a) (Schemes 4 and 5; Table). Phenyl substituents at the N-atom of the amides seem to be effective on the reaction pathways (Table).Introduction. -Carbene transfer to appropriate substrates is a highly versatile tool for the construction of carbon frameworks with increased functional and structural complexity. The formal [7], and other possible derivatives of them. These ring-closure reactions lead to structures frequently occurring in biologically active compounds [8] and extremely useful synthetic intermediates [9] since they can be readily converted to highly functionalized derivatives.We previously reported on [Cu(acac) 2 ]-catalyzed reactions of dimethyl diazomalonate (¼ dimethyl 2-diazopropanedioate; E 2 C¼N 2 ) with aminoenones (acac ¼ pentane-2,3-dionato). These reactions resulted in 1,5-cyclization and formal C(a)ÀH insertion products (see 2 and 3 in Scheme 1). In the case of anilino derivatives (R 1 or R 2 ¼ Ph), products 4 dominated the reaction resulting from an unusual formal insertion to the benzoyl moiety [10]. A probable mechanism for the formation of this novel 3-anilinonaphthalen-1(4H)-one compounds 4 [10] might be realized by a ring-opening reaction of the present benzoyl-substituted push-pull cyclopropane and participation of the present phenyl ring by subsequent loss of two H-atoms. It was the first time that we obtained a product with the loss of two H-atoms. Its final structure 4 was revealed by a crystallographic analysis.

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.

Several furyl/thiophenyl/N‐methylpyrrolyl cores having aldehyde/ketone/ene‐biscarbonyl/diene‐biscarbonyl functions at their 2‐positions were reacted with diazocarbonyl compounds in the presence of metal catalysts. Between the two possible reaction pathways which may take place either on the 2‐substituent of hetaryl or on the core structure, only one of them was dominant for each reaction depending on substituents. Accordingly, in the reaction of thiophene‐2‐carbaldehyde with diazo compounds we obtained epoxy derivatives. On the other hand, dimethyl diazomalonate and furyl‐ene‐diketo/N‐methylpyrrolyl‐ene‐diester yielded only novel dihydrofuran derivatives via [1,5]‐electrocyclic ring closure. However, the reactions of 2‐ene/diene‐diester functionalized furans with dimethyl diazomalonate resulted polymethoxycarboxylate‐substituted oxo‐polyenes chemo‐specifically in good yields.