Functionalization of bicyclic 2-pyridones targeting pilus biogenesis in uropathogenic Escherichia coli

Substituted bicyclic 2-pyridones, termed pilicides, prevent pilus assembly in uropathogenic Escherichia coli. Based on the bioactive methyl ester protected 2-pyridone 4, further functionalization at C-6 has yielded a set of new compounds, which have been evaluated for their ability to inhibit pilus formation in uropathogenic E. coli. The key intermediate in the synthesis was formylated 2-pyridone 5, which could be obtained via a Vilsmeier reaction. This versatile intermediate was converted into secondary and tertiary amines via reductive amination and could also be converted to other interesting functionalities using simple chemical transformations.     

An efficient organocatalytic method for tandem synthesis of functionalized 2-pyridones

Highly functionalized 2-pyridones are obtained via a tandem reaction between primary amines and acetylenic esters in the presence of N-methylimidazole as an organocatalyst.     

Selective synthesis of 2-pyridones and pyrimidine-2,4-diones by neutral rhodium(I) complex-catalyzed cyclocotrimerization of alkynes and isocyanates

A neutral rhodium(I) complex, ‘RhCl(PPh₃)₂’ generated by the combination of [RhCl(C₂H₄)₂]₂ with a fourfold amount of PPh₃, effectively catalyzed the cyclocotrimerization of alkynes (1) and isocyanates (2) to give 2-pyridones (3) and/or pyrimidine-2,4-diones (4), selectively, by controlling the molar ratio of alkynes (1) and isocyanates (2).     

A facile synthesis of novel tricyclic 4-pyridones

A new and efficient synthesis of tricyclic 4-pyridone analogs through the intramolecular Heck coupling cyclization was described. This reaction features mild conditions and good functional group tolerance allowing for the preparation of several novel tricyclic 4-pyridone analogs.     

Synthesis of substituted 3-methylene-2-pyridones from Baylis-Hillman derivatives and its application for the generation of 2-pyridone substituted spiroisoxazolines

The synthesis of substituted 3-methylene-2-pyridones via S_N2 displacement reaction of nucleophiles bearing a keto group on the acetyl derivative of Baylis-Hillman adducts of acrylonitrile followed by TFA/H₂SO₄-mediated intramolecular cyclization is described. The utility of these pyridone derivatives for the synthesis of new spiroisoxazolines in highly regio- and stereo-selective fashion is also illustrated. The structure of the spiroisoxazolines has been secured via X-ray crystallographic analysis.     

An enantioselective ketene-imine cycloaddition method for synthesis of substituted ring-fused 2-pyridinones

Previously, a method for the stereoselective synthesis of beta-lactams, starting from 2H-Delta(2)-thiazolines and Meldrum's acid derivatives, has been reported from our laboratory. We now report a new method for the synthesis of optically active, highly substituted ring-fused 2-pyridinones. This was discovered when 2-alkyl-Delta(2)-thiazolines and Meldrum's acid derivatives were treated with HCl(g) in benzene at 5 --> 78 degrees C. Further refinement of the synthetic protocol revealed that use of 1,2-dichloroethane as solvent at 0 --> 64 degrees C led to the desired 2-pyridinones in good yields and with excellent enantioselectivity. Use of these conditions allowed preparation of 2-pyridinones from several different Delta(2)-thiazolines and Meldrum's acid derivatives and may be a general route to 2-pyridinones.     

A new efficient enantioselective synthesis of malonylphenylalanyl and malonylmethylphenylalanyl derivatives suitable for solid phase peptide synthesis

A new synthesis of enantiomerically pure malonylphenylalanyl and malonylmethylphenylalanyl derivatives was developed in which the corresponding prochiral enamides were treated by asymmetric hydrogenation using the Rh(I)-(S,S)-Me-DuPHOS system. These unnatural amino acids were suitably protected and can be used in solid phase peptide synthesis.     

Direct,enantioselective synthesis of pyrroloindolines and indolines from simple indole derivatives

The (R)-BINOL·SnCl₄-catalyzed formal (3+2) cycloaddition between 3-substituted indoles and benzyl 2-trifluoroacetamidoacrylate is a direct, enantioselective method to prepare pyrroloindolines from simple starting materials. However, under the originally disclosed conditions, the pyrroloindolines are formed as mixtures of diastereomers, typically in the range of 3:1 to 5:1 favoring the exo-product. The poor diastereoselectivity detracts from the synthetic utility of the reaction. We report here that use of methyl 2-trifluoroacetamidoacrylate in conjunction with (R)-3,3′-dichloro-BINOL·SnCl₄ provides the corresponding pyrroloindolines with improved diastereoselectivity (typically ≥10:1). Guided by mechanistic studies, a one-flask synthesis of enantioenriched indolines by in situ reduction of a persistent iminium ion is also described.     

Improved enantioselective synthesis of natural striatenic acid and its methyl ester

This letter describes the improved and efficient enantioselective synthesis of natural striatenic acid, isolated from Cheilolejeunea serpentina, and its methyl ester starting from a readily available enantiopure building block.     

Highly enantioselective organocatalytic cascade reaction for the synthesis of piperidines and oxazolidines

The synthesis of piperidines and piperidines derivatives in enantiopure fashion has been a challenging goal for organic chemists. In this report we developed a nice cascade reaction for piperidine derivatives based in an amidomalonate Michael addition to enals followed by an intramolecular hemiaminal formation with good yields and enantioselectivities. Moreover we studied the ‘in situ’ intramolecular cyclization of this hemiaminals with alcohols forming fused piperidine-oxazolidines.     

Catalytic asymmetric synthesis of 3-hydroxyl-2-oxindoles via enantioselective Morita-Baylis-Hillman reaction of isatins

The enantioselective Morita-Baylis-Hillman reaction of acrylates to isatins was investigated for the first time, employing bifunctional phosphinothiourea organocatalysts based on chiral cyclohexane scaffold. The 3-hydroxyl-2-oxindole derivatives were obtained in excellent yields with moderate enantioselectivity (up to 69% ee) in the presence of 10 mol % catalyst 1b.     

Synthesis and evaluation of dihydroimidazolo and dihydrooxazolo ring-fused 2-pyridones—targeting pilus biogenesis in uropathogenic bacteria

Dihydrothiazolo ring-fused 2-pyridones have previously been shown to inhibit pilus assembly in uropathogenic Escherichia coli. Methods have now been developed to synthesize both dihydroimidazolo and dihydrooxazolo ring-fused 2-pyridones. To obtain the nitrogen analogs, Cbz-protected imidazolines were reacted with an acyl-Meldrum's acid derivative under acidic conditions. To prepare the oxygen analogs, a one-pot procedure was developed that allowed synthesis of dihydrooxazolo ring-fused 2-pyridones starting from acylated serine derivatives. After hydrolysis to their corresponding carboxylic acids and lithium carboxylates, biological evaluation revealed that the sulfur could be replaced by an oxygen atom and still maintains the ability to inhibit pilus assembly in uropathogenic E. coli. However, introducing a secondary amine instead of oxygen resulted in a substantial decrease in biological activity.     

Regio- and selective synthesis of 4,6-disubstituted-2-pyridones

Palladium catalysed regio- and stereoselective annulation of allenyl stannanes by β-iodo vinylic amides gives good yields of the corresponding 2-pyridones. This annulation probably occurs via a Stille reaction/cyclisation sequence.     

Facile synthesis of benzimidazole bearing 2-pyridone derivatives as potential antimicrobial agents

A series of benzimidazole bearing 2-pyridones 5a-k were synthesized and assessed in vitro for their activity as antimicrobial agents using the conventional broth dilution method. The results of the antimicrobial study revealed that compounds 5b, 5c, Sj and 5k exhibited substantial antibacterial activity while compound 5d emerged as amore potent antifungal agent compared to the standard drugs chloramphenicol and ketoconazole, respectively. It was observed that the presence of inductively electron withdrawing groups remarkably enhance the antibacterial activity of the newly synthesized compounds. Cytotoxicity studies suggested that none of the tested compounds exhibited any significant cytotoxic effects.     

First enantioselective synthesis of (−)-neplanocin F

(−)-Neplanocin F, the natural isomer of a component of the neplanocin family was enantioselectively synthesized starting from d-γ-ribonolactone. The synthetic approach was based on the preparation of a suitable carbocyclic precursor bearing three hydroxyl groups orthogonally protected. The key steps of the synthesis were the regioselective protection of a secondary allylic alcohol over a homoallylic one and the coupling of the nucleobase with a triflate intermediate.     

Highly enantioselective synthesis of 3-cycloalkanone-3-hydroxy-2-oxindoles, potential anticonvulsants

Highly enantioselective catalytic synthesis of 3-cycloalkanone-3-hydroxy-2-oxindoles was achieved by using primary-tertiary diamine-Brønsted acid catalyst in both organic medium and aqueous medium. The products, thus obtained act as potential anticonvulsants.     

Cyanoacetanilides intermediates in heterocyclic synthesis. Part 6: Preparation of some hitherto unknown 2-oxopyridine,bipyridine, isoquinoline and chromeno[3,4-c]pyridine containing sulfonamide moiety

Treatment of cyanoacetanilide derivative 1 with tetracyanoethylene (2) in dioxane/triethylamine furnished 2-pyridone derivative 6. Aminopyridine 9 was obtained by cyclization of compound 1 with ketene dithioacetal 7/EtONa. Cyclocondensation of 1 with malononitrile and/or acetylacetone (1:1 M ratio) gave pyridine derivatives 11 and 13. Ternary condensation of compound 1, aliphatic aldehydes and malononitrile (1:1:1 M ratio) yielded the 2-pyridones 20a and b. Bipyridines 22a–c were prepared by refluxing of compound 21 with active methylene reagents. Cyclization of chromene derivatives 24 and 28 with malononitrile produced the novel chromeno[3,4-c]pyridine 26 and pyrano[3′,2′:6,7]chromeno[3,4-c]pyridine 29.     

Regio- and enantioselective synthesis of functionalized tetrahydroquinolines by palladium-catalyzed cyclization of 2-amidophenylmalonates with allylic bisacetates

A palladium-catalyzed cyclization of 2-amidophenylmalonates with allylic bisacetates is described. Tetrahydroquinolines having a vinyl group at the 3- or 2-position were produced, in which the regioselectivity of the resulting products was altered depending on the substituent on the amino group. The product was transformed to the azabicyclo[3.3.1]nonene via the ring-closing metathesis. Enantioselective reactions also successfully proceeded in the presence of (S)-BINAP to give the optically active tetrahydroquinoline with high enantioselectivity.     

The enantioselective synthesis of tetracyclic methyllycaconitine analogues

A new enantioselective synthesis of ABEF ring analogues of methyllycaconitine has been developed using a chiral cobalt(III) salen-catalyzed Diels-Alder reaction to form the B ring. Subsequent elaboration to form the A, E and F rings was achieved by sequential Dieckmann, Mannich and Wacker-type cyclizations to afford tetracyclic analogues in 97.5% ee.     

A new construction for a potentiometric, enantioselective membrane electrode--its utilization to the S-captopril assay

A novel potentiometric, enantioselective membrane electrode based on graphite paste (graphite powder and paraffin oil) has been constructed. The graphite paste is impregnated with 2-hydroxy-3-trimethylammoniopropyl-beta-cyclodextrin (as chloride salt) solution, 10(-3) mol l(-1). The potentiometric, enantioselective membrane electrode can be used reliable for S-captopril assay as raw material and from Novocaptopril tablets, using a chronopotentiometry (zero current) technique, in the 10(-6)-10(-2) mol l(-1) concentration range (detection limit 2 x 10(-7) mol l(-1)), with an average recovery of 99.99% (RSD=0.05%). The enantioselectivity was determined over R-captopril and D-proline. The response characteristics of the enantioselective, potentiometric membrane electrode were determined also for R-captopril. It was shown that only L-proline is the main interfering compound. The surface of the electrode can be regenerated by simply polishing, obtaining fresh surface ready to be used in a new assay.