Design, synthesis, and evaluation of a novel bridged nucleic acid, 2′,5′-BNA, with S-type sugar conformation fixed by N-O linkage

We designed a novel 2′-O,5′-N bridged nucleic acid, 2′,5′-BNA^ON, whose sugar puckering was fixed to S-type conformation by an N-O linkage. A dimer unit formed from 2′,5′-BNA^ON-U and thymidine was synthesized via a coupling reaction between a protected 2′,5′-BNA^ON-U monomer and a thymidine derivative. Introduction of 2′,5′-BNA^ON-U into DNA was carried out using conventional phosphoramidite chemistry with a DNA synthesizer. The hybridization abilities of 2′,5′-BNA^ON-U-modified oligonucleotides against DNA or RNA complement were evaluated.     

N,N,N,N-Tetramethyl-1,3-propanediamine as the catalyst of choice for the Baylis-Hillman reaction of cycloalkenone: rate acceleration by stabilizing the zwitterionic intermediate via the ion-dipole interaction

N,N,N^′,N^′-Tetramethyl-1,3-propanediamine (TMPDA) can be used as an efficient catalyst for the Baylis-Hillman reaction of cycloalkenones. The increased reaction rate was thought be derived from the stabilizing effect of the zwitterionic intermediate via the ion-dipole interaction.     

An efficient, mild, and selective Ullmann-type N-arylation of indoles catalyzed by copper(I) complex

A wide range of N-arylated indoles are selectively synthesized through intermolecular C(aryl)-N bond formation from the corresponding aryl iodides and indoles through Ullmann-type coupling reactions in the presence of a catalytic amount of easily available N,N,N′,N′-tetramethyl-BINAM-CuI complex under very mild reaction conditions.     

Efficient synthesis of N,N′-dialkyl-N″-dialkylaminocarbothioyl thioureas from cyclic secondary amines, CS2, and N,N′-dialkyl carbodiimides in water

A mild, convenient, and practical one-pot procedure for direct synthesis of N,N′-dialkyl-N″-dialkylaminocarbothioyl thioureas is described via three-component reaction of cyclic secondary amines, CS₂, and N,N′-dialkyl carbodiimides in water at room temperature.     

An efficient convergent synthesis of adenosine-5′-N-alkyluronamides

Herein we report an efficient synthesis of adenosine-5′-N-alkyluronamides in which an enzyme-mediated deacetylation reaction is a key to the selective modification of the 5′-N-position, prior to coupling the ribose and purine components via a microwave-assisted Vorbrüggen coupling. This approach provides access to highly functionalised adenosines with 2- and N⁶-substitutents, which can be incorporated before or after the ribose-coupling step. In all cases the microwave-assisted Vorbrüggen coupling conditions afforded anomerically pure purine ribosides in good to excellent yields.     

A concise synthesis of asymmetrical N,N′-disubstituted guanidines

We present a new and concise method for the preparation of asymmetrical N,N′-disubstituted guanidines starting from thiourea via the reaction of N-Boc-protected N′-alkyl/aryl substituted thioureas with an amine in the presence of mercury(II) chloride and triethylamine.     

Synthesis of fluorinated imines and carbodiimides from azides via aza-Wittig reaction

The Staudinger reaction of fluoroalkylazides were studied. A series of N-fluoroalkylimines were synthesized via aza-Wittig reaction of N-fluoroalkyliminophosphoranes. The N,N′-difluoroalkylated carbodiimide was also synthesized via the reaction of N-fluoroalkyliminophosphoranes with carbon dioxide or carbon disulfide.     

Efficient synthesis of tetramethylsulfonylguanidines between a free sulfonamide group and HBTU

The reaction of a sulfonamide moiety with HBTU (O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) during amide coupling, leading to the formation of tetramethylsulfonylguanidines, is described. Optimised conditions showed that HBTU was as a convenient agent for the synthesis of tetramethylsulfonylguanidines, in basic conditions. A panel of diverse sulfonamides was used to demonstrate the scope of this procedure.     

Effects of solvent and base on the palladium-catalyzed amination: PdCl2(Ph3P)2/Ph3P-catalyzed selective arylation of primary anilines with aryl bromides

A readily accessible catalytic system, PdCl₂(Ph₃P)₂/Ph₃P, was developed for the selective arylation of primary anilines with aryl bromides. The strong influence of solvents and bases on the catalytic activity was observed. In refluxing o-xylene, triphenylphosphine shows high efficiency for Pd-catalyzed intermolecular amination reactions. By changing the bases, mono- and diarylation of primary amines could be selectively achieved in high yields. Moreover, the catalytic system showed good toleration for the steric hindrance of anilines. A series of N,N,N′,N′-tetraaryl-1,1′-biphenyl-4,4′-diamines, important intermediates of OLED hole transport materials, were synthesized facilely via coupling reactions between 4,4′-diaminobiphenyls and aryl bromides.     

The first synthesis of N,O-protected β-isoserines bearing two adjacent quaternary stereogenic centers and their corresponding β-lactams

The reaction of chiral (2S)-enolates of dioxolan-4-ones, derived from lactic and mandelic acids, with (S_R)-tert-butyl sulfinyl ketimines, derived from butan-2-one, pentan-2-one, and decan-2-one, afforded conformationally restrained β^2,2,3,3-isoserines bearing two adjacent quaternary stereogenic centers in the form of N-sulfinyl protected 1′-amino-dioxolan-4-ones. The selective acid-induced removal of the sulfinyl protecting group provided the corresponding 1′-aminodioxolanones, whose base-induced cyclization afforded the corresponding chiral tetra-substituted 3-hydroxy-β-lactams. The synthesis of a dipeptide by reaction coupling between the 1′-aminodioxolanone (2S,5R,1′R)-19 and N,N-dimethylglycine was successfully achieved.     

Copper-catalyzed N-arylation of oxindoles

The coupling of aryl bromides or iodides with oxindoles using a copper iodide-N,N′-dimethylethylene diamine system is presented. The reaction proceeds efficiently and tolerates a variety of substitution patterns.     

Highly stereoselective synthesis of 2′-deoxy-β-ribonucleosides via a 3′-(N-acetyl)-glycyl-directing group

A facile synthesis of 2′-deoxy-β-ribonucleosides from 3′-O-(N-acetyl)-glycyl-protected 2′-deoxyribofuranose has been developed. The coupling reactions between the protected 2′-deoxyribose and silylated bases exhibited β-selectivity up to 98% presumably via a 1′,3′-participation mechanism. The 3′-directing group can be introduced and removed easily under mild conditions. This approach provides an efficient and highly stereoselective entry for the synthesis of 2′-deoxy-ribonucleosides.     

A greener approach for the synthesis of 1-N-methyl-(spiro[2.3′]oxindolespiro[3.2″]/spiro[2.3′]indan-1,3-dionespiro[2.2″])cyclopentanone-4-aryl pyrrolidines

N,N-Dimethylammonium N′,N′-dimethyl carbamate (DIMCARB), a reusable reaction medium, has been used in the synthesis of a number of monoarylidene cyclopentanones. These compounds are used as dipolarophiles in the 1,3-dipolar cycloaddition reaction of an azomethine ylide, generated in situ by the decarboxylation method for the synthesis of spiropyrrolidines by the application of microwave methodology.     

Cu(I) mediated one-pot synthesis of azobenzenes from bis-Boc aryl hydrazines and aryl halides

N,N^′-bis-Boc aryl hydrazines underwent Cu(I) catalyzed couplings with aryl halides to provide N,N^′-bis-Boc diaryl hydrazines. The resulting N,N^′-bis-Boc diaryl hydrazines are readily oxidized to the azobenzenes in the presence of Cu(I) and a base. A prolonged heating of the initial coupling reactions directly provides the corresponding azobenzenes in one pot.     

Asymmetric syntheses of dihydroxyhomoprolines via doubly diastereoselective lithium amide conjugate addition reactions

The asymmetric syntheses of novel dihydroxyhomoprolines have been achieved using the doubly diastereoselective conjugate additions of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide to a set of four chiral α,β-unsaturated esters (derived from d-pentoses) as one of the key steps. A full account of the diastereoselectivity observed in these conjugate additions is presented and the stereochemical outcomes of these reactions have been established unambiguously via a combination of hydrogenolytic chemical correlation and single crystal X-ray diffraction analyses. A tandem hydrogenolysis/intramolecular reductive amination reaction was then used to create the corresponding enantiopure pyrrolidines, providing access to (2′S,3′S,4′R)-dihydroxyhomoproline and (2′S,3′R,4′S)-dihydroxyhomoproline after deprotection.     

Characterisation of N-vinyl-2-pyrrolidone-based hydrogels prepared by a Diels-Alder click reaction in water

N-vinyl-2-pyrrolidone-based hydrogels were prepared by the Diels-Alder reaction in water for the first time. Copolymers of N-vinyl-2-pyrrolidone(VP) and furfuryl methacrylate(FM) were synthesised by free radical polymerisation in toluene at 70 °C by using 2,2′-azobisisobutyronltrile as an initiator. Polymeric dienophile (PEG-AMI) was prepared from N-alaninyl maleimide (AMI) and poly(ethylene glycol) (PEG) by using N,N′-dicyclohexylcarbodiimide (DCC) as a dehydrating agent. The prepared dienes and dienophile were then dissolved in water and mixed, leading to gelation via Diels-Alder reaction after some time. The gelation times of different copolymers and PEG-AMI in different solvents and at different temperatures were measured by the vial inversion method, and the swelling behaviour of dried hydrogels was studied using a general gravimetric method. The gelation time was shorter in water than in organic solvents, and the gelation time decreased with the increase of temperature and FM content in copolymers. Conversely, the swelling ratios increased with the decrease of temperature and FM content in the copolymers. Disassembly experiments suggested that N,N-dimethylformamide (DMF) could accelerate the retro-DA reaction.     

An improved Ullmann-Ukita-Buchwald-Li conditions for CuI-catalyzed coupling reaction of 2-pyridones with aryl halides

An effective CuI-trans-N,N′-dimethylcyclohexane-1,2-diamine (DMCDA)-K₂CO₃-catalyzed coupling reaction of 2-pyridones with aryl halides is described. Under our conditions, DMCDA was found to be an effective catalyst that facilitates the coupling reactions even in toluene, a common industrial solvent. In addition, 3-bromopyridine could also be coupled effectively under these conditions, indicating that the catalytic reactivity of this system is high. The reaction could be applied for polymer modification and iterative oligo-pyridone synthesis.     

A quantum chemical study on the mechanism of chiral N-oxides-catalyzed Strecker reaction

The mechanism for the Strecker reaction of silyl cyanide (H₃SiCN) and benzaldehyde N-methylimine (PhCHNCH₃) catalyzed by chiral 3,3′-dimethyl-2,2′-bipyridine N,N′-dioxide was investigated using the density functional theory (DFT) at the B3LYP/6-31G* level. The calculations revealed that the non-catalyzed reaction proceeded in a concerted way via a five-membered ring transition state, while the catalytic one occurred stepwisely via a hexacoordinate hypervalent silicate intermediate. It was predicted that both non-catalyzed and catalytic Strecker reactions involved two competitive reaction pathways, that is, addition followed by isomerization or isomerization followed by addition. The calculations indicated that two reaction pathways were comparable for both non-catalyzed and catalytic Strecker reactions. In the catalytic reaction, the strong electron donor (N-O) of chiral N-oxide played an important role in enhancing the reactivity and nucleophilicity of H₃SiCN by coordinating O atom to the Si atom of H₃SiCN. Chiral N-oxide could be used as a good catalyst for the reaction, which was in agreement with the experimental observations.     

Synthesis, properties, and hepatic metabolism of strongly fluorescent fluorodipyrrinones

From non-fluorescent 8-H fluorophenyldipyrrinones, highly fluorescent (?_F 0.4-0.6) analogs have been synthesized by reaction with 1,1′-carbonyldiimidazole to bridge the dipyrrinone nitrogens and form an N,N′-carbonyldipyrrinone (3H,5H-dipyrrolo[1,2-c:2′,1′-f]pyrimidine-3,5-dione). Amphiphilic, water-soluble 8-sulfonic acid derivatives are then obtained by reaction with concd H₂SO₄. The resulting fluorinated and sulfonated N,N′-carbonyl-bridged dipyrrinones, isolated as their sodium salts, are potential cholephilic fluorescence and ¹⁹F MRI imaging agents for use in probing liver and biliary metabolism. After intravenous injection in the rat they were excreted rapidly and largely unchanged in bile. ¹⁹F NMR spectroscopy of a pentafluorophenyl-tosylpyrrolinone synthetic precursor exhibited rarely seen diastereotopicity.     

Novel monolithic enzymatic microreactor based on single-enzyme nanoparticles for highly efficient proteolysis and its application in multidimensional liquid chromatography

In this work, a novel and facile monolithic enzymatic microreactor was prepared in the fused-silica capillary via a two-step procedure including surface acryloylation and in situ aqueous polymerization/immobilization to encapsulate a single enzyme, and its application to fast protein digestion through a direct matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF-MS) analysis was demonstrated. At first, vinyl groups on the protein surface were generated by a mild acryloylation with N-acryloxysuccinimide in alkali buffer. Then, acryloylated enzyme was encapsulated into polyacrylates by free-radical copolymerization with acrylamide as the monomer, N,N′-methylenebisacrylamide as the cross-linker, and N,N,N′,N′-tetramethylethylenediamine/ammonium persulfate as the initiator. Finally, polymers were immobilized onto the activated inner wall of capillaries via the reaction of vinyl groups. Capability of the enzyme-immobilized monolithic microreactor was demonstrated by myoglobin and bovine serum albumin as model proteins. The digestion products were characterized using MALDI-TOF-MS with sequence coverage of 94% and 29% observed. This microreactor was also applied to the analysis of fractions through two-dimensional separation of weak anion exchange/reversed-phase liquid chromatography of human liver extract. After a database search, 16 unique peptides corresponding to 3 proteins were identified when two RPLC fractions of human liver extract were digested by the microreactor. This opens a route for its future application in top–down proteomic analysis.