Nucleophilic Cleavage Research Articles

Amino-containing donor-acceptor biaryls with lactone bridging units as three-state halochromic pi-expanded coumarins

This report describes the synthesis and study of two new amino-containing donor-acceptor lactone-bridged biaryls as pi-expanded, or benzannulated, coumarins based on the 6H-benzo[c]chromen-6-one (benzo[c]coumarin) structural unit. These fluorescent and planar compounds exhibit strong intramolecular charge transfer (ICT) through the conjugated biaryl unit via a diethylamino donor on one arene and either a nitro or cyano acceptor unit on the opposing arene. The ICT of these systems can be reversibly altered via two different stimuli: 1) addition of a strong base (hydroxide) results in nucleophilic cleavage of the lactone bridge which dramatically weakens ICT by disrupting conjugation between the individual arenes and 2) addition of a strong acid protonates the diethylamino donor unit, disrupting its ability to donate, thereby causing ICT to be attenuated. The presence of strong acid or base results in dramatic changes in optical absorption and emission properties of these systems which can be readily observed both spectroscopically and visually. Ultimately compounds containing the benzo[c]coumarin structural unit with amine donors could act as three-state halochromic molecular switches and dyes.

Comprehensive studies on building a scalable downstream process for mRNAs to enable mRNA therapeutics.

In recent years, mRNA-based therapeutics have been a fast-growing new class of biologics that can, in principle, encode any protein(s) directly in patients to treat various diseases. mRNA vaccines have been proven to work efficiently, have high potency, and can be rapidly developed and deployed, which is critical for a quick responses in the case of a pandemic. Such agile development is enabled by rapid synthesis of RNA in vitro using recombinant enzymes rather than relying on lengthy and complex cell culture processes. mRNA exhibits physical and chemical properties differing from protein-based therapeutics. It is highly negatively charged and the hydroxyl group makes mRNA less stable and more susceptible to hydrolysis and nucleophilic cleavage. This novel work shares comprehensive studies carried out to compare the performance of various mRNA purification strategies by considering its scalability and critical quality attributes. In addition, the paper provides insights on how to establish a scalable mRNA purification process that consists of ultrafiltration/diafiltration and chromatography steps with good recoveries. Alternative Oligo(dT) based columns were further explored aiming to improve total process recovery. With Oligo(dT) as a capture step, overall recoveries of 70% can be achieved for mRNAs studied here that encode anti-influenza immunoglobulin G monoclonal antibodies.

Aminoalkoxy-substituted coumarins: Synthesis and evaluation for reactivation of inhibited human acetylcholinesterase.

Reactivation of inhibited acetylcholinesterase remains animportant therapeutic strategy for the treatment of poisoning by organophosphorus compounds, such as nerve agents or pesticides. Although drugs like obidoxime or pralidoxime have been used with considerable success, there is a need for new substances capable of reactivating acetylcholinesterase with a broader scope and increased efficacy. Possible screening candidates must fulfill two fundamental requirements: They must (i) show an affinity to acetylcholinesterase well balanced between sufficient binding and competitive inhibition and (ii) facilitate the nucleophilic cleavage of the phosphorylated catalytic serine residue. We attached a variety of nonaromatic primary and secondary amines to a coumarin core through selected alkoxy side linkers attached at coumarin positions 6 or 7 to obtain a small set of possible reactivators. Evaluation of their inhibition and reactivation potential in vitro showed some activity with respect to acetylcholinesterase inhibited by cyclosarin.

4′‐Selenonucleosides: Regio‐ and Stereoselective Synthesis of Novel Ribavirin and Acadesine Analogs as Anti‐Hepatitis C Virus (HCV) Agents

AbstractIntrigued by the biological activity of 2′‐C‐methylribofuranosyl nucleosides, and ribavirin/acadesine, based on the bioisosteric rationale between oxygen and selenium, we herein report a design and synthesis of the 2′‐C‐methyl‐4′‐seleno‐ribavirin and ‐acadesine as potential anti‐HCV agents. The 2′‐C‐methyl 4′‐selenoribavirin was synthesized in a regio‐ and stereoselective manner and completely characterized through 2D NMR and X‐ray crystallography. While the 2′‐C‐methyl 4′‐selenoacadesine has been efficiently synthesized by utilizing purine‐ring opening/degradation procedure via nucleophilic cleavage of N3−C2 bond of a purine by ethylenediamine (EDA) as the key step.

Unprecedented copper(ii) coordination induced nucleophilic cleavage of a quinoxaline heterocycle: structural and computational studies

This research work deals with the unprecedented copper(ii) induced nucleophilic cleavage of a quinoxaline heterocycle with spectroscopic, structural and computational studies.

Nucleophilic Cleavage of the Ether Bond of Chlorex in the Chalcogenation with Diphenyl Dichalcogenides in the System Hydrazine Hydrate–KOH

The synthesis of unsymmetrical pincer ligands by reactions of diphenyl disulfide and diphenyl diselenide with bis(2-chloroethyl) ether in the system hydrazine hydrate–KOH was accompanied by the formation of 1,2-bis(phenylsulfanyl)ethane, 1,2-bis(phenylselanyl)ethane, and 1-(phenylselanyl)-2-(phenylsulfanyl)ethane as by-products with an overall yield of 23% as a result of nucleophilic cleavage of the C–O–C bond in the initial ether.

An example of green surfactant systems based on inherently biodegradable IL-derived amphiphilic oximes

Abstract Progress in the development of biodegradable ionic liquids (ILs) leads to designing green surfactant formulations for miscellaneous applications. In this work, we present synthesis of a series of novel IL-derived amphiphilic pyridinium oximes composed by octylamide tail linked to the headgroup by means of amide, 4-((hydroxyimino)methyl)-1-(2-(octylamino)-2-oxoethyl)pyridin-1-iumbromide, 4-PyC8), alanyl ((S)-4-((hydroxyimino)methyl)-1-(2-((1-(octylamino)-1-oxopropan-2-yl)amino)-2-oxoethyl) pyridin-1-ium bromide, 4-PyAlaC8), or phenylalanyl ((S)-2-((hydroxyimino)methyl)-1-(2-((1-(octylamino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)pyridin-1-ium bromide, 2-PyPheC8), S)-3-((hydroxyimino)methyl)-1-(2-((1-(octylamino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)pyridin-1-iumbromide, 3-PyPheC8), and (S)-4-((hydroxyimino)methyl)-1-(2-((1-(octylamino)-1-oxo-3-phenylpropan-2yl)amino)-2-oxoethyl) pyridin-1-ium bromide, 4-PyPheC8) moiety. Their biodegradability examined in the closed bottle test shown the dependence on the amino acid structure and follows the tendency Phe > Ala > amide. Phenylalanine-based oximes demonstrate >30% of degradation in the CBT after 42 days and can be considered as inherently degradable. The acid ionization constant (pKa) of studied oximes determined by means of UV–vis spectroscopy at 27 °C were found to be in the range from 8.00 to 9.00. The pKa,app values of oximes in the presence of cationic gemini surfactants, 12-4-12- and 16-10-16, change insignificantly whereas they shifted upwards in the presence of anionic surfactant SDS. The nucleophilic cleavage of organophosphorus triester PNPDPP under optimal concentration conditions of 4-PyC8 come about with half-life times 40 s under mild condition (pH 9.00). These results provide new information on control the green microorganized nucleophilic systems for chemical decontamination.

Synthesis and reactivity of precolibactin 886.

The clb gene cluster encodes the biosynthesis of metabolites known as precolibactins and colibactins. The clb pathway is found in gut commensal E. coli, and clb metabolites are thought to initiate colorectal cancer via DNA cross-linking. Here we report confirmation of the structural assignment of the complex clb product precolibactin 886 via a biomimetic synthetic pathway. We show that a α-ketoimine linear precursor undergoes spontaneous cyclization to precolibactin 886 upon HPLC purification. Studies of this α-ketoimine and the related α-dicarbonyl revealed that these compounds are unexpectedly susceptible to nucleophilic cleavage under mildly basic conditions. This cleavage pathway forms other known clb metabolites or biosynthetic intermediates and explains the difficulties in isolating fully mature biosynthetic products. This cleavage also accounts for a recently identified colibactin–adenine adduct. The colibactin peptidase ClbP deacylates synthetic precolibactin 886 to form a non-genotoxic pyridone, suggesting precolibactin 886 lies off-path of the major biosynthetic route.

Nucleophilic Cleavage of Lignin Model Compounds under Acidic Conditions in an Ionic Liquid: A Mechanistic Study.

A range of lignin model compounds were examined for their reactivity with hydrogen bromide in the ionic liquid N-butylpyridinium triflate. It was found that the ionic liquid enabled rapid reaction at both the hydroxy and methyl ether sites of the model compounds at room temperature. Reactions at the phenyl ether moieties were more complex; rather than facilitating cleavage at these sites, alternate breakdown products that had not been seen in previous studies were observed; these products are consistent with functionalisation of the aromatic components of the model compounds.

Synthesis and characterization of click-decahydrodecaborate derivatives by the copper(I) catalyzed [3+2] azide-alkyne cycloaddition reaction

A facile and rapid access to a wide range of novel 1,2,3-triazoles bearing closo-decahydrodecaborate anion [B10H10]2− has been developed through an efficient general synthetic approach. It is based on the nucleophilic cleavage of 2-tetrahydrofuranium decaborate with sodium azide to form the known [B10H9O(CH2)4N3]2−. This azide derivative obtained reacted with various linear alkynes (phenylacetylene, 5-chloro-1-pentyne, heptyne, octyne, N-Boc-propargylamine and diethyl acetylenedicarboxylate) by the copper(I) catalyzed [3 + 2] azide-alkyne cycloaddition reaction (CuAAC) to form click-decaborate derivatives. In absence of copper and with strained cycloalkynes, the reaction is a strain-promoted cycloalkyne-azide cycloaddition (SPAAC). All click-decaborate derivatives were obtained in pure form with high yields and characterized by 11B, 1H and 13C NMR, MS-ESI, and Atomic Absorption.

Cyanopivaloyl Ester in the Automated Solid-Phase Synthesis of Oligorhamnans.

The development of effective protecting group chemistry is an important driving force behind the progress in the synthesis of complex oligosaccharides. Automated solid-phase synthesis is an attractive technique for the rapid assembly of oligosaccharides, built up of repetitive elements. The fact that (harsh) reagents are used in excess in multiple reaction cycles makes this technique extra demanding on the protecting groups used. Here, the synthesis of a set of oligorhamnan fragments is reported using the cyanopivaloyl (PivCN) ester to ensure effective neighboring group participation during the glycosylation events. The PivCN group combines the favorable characteristics of the parent pivaloyl (Piv) ester, stability, minimal migratory aptitude, minimal orthoester formation, while it can be cleaved under mild conditions. We show that the remote CN group in the PivCN renders the PivCN carbonyl more electropositive and thus susceptible to nucleophilic cleavage. This feature is built upon in the automated solid-phase assembly of the oligorhamnan fragments. Where the use of a Piv-protected building block failed because of incomplete cleavage, PivCN-protected synthons performed well and allowed the generation of oligorhamnans, up to 16 monosaccharides in length.

Modified Atomic Orbital Overlap: Molecular Level Proof of the Nucleophilic Cleavage Propensity of Dinitrophenol-Based Probes.

Out of six possible positional isomers of dinitrophenol, only 2,4-DNP has been used extensively by many researchers for developing reactive molecular probes. But the question remains unanswered: why has only the 2,4-isomer emerged as a labile protecting group? To answer this question, six molecular probes using available DNP isomers were developed and investigated to evaluate the effect of the extent of atomic orbital overlap on their reactivity. We have proved for the first time at the molecular level that the o-NO2 group contributes less compared to the p-NO2 group toward the reactivity of 2,4-DNP-based probes. Crystal structure analysis revealed that the 2p orbital of N atom and the 2p orbital of the adjacent ring C atom to which the o-NO2 is attached are inclined at >30° to each other, leading to substantial reduction in π overlap (as these two p-orbitals loose coplanar state) resulting in a very weak -M effect of the o-NO2 group, whereas the 2p orbitals of the N atom of the p-NO2 group and the adjacent ring C atom are almost coplanar (11° inclined to each other), leading to strong π overlap. Hence, the p-NO2 group contributes largely toward the molecular reactivity through its -M effect.

C-Terminally modified peptides via cleavage of the HMBA linker by O-, N- or S-nucleophiles.

A large variety of C-terminally modified peptides was obtained by nucleophilic cleavage of the ester bond in solid phase linked peptide esters of 4-hydroxymethyl benzamide (HMBA). The developed methods provided peptides, C-terminally functionalized as esters, amides and thioesters, with high purity directly from the resin in a single reaction step. A comprehensive screening of the reaction conditions and scope for nucleophilic cleavage of peptides from the HMBA linker was performed.

Sulfur-assisted ring contraction of polyfluoroalkylthiopyran derivatives as a route to functionalized fluorine-containing thiophenes

A synthetic route to functionalized α-(polyfluoroalkyl)thiophenes based on the reactions of ring contraction of polyfluoroalkyl substituted thiopyran derivatives has been explored. Potent 6-membered precursors for the preparation of thiophenes were obtained by the addition of bromine to the double bonds of 2-chloro-2-(trifluoromethyl)-3,6-dihydro-2H-tetrahydrothiopyran and 6-(polyfluoroalkyl)-2H-thiopyrans. The reactions of the resulted 4,5-dibromo-2-chloro-2-(trifluoromethyl)tetrahydrothiopyrans and trans-3,4-dibromo-6-(polyfluoroalkyl)-3,4-dihydro-2H-thiopyrans with sodium acetate in acetic acid produced 2-(acetoxymethyl)-5-(polyfluoroalkyl)thiophenes. Base-catalyzed methanolysis of the acetoxymethyl derivatives allowed preparing the corresponding 2-(hydroxymethyl)-5-(polyfluoroalkyl)thiophenes. The mechanism, which includes formation and nucleophilic cleavage of thiiranium cations, has been suggested for the transformation of dibromothiopyran derivatives to substituted thiophenes.

Photoreaction of 3-Allyloxy-2-pentamethyldisilanylpyridine

It is well established that the photoreactions of phenyldisilanes proceed through four pathways: 1) formation of a silaethene, Si=C, 2) formation of a silatriene via 1,3-trimethylsilyl radical migration, 3) elimination of a silylene, and 4) nucleophilic cleavage of a Si-Si bond in the photoexcited state since the first report on the photolysis of phenylpentamethyldisilane and (p-tolyl)pentamethyldisilane by Ishikawa et al. in 1975. However, relatively little is known about the photoreactions of ortho-substituted phenylpentamethyldisilanes. Recently, we have found that the photoreactions of various ortho-substituted phenylpentamethyldisilanes afforded the novel intramolecular photoproducts via silatriene intermediates. As part of our ongoing investigations for the organic synthesis of silicon-having heterocyclic compounds, we were, now, interested in the pyridine ring instead of the phenyl ring as an aromatic ring. And, we would like to report detailed photochemical investigations of 3-allyloxy-2-pentamethyldisilanylpyridine 2, aza analogue of (2-allyloxyphenyl)pentamethyldisilane, since novel photoproducts from the photoreaction of 2 via new intermediates are expected. The starting 3-allyloxy-2-pentamethyldisilanylpyridine 2 was prepared by the reaction of pentamethyldisilanyl chloride with 3-allyloxy-2-pyridyl magnesium bromide in tetrahydrofuran as shown in Scheme 1. In this reaction, a compound 3 formed from the allyl group cleavage of 2 was also obtained. Irradiation of 2 in deaerated benzene with 300nm UV light afforded a novel photoproduct 4 (9%yield) in addition to 5 (15%yield) along with several decomposition products of unknown structure as shown in Scheme 1, when 92% of 2 was photolyzed. Indeed, the atomic charges of 2-, 3-, and 4pyridyl radical site (+0.015, −0.268, and −0.007, respectively) have been calculated at the BPW91/cc-pVDZ// BPW91/cc-pVDZ. In this paper, it is revealed that 2pyridyl radical with a partial positive charge behaves like an electrophilic radical, but 3and 4-pyridyl radical behave like a nucleophilic radical. And, the relative energies of 2-, 3-, and 4-pyridyl radical (0, 26, and 21 kJ/mol, respectively) have been calculated by G3B3. Therefore, it is revealed that 2-pyridyl radical is more stable than the 4-isomer, which is in turn more stable than 3-isomer in this paper. These above results suggested that the photoproduct 4 is formed from the reaction of electrophilic silylene and 2 mol of nucleophilic, unstable 3-pyridyl radical 9, formed via 1,4radical shift from the electrophilic, stable 2-pyridyl radical 8 (Scheme 2). In this case, it is thought that the reaction of nucleophilic 4-pyridyl radical and electrophilic silylene was not occurred because of the steric hindrance of the allyoxy group. The formation of 5 is explained by the allyl group cleavage from the radical intermediates, 8 or 9 as shown in Scheme 2. The structure of the photoproduct 4 was determined by various physical methods. The H NMR spectrum of the photoproduct 4 shows the characteristic 3,5-disubstituted pyridine structure. The two protons (2 and 6 positions in the

New Members of a Class of Monomeric {Fe(NO)2}10 Dinitrosyliron Complexes and a Dimeric {Fe(NO)2}10–{Fe(NO)2}10 Dinitrosyliron Complex

AbstractThe monomeric {Fe(NO)2}10 dinitrosyliron complexes (DNICs) [K‐18‐crown‐6‐ether][(NO)2Fe(NC9H6‐NH)] (1), [K‐18‐crown‐6‐ether][(NO)2Fe(NC9H6‐O)] (2), and [K‐18‐crown‐6‐ether][(NO)2Fe(NC9H6‐S)] (3) containing [N,NH], [N,O], and [N,S] ligations were synthesized by displacing the N,N,N′,N′‐tetramethylethylenediamine (tmeda) group of {Fe(NO)2}10 (tmeda)Fe(NO)2 with quinolin‐8‐amide, quinolin‐8‐olate, and quinolin‐8‐thiolate, respectively. Anionic {Fe(NO)2}10 DNICs 1–3 were characterized by IR, 1H NMR, and UV/Vis spectroscopy and single‐crystal X‐ray diffraction. The binding affinity of the ligands (i.e., [NC9H6NH]–, [NC9H6O]–, and [NC9H6S]–) toward the {Fe(NO)2}10 fragment was also investigated, and ligand substitution was found to follow the order [NC9H6S]– > [NC9H6O]– > [NC9H6NH]–. Displacement of the tmeda group of (tmeda)Fe(NO)2 by [K‐18‐crown‐6‐ether][SC6H4‐o‐NH2] and [PPh4][SC6H4‐o‐NH2] afforded monomeric {Fe(NO)2}10 DNIC [K‐18‐crown‐6‐ether][(NO)2Fe(SC6H4‐o‐NH2)] (4) and dimeric {Fe(NO)2}10–{Fe(NO)2}10 DNIC [PPh4]2[(NO)2Fe(μ‐SC6H4‐o‐NH2)]2 (5), respectively. The function of the countercation in the formation of monomeric {Fe(NO)2}10 DNIC 4 or dimeric {Fe(NO)2}10–{Fe(NO)2}10 DNIC 5 was also demonstrated upon reduction of the {Fe(NO)2}9 DNICs [cation][(NO)2Fe(SC6H4‐o‐NH2)2] (6) {cation = K‐18‐crown‐6‐ether (6a), [PPh4] (6b)}. In contrast to the formation of thiolate‐containing {Fe(NO)2}9 DNICs through nucleophilic cleavage of the bridging thiolates of Roussin's red esters, the transformation of complexes 4 and 5 into complexes 6a and 6b, respectively, in the presence of disulfide provides a new synthetic pathway for the synthesis of thiolate‐containing {Fe(NO)2}9 DNICs.

2,2′-Dihydroxybenzophenones and their carbonyl N-analogues as inhibitor scaffolds for MDR-involved human glutathione transferase isoenzyme A1-1

The MDR-involved human GSTA1-1, an important isoenzyme overexpressed in several tumors leading to chemotherapeutic-resistant tumour cells, has been targeted by 2,2′-dihydroxybenzophenones and some of their carbonyl N-analogues, as its potential inhibitors. A structure-based library of the latter was built-up by a nucleophilic cleavage of suitably substituted xanthones to 2,2′-dihydroxy-benzophenones (5–9) and subsequent formation of their N-derivatives (oximes 11–13 and N-acyl hydrazones 14–16). Screening against hGSTA1-1 led to benzophenones 6 and 8, and hydrazones 14 and 16, having the highest inhibition potency (IC50 values in the range 0.18±0.02 to 1.77±0.10μM). Enzyme inhibition kinetics, molecular modeling and docking studies showed that they interact primarily at the CDNB-binding catalytic site of the enzyme. In addition, the results from cytotoxicity studies with human colon adenocarcinoma cells showed low LC50 values for benzophenone 6 and its N-acyl hydrazone analogue 14 (31.4±0.4μM and 87±1.9μM, respectively), in addition to the strong enzyme inhibition profile (IC50(6)=1,77±0.10μM; IC50(14)=0.33±0.05μM). These structures may serve as leads for the design of new potent mono- and bi-functional inhibitors and pro-drugs against human GTSs.

ChemInform Abstract: Electrophilic Intramolecular Cyclization of Functional Derivatives of Unsaturated Compounds. Part 4. Cyclosulfenylation of 5‐Hexenoic Acid Amides and Nucleophilic Cleavage of Reaction Products.

AbstractCompounds (I) react with arylsulfenyl chlorides (II) to give products of electrophilic cyclization (III).

Thermal Treatment of Cerium Oxide and Its Properties: Adsorption Ability versus Degradation Efficiency

Cerium oxide belongs to the most important heterogeneous catalysts, but its applicability as so-called reactive sorbent for the degradation of toxic chemicals was only recently discovered. For these purposes, cerium oxide is prepared by precipitation of insoluble cerium salts (carbonates) with a subsequent thermal decomposition. Properties of cerium oxide prepared from the carbonate precursor are strongly affected by the temperature during the calcination. Main physicochemical properties of cerium oxide (specific surface area, crystallinity, and surface chemistry) were examined in dependence on the calcination temperature. As the adsorptive properties of CeO2are undoubtedly of great importance in the abovementioned applications, the adsorption ability was studied using an azo dye Acid Orange 7 (AO7) as a model compound. The highest sorption efficiency towards AO7 exhibited sorbents prepared at temperatures below 700°C, which was attributed mainly to the presence of hydroxyl groups on the oxide surface. A strong correlation was found between an adsorption efficiency of cerium oxides and their degradation efficiency for organophosphate pesticide parathion methyl. The >Ce–OH groups on the sorbent surface are responsible for the dye binding by the surface-complexation mechanism, and probably also for the nucleophilic cleavage of the P–O–aryl bond in the pesticide molecule.

SYNTHESIS OF SUBSTITUTED 4-AMINOTHIENO[2,3- d ]-, 4-AMINOTHIENO[3,2- d ]- AND 4-AMINOTHIENO[3,4- d ]PYRIMIDINES

A study was carried out on the nucleophilic cleavage of the lactam bond in 4-amino(pyrrolidino, piperidino, morpolino)thieno[2,3- d ]-, -[3,2- d ]-, and -[3,4- d ]pyrimido[1,2-b]isoquinolin-11-ones. This bond is readily cleaved upon heating in methanolic NaOH at reflux for 1-2 h to give previously unreported 4-amino-2-(o-carboxyphenylmethyl)thienopyrimidines. Replacement of the amine group by an OH group is possible under the reaction conditions, leading to the corresponding, already reported 2-(o-carboxyphenylmethyl)-4-oxothienopyrimidines. Prolonged refluxing (8-12 h) resulted in oxothienopyrimidines as the major products of the transformations of all the thienopyrimido-isoquinolinones studied. Biological activity predictions of these new products were compared in silico . Author: A. V. Zadorozhny. English Translation in Chemistry of Heterocyclic Compounds , 2012, 48 (7), pp 1028-1032 http://link.springer.com/article/10.1007/s10593-012-1095-y