Tosyl Derivatives Research Articles

Total Synthesis of Neuroprotective Agents, (+)-Lycibarbarine A and (-)-Lycibarbarine B.

We describe the convergent total syntheses of lycibarbarines A and B which are potent neuroprotective agents recently isolated from the fruits of Lycium barbarum. The synthesis highlights the construction of a unique spiro oxazine heterocyclic motif imbedded in these natural products. The synthesis is accomplished from the commercially available 8-hydroxyquinaline and 2-deoxy-d-ribose as key starting materials. The synthesis features a Reimer-Tiemann reaction, selective amine alkylation with a keto tosylate derivative, and spiroketalization to form an oxazine core.

Synthesis and Evaluation of 1-hydroxybenzotriazole Derivatives: Dual Inhibitors of Carbonic Anhydrase II and Sodium Hydrogen Exchanger I

Ischemia reperfusion injury is responsible for impaired graft functioning in organ transplants, cerebral dysfunction, ischemic heart diseases, systemic inflammatory response syndrome, gastrointestinal dysfunction, and multiple organ dysfunction syndromes. Intracellular pH is critical for cell survival in ischemia reperfusion injury. Sodium hydrogen exchanger I and carbonic anhydrase II are critical in the regulation of intracellular pH. Inhibition of sodium hydrogen exchanger I and carbonic anhydrase II during reperfusion is found to ameliorate ischemia reperfusion injury separately. An attempt is made to synthesize dual inhibitors of sodium hydrogen exchanger and carbonic anhydrase to have better potential drug molecule in ischemia reperfusion injury treatment. The hydroxybenzotriazole is considered as a central pharmacophore for this dual activity and 12 derivatives are synthesized. All derivatives are tested for sodium hydrogen exchanger I and carbonic anhydrase II inhibitory activity. The tosylate derivative (12) is found to be the most potent derivative with IC50 158.7± 8.4 μM for carbonic anhydrase II and 31.07 ± 1.06 μM for sodium hydrogen exchanger I. Although the potency is less than standard drugs but this is the first report of dual inhibitor of carbonic anhydrase II and sodium hydrogen exchanger.

Synthesis of Morpholine-Based Analogues of (-)-Zampanolide and Their Biological Activity.

We describe the convergent synthesis of three prototypical examples of a new class of analogues of the complex, cytotoxic marine macrolide (-)-zampanolide that incorporate an embedded N-substituted morpholine moiety in place of the natural tetrahydropyran ring. The final construction of the macrolactone core was based on a high-yielding intramolecular HWE olefination, while the hemiaminal-linked side chain was elaborated through a stereoselective, BINAL-H-mediated addition of (Z,E)-sorbamide to a macrocyclic aldehyde precursor. The synthesis of the common functionalized morpholine building block involved two consecutive epoxide openings with tosylamide and the product of the first opening reaction, respectively, as nucleophiles. Of the three morpholino-zampanolides investigated, the N-acetyl and the N-benzoyl derivatives both exhibited nanomolar antiproliferative activity, thus being essentially equipotent with the natural product. In contrast, the activity of the N-tosyl derivative was significantly reduced.

Synthesis, identification and molecular docking studies of N-functionalized piperidine derivatives linked to 1,2,3-triazole ring

New derivatives of piperidine bearing a 1,2,3-triazole ring designed and synthesized smoothly over six steps from N-protected piperidone-4-one. These steps included reduction of the carbonyl group/tosylation of the resulting alcohol providing tosyl derivative in a good yield, followed by nucleophilic substitution and Cu-catalysed azide-alkyne cycloaddition. By removing the protecting group and functionalizing amine group via reductive amination gave the desired design in moderate to very good yields. Molecular modeling studies of these compounds predicted possible binding modes into the active site of dopamine receptor D2.

Synthesis and cholinesterase inhibiting potential of A-ring azepano- and 3-amino-3,4-seco-triterpenoids

In this study, a series of A-ring azepano- and 3-amino-3,4-seco-derivatives were synthesized from betulin, oleanolic, ursolic and glycyrrhetinic acids aiming to develop new cholinesterase inhibitors. Azepanobetulin, azepanoerythrodiol and azepanouvaol were modified to give amide and tosyl derivatives, while azepano-anhydrobetulines and azepano-glycyrrhetols were obtained for the first time. Oleanane and ursane type 3-amino-3,4-seco-4(23)-en triterpenic alcohols were synthesized by reducing the corresponding 2-cyano-derivatives accessible from Beckmann type 2 rearrangements. The compounds were screened in colorimetric Ellman’s assays to determine their ability to act as inhibitors for the enzymes acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum). While most of these compounds were only moderate inhibitors for AChE, several of them were shown to be inhibitors for BChE acting as mixed-type inhibitors. Azepanobetulin 1, its C28-amide derivatives 7 and 8, azepano-11-deoxo-glycyrrhetol 12 and azepanouvaol 18 held inhibition constants Ki ranging between 0.21 ± 0.06 to 0.68 ± 0.19 μM. Thus, they were approximately 4 to 10 times more active than standard galantamine hydrobromide. For all of the compounds reasonably high docking scores for BChE were obtained being in good agreement with the experimental results from the enzymatic studies. As a result, A-ring azepano-triterpenoids were found to be new scaffolds for the development of BChE inhibitors.

Synthesis, Properties, and Biodegradation of Sequential Poly(Ester Amide)s Containing γ-Aminobutyric Acid.

Poly(ester amide)s are attracting attention because they potentially have excellent thermal and mechanical properties as well as biodegradability. In this study, we synthesized a series of novel poly(ester amide)s by introducing γ-aminobutyric acid (GABA) regularly into polyesters, and investigated their properties and biodegradabilities. GABA is the monomer unit of biodegradable polyamide 4 (PA4). The new poly(ester amide)s were synthesized from the reaction of ammonium tosylate derivatives of alkylene bis(γ-aminobutylate) and p-nitrophenyl esters of dicarboxylic acids. All the obtained polymers showed relatively high melting temperatures (Tm). Their thermal decomposition temperatures were improved in comparison with that of PA4 and higher enough than their Tm. The poly(ester amide)s exhibited higher biodegradability in seawater than the corresponding homopolyesters. Their biodegradabilities in activated sludge were also studied.

Selected arylsulphonyl pyrazole derivatives as potential Chk1 kinase ligands\u2014computational investigations

Protein kinases control diversity of biochemical processes in human organism. Checkpoint 1 kinase (Chk1) is an important element of the checkpoint signalling pathways and is responsible for DNA damage repair. Hence, this kinase plays an essential role in cancer cells survival and has become an important target for anticancer agents. Our previous investigations showed that some arylsulphonyl indazole derivatives displayed anticancer effect in vitro. In the present study, in order to verify possibility of interactions of pyrazole and indazole derivatives with Chk1, we focused on the docking of selected tosyl derivatives of indazole and condensed pyrazole 1–7 to the Chk1 pocket, analysis of interactions involving optimized ligand–protein system using DFT formalism, and estimation of the interaction enthalpy of the ligand–protein complex by applying the PM7 method. The estimation of binding affinity seems to indicate that the indazole 5-substituted with 3,5-dimethylpyrazole 4 and condensed pyrazoloquinoline derivative 7 fit the best to the Chk1-binding pocket. The values of the energy of interaction, i.e. the enthalpy change (ΔHint), were between − 85.06 and − 124.04 kcal mol−1 for the optimized ligand–Chk1 complexes. The relaxation of the ligands within the complexes azole–protein as well as the distribution of hydrogen contacts between the ligands and kinase pocket amino acids was also analysed using molecular dynamics as a supporting method.Graphical Presentation of methods used to describe the interactions between arylsulphonyl pyrazole derivatives and Chk1 kinase

Synthesis of 1-(4-hydroxy-3-methoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid derivatives as mast cell stabilizers

The role of mast cells can be protective or harmful; depending upon the physiological/pathological condition in which they get activated. The latter role is due to mast cell degranulation and release of an array of incendiary mediators. Mast cells have a well-established role in diseases like allergy, eczema, anaphylactic shock, mastocytosis, and other miscellaneous mast cell diseases. Previously, we have shown that spiro-β-carboline alkylated analogs have mast cells stabilization activity. Recently, tryptophan has been reported to suppress the mast cell activation. Indeed, vanillin analogs were reported to inhibit degranulation. Hence, it is worthwhile to synthesize 21 constrained analogs of tryptophan with vanillin which are derivatives of 2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid and their evaluation for ex-vivo inhibition of the compound 48/80 induced mast degranulation activity. By comparing IC50 (µM) values with standard drug cromolyn sodium (IC50 = 0.486 ± 0.003 µM), the bulky group compounds like tri-substituted isopropyl (compound 7; cis-1-(4-Isopropoxy-3-methoxyphenyl)-2,9-diisopropyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid; IC50 = 0.389 ± 0.015 µM) and tri-substituted octyl (compound 17; cis-1-(3’-Methoxy-4’-(octyloxy)phenyl)-2,9-dioctyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid; IC50 = 0.237 ± 0.031 µM) were found to be equipotent. Furthermore, the polar group SO2 containing compound tosyl derivative (compound 21; cis-1-(4’-hydroxy-3’-methoxyphenyl)-2-tosyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid; IC50 = 1.16 ± 0.080 µM) also showed marked potency. This is an important study of β-carboline derivatives showing mast cell stabilization having a wider scope in mast cell research, although their mechanism remains to be unknown.

Molecular Structures Polymorphism the Role of F…F Interactions in Crystal Packing of Fluorinated Tosylates

The peculiarities of interatomic interactions formed by fluorine atoms were studied in four tosylate derivatives p-CH3C6H4OSO2CH2CF2CF3 and p-CH3C6H4OSO2CH2(CF2)nCHF2 (n = 1, 5, 7) using X-ray diffraction and quantum chemical calculations. Compounds p-CH3C6H4OSO2CH2(CF2)nCHF2 (n = 1, 5) were crystallized in several polymorph modifications. Analysis of intermolecular bonding was carried out using QTAIM approach and energy partitioning. All compounds are characterized by crystal packing of similar type and the contribution of intermolecular interactions formed by fluorine atoms to lattice energy is raised along with the increase of their amount. The energy of intra- and intermolecular F…F interactions is varied in range 0.5–13.0 kJ/mol. Total contribution of F…F interactions to lattice energy does not exceed 40%. Crystal structures of studied compounds are stabilized mainly by C-H…O and C-H…F weak hydrogen bonds. The analysis of intermolecular interactions and lattice energies in polymorphs of p-CH3C6H4OSO2CH2(CF2)nCHF2 (n = 1, 5) has shown that most stabilized are characterized by the least contribution of F…F interactions.

Interaction of β-cyclodextrin with tosyl chloride in an aqueous alkaline medium

The regioselective functionalisation of the cyclodextrin matrix provides the possibility of purposefully altering the ability of cyclodextrins to form inclusion compounds, as well as to ensure their solubility, thus expanding the scope of their practical application [1, 2]. The most significant and promising trend in the selective modification of β-cyclodextrins consists in the preparation of tosyl derivatives, given that the substitution of such nucleophilic reagents as iodide, azide, thioacetate, hydroxylamine, alkylamide or polyalkylamide for the tosyl group results in the corresponding monosubstituted derivatives. In this study, we impl emented a method for the synthesis of mono-6-O-(p-toluenesulphonyl)-β-cyclodextrin, which was improved by β-cyclodextrin reacting with tosyl chloride in an aqueous medium in the presence of a base. The reaction of β-cyclodextrin with tosyl chloride in an aqueous alkaline medium produced a 58% yield of mono -6- O-(p-toluenesulphonyl)-β-cyclodextrin not requiring additional purification. The optimal concentrations of β-cyclodextrin and tosyl chloride were found to be 0.0032 mol/l and 0.0015 mol/l, respectively. It was shown that a decrease in the rate of filtering the unreacted tosyl chloride out of the reaction mixture is acc ompanied by an increase in the proportion of ditosyl derivatives and mono(3,6-anhydro)-β-cyclodextrin resulting from the intramolecular cyclisation of mono-6-O-(p-toluenesulphonyl)-β-cyclodextrin at room temperature under alkaline conditions. The structure of the obtained mono-6-O-(p-toluenesulphonyl)-β-cyclodextrin was confirmed using Proton NMR Spectroscopy. The proton NMR spectrum of the product resulting from the reaction of β-cyclodextrin with tosyl chloride contains signals corresponding to a tosyl radical: a singlet (2.42 ppm) and two doublets (7.41–7.43 ppm) produced by hydrogens of the benzene ring having radicals in the para position. Monosubstitution was confirmed by comparing the integrated intensities of signals produced by the protons of the cyclodextrin skeleton and the protons from the aromatic part of the reaction product. Their ratio indicated that only one of the seven primary hydroxyl groups of β-cyclodextrin was substituted.

Metal-free C(sp3)-H bond sulfonyloxylation of 2-alkylpyridines and alkylnitrones.

Pyridin-2-ylmethyl tosylate derivatives are obtained in high yields from 2-alkylpyridine 1-oxides via a [3,3]-sigmatropic rearrangement of the adduct between 2-alkylpridine 1-oxides with benzenesulfonyl chlorides. Moreover, alkylnitrones also undergo [3,3]-sigmatropic rearrangement to give α-tosylated ketones after hydrolysis. Substitution reactions with nucleophiles then lead to diverse useful functionalizations for the synthesis of pincer ligands.

Development and optimization of a new synthetic process for lorcaserin

A two-step process to synthesize racemic lorcaserin was developed from 2-(4-chlorophenyl)ethanol via formation of bromide or tosylate derivatives. These derivatives were reacted with allylamine in neat conditions to provide pure N-(4-chlorophenethyl)allylammonium chloride. This compound was cyclized in neat conditions using aluminum or zinc chloride to give racemic lorcaserin. After resolution of enantiomers, the wrong enantiomer was racemized and recycled to give new R-lorcaserin.

Efficient synthesis of 9-(4-[18F]fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG) and 9-[(3-[18F]fluoro-1-hydroxy-2-propoxy)methyl]guanine ([18F]FHPG)

A new, high radiochemical yield synthesis of [18F]FHBG and [18F]FHPG, the most popular imaging agents currently in use for monitoring gene therapy using positron emission tomography (PET), is reported in this work. Protection of sensitive sites in the precursors generally utilized for the preparation of [18F]FHBG and [18F]FHPG using the nucleophilic 18F-fluorination reaction was found to be critical for good radiochemical yields, reliability and reproducibility of the synthetic process. As an initial approach, protection at O6-oxygen in the guanine moiety of the currently used monomethoxytrityl-protected penciclovir tosylate derivative 9 with carbamoyl groups was carried out. Subsequently, full protection of both O6-oxygen and N2-nitrogen in the monomethoxytrityl-protected penciclovir and ganciclovir tosylate analogs 9 and 10 were achieved by their reaction with di-tert-butyl dicarbonate, which resulted in O6-tert-butyl-N2-Boc-monomethoxytrityl-protected penciclovir tosylate 18 and O6-tert-butyl-N2-Boc-monomethoxytrityl-protected ganciclovir tosylate 19, respectively. The newly synthesized carbamoyl- and the Boc- protected precursors were first reacted with non-radioactive KF complexed with Kryptofix 222 to isolate the fluorinated products. Acid hydrolysis of the purified fluorinated intermediates provided the nucleosides FHBG and FHPG. Full characterization of the new precursors as well as the products obtained by fluorination and hydrolysis reactions were carried out by one- and two-dimensional NMR spectroscopy and high resolution mass spectrometry. Single crystal X-ray crystallographic analysis of a model ganciclovir analog 22 confirmed the structural characterization of the new Boc-protected tosylate precursors 18 and 19 by NMR spectroscopy. The carbamoyl- and the Boc-protected precursors were further subjected to radiofluorination followed by acid hydrolysis reactions to furnish [18F]FHBG and [18F]FHPG reliably and reproducibly in excellent radiochemical yields (>65%), much higher than those previously achieved.

Understanding the fragmentation mechanisms of methoxy-, mesyl-, and tosyl-lapachol derivatives by computational chemistry and mass spectrometry analysis

Quinone derivatives are promising anticancer, antimalarial, and antileishmanial drug candidates. Lapachol is the main natural quinonoid compound studied to date. The synthesis of lapachol (2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone) derivatives can help characterization of these compounds in biological matrixes or extracts, particularly by electrospray ionization tandem mass spectrometry (ESI–MS/MS). The synthesized 2-methoxy-, 2-tosyl- and 2-mesyl- derivatives were protonated and fragmented by collisional-induced dissociation (CID); their fragmentation mechanisms were proposed based on CID results and DFT calculations. Quantum Theory of Atoms-in-Molecules, QTAIM, was performed and the bond weakening/reinforcement from bond critical point analysis of electronic densities was used to suggest the fragmentation pathways.Results herein were compared to data previously reported for lapachol (2-hydroxy-1,4-naphthoquinone). The tosyl derivative underwent an interesting fragmentation mechanism, which was comparable to the mechanism undergone by protonated lapachol. Therefore, identifying these compounds by the product-ions produced during ESI–MS/MS spectrometry is feasible.

Ultrasound-Promoted Synthesis of 4-Pyrimidinols and Their Tosyl Derivatives

Ultrasound irradiation promoted the cyclocondensation of β-keto esters and amidines in good to excellent yields to form sixteen highly substituted 4-pyrimidinols. Tosylation of these compounds, in another ultrasound-promoted conversion, formed 4-pyrimidyl tosylates in high yields. The use of the developed protocol as an alternative route to 4-arylpyrimidines was illustrated with three examples of the Suzuki–Miyaura cross-coupling of the prepared tosylates with phenylboronic acid.

4-Aryl-Pyrimidin-2-Yl Tosylates as Efficient Reaction Partners: Application to the Synthesis of Pyrimidines Functionalised with Propargyloxy and 1,2,3-Triazolo Groups

The 4-arylated pyrimidin-2-yl tosylate derivatives, easily prepared from cheap commercial materials, reacted efficiently with propargyl alcohol/NaOBut to give the corresponding 4-arylated 2-propargyloxy-pyrimidine derivatives which, in a one-pot reaction catalysed by CuSO4·5H2O/sodium ascorbate, reacted with NaN3 and hexyl or benzyl bromide to give a series of 2-(1-hexyl- or 1-benzyl-1,2,3-triazol-4-yl)methoxy-pyrimidine derivatives in good yields.

Synthesis of N-(2-(Methylamino)ethyl) Derivatives of 2H-Phthalazin-1-ones

A series of new alkyl, tosyl, acetyl, and tert-butoxycarbonyl derivatives of 2-(2-aminoethyl)-phthalazinones were efficiently synthesized by reaction of lactams with N-Boc-, N-acetyl-, or N,O-ditosyl derivatives of N-methylethanolamine in the presence of MeONa or under Mitsunobu reaction conditions. Selected compounds were converted into corresponding 2-[2-(methylamino)ethyl]phthalazinones in good yields.

Facile synthesis of 1-alkoxy-1H-benzo- and 7-azabenzotriazoles from peptide coupling agents, mechanistic studies, and synthetic applications

(1H-Benzo[d][1,2,3]triazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1H-benzo[d][1,2,3]triazol-1-yl 4-methylbenzenesulfonate (Bt-OTs), and 3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl 4-methylbenzenesulfonate (At-OTs) are classically utilized in peptide synthesis for amide-bond formation. However, a previously undescribed reaction of these compounds with alcohols in the presence of a base, leads to 1-alkoxy-1H-benzo- (Bt-OR) and 7-azabenzotriazoles (At-OR). Although BOP undergoes reactions with alcohols to furnish 1-alkoxy-1H-benzotriazoles, Bt-OTs proved to be superior. Both, primary and secondary alcohols undergo reaction under generally mild reaction conditions. Correspondingly, 1-alkoxy-1H-7-azabenzotriazoles were synthesized from At-OTs. Mechanistically, there are three pathways by which these peptide-coupling agents can react with alcohols. From 31P{1H}, [18O]-labeling, and other chemical experiments, phosphonium and tosylate derivatives of alcohols seem to be intermediates. These then react with BtO− and AtO− produced in situ. In order to demonstrate broader utility, this novel reaction has been used to prepare a series of acyclic nucleoside-like compounds. Because BtO− is a nucleofuge, several Bt-OCH2Ar substrates have been evaluated in nucleophilic substitution reactions. Finally, the possible formation of Pd π–allyl complexes by departure of BtO− has been queried. Thus, alpha-allylation of three cyclic ketones was evaluated with 1-(cinnamyloxy)-1H-benzo[d][1,2,3]triazole, via in situ formation of pyrrolidine enamines and Pd catalysis.

Development of Efficient Processes for the Preparation of Di-tert-butyl Potassium Phosphate and Di-tert-butyl (Chloromethyl) Phosphate

A new and efficient process to prepare di-tert-butyl (chloromethyl) phosphate, a key compound in the formation of many phosphon-oxymethyl pro-drugs, from chloromethyl chlorosulfate (CMCS) and di-tert-butyl potassium phosphate (DTBPP) is described. To develop a process to this important compound with overall efficiency, an improved synthesis of DTBPP was required. The two-step process to DTBPP starts from PCl3 and leverages a H2O2/catalytic KI mediated oxidation of di-tert-butyl phosphite to provide DTBPP in 81% yield and high purity. In the development of the new process to di-tert-butyl (chloromethyl) phosphate, a comparison to the corresponding tosylate derivative was made. A rational selection of base, phase-transfer catalyst (PTC), and stabilizing additive minimized CMCS decomposition and led to an optimized yield (90% solution yield), improved product purity, and identification of a technique to enable the long-term storage of di-tert-butyl (chloromethyl) phosphate.

Synthesis, Crystal Growth and Characterization of Organic Nonlinear Optical Co-Crystal: 4-N, N-dimethylamino-4-N-methyl-stilbazolium (3-nitrobenzenesulfonate)<sub>0.6</sub>I<sub>0.4</sub>

This report presents the synthesis, growth, crystal structure determination and second-harmonic generation efficiency of nonlinear optical co-crystal 4-N, N-dimethylamino-4-N-methyl-stilbazolium (m-nitrobenzenesulfonate)0.6I0.4 (DSIMNS). It is co-crystal of two DAST (4-N,N-dimethylamino-4-N-methyl-stilbazolium tosylate) derivatives. X-ray crystallographic analyses revealed that the crystal structure of DSIMNS is monoclinic, with space group P21. Kurtz powder test has shown that DSIMNS exhibits a large second-harmonic generation efficiency 500 times of that of urea.