Ketal Derivatives Research Articles

Synthesis and Biological Activities of Scleropentaside D.

We report the first total synthesis of scleropentaside D, a unique C-glycosidic ellagitannin, from the ketal derivative of scleropentaside A employing site-selective O4-protection of C-acyl glycoside and copper-catalyzed oxidative coupling reaction of galloyl groups as the key steps. Our study confirms the proposed structure of this natural product, scleropentaside D, and demonstrates its effectiveness as an inhibitor of α-glycosidase.

Photoredox Catalyzed Single C-F Bond Activation of Trifluoromethyl Ketones: A Solvent Controlled Divergent Access of gem-Difluoromethylene Containing Scaffolds.

Selective defluorinative functionalization of trifluoromethyl ketones is a long-standing challenge owing to the exhaustive mode of the process. To meet the demands for the installation of the gem-difluoromethylene unit for the construction of the molecular architectures of well-known pharmaceuticals and agrochemicals, a distinct pathway is thereby highly desirable. Here, a protocol is introduced that allows the divergent synthesis of gem-difluoromethylene group containing tetrahydrofuran derivatives and linear ketones via single C-F bond activation of trifluoromethyl ketones using visible-light photoredox catalysis in the presence of suitable olefins as trapping partner. The choice of appropriate solvent and catalyst plays a significant role in controlling the divergent behavior of this protocol. Highly reducing photo-excited catalysts are found to be responsible for the generation of α,α-difluoromethyl ketone (DFMK) radicals as the key intermediate via a SET process. This protocol also results in a high diastereoselectivity towards the formation of partially fluorinated cyclic ketal derivatives with simultaneous construction of one C-C and two C-O bonds. State-of-the-art DFT calculations are performed to address the origin of diastereoselectivity as well as the divergence of this protocol.

Levoglucosenone-derived synthesis of bio-based solvents and polyesters

ABSTRACT Polyesters are important materials with a wide range of applications, but there has been increasing concern over their sustainability. One example is the need for safer, bio-derived solvents to replace those currently in use for the polymer’s synthesis and processing. In this work, several variants of the bio-based cellulose/levoglucosenone derived solvent Cyrene, namely the ketal derivatives dioxolane Cygnet, dioxane Cygnet and dioxepane Cygnet were synthesized and tested as media for enzymatic polycondensation reactions using bio-based building blocks. Dioxolane Cygnet and dioxepane Cygnet were found to be suitable solvents for enzymatic polycondensation reactions, with dioxolane Cygnet being the preferred solvent, yielding polymers with a Mn >22 kDa. In addition, these solvents were tested in the biocatalyzed synthesis of levoglucosenone-based polyesters. The alternative solvents gave superior yields to those previously observed, demonstrating the versatility of these solvents in enzymatic polycondensation reactions, representing the first synthetic polymer-solvent system fully derived from cellulose.

Theoretical investigations on mechanisms and kinetics of methylketene with O(3P) reaction in the atmosphere.

The O(3P)-initiated conversion mechanism and dynamics of CH3CHCO were researched in atmosphere by executing density functional theory (DFT) computations. Optimizations of all the species and single-point energy computations were implemented at the B3LYP/6-311++G(d,p) and CCSD(T)/cc-pVTZ level, respectively. The explicit oxidation mechanism was introduced and discussed. The results state clearly that the O(3P) association was more energetically beneficial than the abstraction of H. The rate coefficients over the probable temperature range of 200-3000K were forecasted by implementing Rice-Ramsperger-Kassel-Marcus (RRKM) theory. Specifically, the total rate coefficient of O(3P) association reactions is 1.19 × 10-11cm3 molecule-1s-1 at 298K, which is consistent with the experimental results (1.16 × 10-11cm3 molecule-1s-1). The rate coefficients for the O(3P) with CH2CO, CH3CHCO, and (CH3)2CCO suggest that rate coefficient of ketene derivatives increase with the increase of methylation degree. Graphical abstract.

ParaHydrogen Polarized Ethyl-[1-13 C]pyruvate in Water, a Key Substrate for Fostering the PHIP-SAH Approach to Metabolic Imaging.

An efficient synthesis of vinyl‐[1‐13C]pyruvate has been reported, from which 13C hyperpolarized (HP) ethyl‐[1‐13C]pyruvate has been obtained by means of ParaHydrogen Induced Polarization (PHIP). Due to the intrinsic lability of pyruvate, which leads quickly to degradation of the reaction mixture even under mild reaction conditions, the vinyl‐ester has been synthesized through the intermediacy of a more stable ketal derivative. 13C and 1H hyperpolarizations of ethyl‐[1‐13C]pyruvate, hydrogenated using ParaHydrogen, have been compared to those observed on the more widely used allyl‐derivative. It has been demonstrated that the spin order transfer from ParaHydrogen protons to 13C, is more efficient on the ethyl than on the allyl‐esterdue to the larger J‐couplings involved. The main requirements needed for the biological application of this HP product have been met, i. e. an aqueous solution of the product at high concentration (40 mM) with a good 13C polarization level (4.8 %) has been obtained. The in vitro metabolic transformation of the HP ethyl‐[1‐13C]pyruvate, catalyzed by an esterase, has been observed. This substrate appears to be a good candidate for in vivo metabolic investigations using PHIP hyperpolarized probes.

Substituted ketenes offer exceptional carbon bases in gas phase: Computational study by density functional theory method

AbstractIn the present study, ketene derivatives with cyclopropene and methylenecyclopropene substituents have been investigated by B3LYP/6‐311+G(d,p) level of theory to evaluate their suitability as powerful carbon superbases. The protonation at C (sp) site provides new neutral organic bases with proton affinities (PAs) = 879–1,218 kJ/mol, in which some are more basic than 1,8‐bis(dimethylamino)‐naphthalene, whose gas‐phase PA of 1,028 kJ/mol is considered the threshold of superbasicity. The PAs of designed ketenes were amplified by substitution of electron‐releasing groups such as methyl and dimethylamino on the molecular framework. Two indices of aromaticity, nucleus‐independent chemical shift and harmonic oscillator model of aromaticity, were also used for elucidation of ketene basicity, which reveals that a cyclopropene ring on the proposed ketene derivatives becomes aromatic upon protonation.

Millimeter wave spectroscopy of cyanoketene (NC–CH=C=O) and an observational search in the ISM

Context. Ketene was detected in the interstellar medium (ISM) in 1977. Until now, only one derivative, the ketenyl radical, has been observed in this medium. Due to its large dipole moment value, cynaoketene is one of the best candidates for possible ketene derivative detection. Aims. To date, the measurements of the rotational spectra have been limited to 60 GHz. The extrapolation of the prediction in the millimeter wave domain is inaccurate and does not permit an unambiguous detection. Methods. The rotational spectra were re-investigated up to 330 GHz. Using the new prediction cyanoketene was sought after in a variety of astronomical sources: NGS 63341, SgrB2(N), and ASAI sources. Results. A total of 1594 transitions were newly assigned and fitted together with those from previous studies, reaching quantum numbers up to J = 82 and Ka = 24. Watson’s asymmetric top Hamiltonian in the Ir representation was used for the analysis; both reductions A and S were tested. Logically, the S reduction gave the best results confirming that the molecule is very close to the prolate limit. Cynaoketene was not found in ISM; upper limits to the column density were derived in each source.

Gold-Catalyzed Oxidation of Thioalkynes To Form Phenylthio Ketene Derivatives via a Noncarbene Route.

Gold-catalyzed oxidations of thioalkynes with 8-methylquinoline oxides afford 2-phenylthioketenes that can be trapped efficiently with alcohols. The synthetic utility is manifested by terminal and internal thioalkynes over a wide scope, bearing esters, ketones, alkyl, and oxime substituents. Our density functional theory calculations suggest that gold-catalyzed oxidations of terminal and internal thioalkynes with 8-methylquinoline oxides generate gold-bound ketene intermediates without the intermediacy of α-oxo gold carbene.

Guanosine Nucleolipids: Synthesis, Characterization, Aggregation and X-Ray Crystallographic Identification of Electricity-Conducting G-Ribbons.

The lipophilization of β-d-riboguanosine (1) with various symmetric as well as asymmetric ketones is described (→3a-3f). The formation of the corresponding O-2',3'-ketals is accompanied by the appearance of various fluorescent by-products which were isolated chromatographically as mixtures and tentatively analyzed by ESI-MS spectrometry. The mainly formed guanosine nucleolipids were isolated and characterized by elemental analyses, 1 H-, 13 C-NMR and UV spectroscopy. For a drug profiling, static topological polar surface areas as well as 10 logPOW values were calculated by an increment-based method as well as experimentally for the systems 1-octanol-H2 O and cyclohexane-H2 O. The guanosine-O-2',3'-ketal derivatives 3b and 3a could be crystallized in (D6 )DMSO - the latter after one year of standing at ambient temperature. X-ray analysis revealed the formation of self-assembled ribbons consisting of two structurally similar 3b nucleolipid conformers as well as integrated (D6 )DMSO molecules. In the case of 3a ⋅ DMSO, the ribbon is formed by a single type of guanosine nucleolipid molecules. The crystalline material 3b ⋅ DMSO was further analyzed by differential scanning calorimetry (DSC) and temperature-dependent polarization microscopy. Crystallization was also performed on interdigitated electrodes (Au, distance, 5 μm) and visualized by scanning electron microscopy. Resistance and amperage measurements clearly demonstrate that the electrode-bridging 3b crystals are electrically conducting. All O-2',3'-guanosine ketals were tested on their cytostatic/cytotoxic activity towards phorbol 12-myristate 13-acetate (PMA)-differentiated human THP-1 macrophages as well as against human astrocytoma/oligodendroglioma GOS-3 cells and against rat malignant neuroectodermal BT4Ca cells.

Acid-activated clay as heterogeneous and reusable catalyst for the synthesis ofbioactive cyclic ketal derivatives

A new heterogeneous acid catalyst based on a natural resource, Tunisian clay (Clay-H0.5), has been prepared and characterized by FT-IR, FE-SEM, and powder X-ray diffraction (XRD), as well as chemical composition, cation exchange capacity, specific surface area, and pore volume. Acid treatment for 0.5 h enlarged the surface area from 78.24 to 186.10 m$^{2}$/g and pore volume (PV) from 0.186 to 0.281 cm$^{3}$/g. The catalytic activity of this material was investigated in ketalization reaction under mild solvent-free conditions. This achieved up to 92% isolated yield for only 10 wt.% of the catalyst. This environmentally friendly method has advantages such as simple work-up procedure, avoidance of organic solvents, and good performance in ketalization reactions. Importantly, the Clay-H0.5 catalyst showed good recyclability where insignificant activity loss was exhibited even after six runs. Synthesized cyclic ketals were tested for their possible antileishmanial and antibacterial activities as well as antifungal activity. Biological screening showed that compound 11 had important antileishmanial activity against both L. major and L. infantum, while compound 14 also had significant antibacterial activity against four gram-positive and two gram-negative bacteria, and antifungal activity against Candida albicans, with minimal inhibitory concentration values ranging from 15.62 μg/mL to 125 μg/mL.

Synthesis of 2-Azaadamantan-6-one: A Missing Isomer.

2-Azaadamantan-6-one and its Boc and ethylene ketal derivatives were synthesized from 9-oxo endo-bicyclo[3.3.1]non-6-ene-3-carboxylic acid. Similarly, the Cbz, Boc, and ethylene ketal derivatives of 2-azaadamantan-4-one were synthesized from endo-bicyclo[3.3.1]non-6-ene-3-carboxylic acid. Key steps were Curtius rearrangements to form benzyl carbamates, followed by spontaneous intramolecular attack of the carbamate nitrogen on transient bromonium ion or epoxide intermediates to effect ring closure to azaadamantane intermediates. The reaction sequence leading to 2-azaadamantan-6-one is consistent with the formation of a transient tetracyclic keto aziridine intermediate.

Global analysis of pre-mRNA subcellular localization following splicing inhibition by spliceostatin A

Spliceostatin A (SSA) is a methyl ketal derivative of FR901464, a potent antitumor compound isolated from a culture broth of Pseudomonas sp. no. 2663. These compounds selectively bind to the essential spliceosome component SF3b, a subcomplex of the U2 snRNP, to inhibit pre-mRNA splicing. However, the mechanism of SSA's antitumor activity is unknown. It is noteworthy that SSA causes accumulation of a truncated form of the CDK inhibitor protein p27 translated from CDKN1B pre-mRNA, which is involved in SSA-induced cell-cycle arrest. However, it is still unclear whether pre-mRNAs are uniformly exported from the nucleus following SSA treatment. We performed RNA-seq analysis on nuclear and cytoplasmic fractions of SSA-treated cells. Our statistical analyses showed that intron retention is the major consequence of SSA treatment, and a small number of intron-containing pre-mRNAs leak into the cytoplasm. Using a series of reporter plasmids to investigate the roles of intronic sequences in the pre-mRNA leakage, we showed that the strength of the 5′ splice site affects pre-mRNA leakage. Additionally, we found that the level of pre-mRNA leakage is related to transcript length. These results suggest that the strength of the 5′ splice site and the length of the transcripts are determinants of the pre-mRNA leakage induced by SF3b inhibitors.

Biohydrocarbons Production under Standard Refinery Conditions by means of a Representative Ketal Compound of Biocrude

AbstractAny standard oil refinery is based on mature processes that have been adapted to poorly reactive hydrocarbon feeds. In contrast, biomass‐derived compounds are highly functionalized and reactive compared to hydrocarbons. The goal to connect these two different chemical worlds is simple: to transform biomass by ketalization under mild conditions (≈120 °C) to afford a biocrude that is composed of ketal derivatives; 1,2:3,5‐di‐O‐isopropylidene‐β‐d‐xylofuranose (DX) is present in the range of 20–30 wt % in biocrude. Herein, DX mixed in n‐hexane was used as a model under cracking and hydrotreatment conditions. A mixture of DX up to 30 wt % in n‐hexane was converted at 500 °C in fixed‐bed reactor under continuous flow using ZSM‐5 and USY zeolites as catalysts. Remarkably, ZSM‐5 was able to convert DX into monoaromatics. At 1.5 min residence time, 64–94 % of DX was converted into monoaromatics. Additionally, ZSM‐5 showed a coke yield lower than 4 wt %. In contrast, USY increased the coke yield by 10‐fold and afforded fewer monoaromatics. A DX mixture up to 30 % in n‐hexane was converted fully by hydrotreatment in a fixed‐bed reactor using Pd‐USY as the catalyst at 300 °C and 30 bar to produce saturated hydrocarbons only up to 12 atoms. 13C‐labeled DX (in all 13C‐xylofuranose) showed indubitably that xylofuranose carbon atoms were converted into hydrocarbons.

Design, synthesis and biological evaluation of novel benzimidazole-2-substituted phenyl or pyridine propyl ketene derivatives as antitumour agents

A series of novel benzimidazole-2-subsituted phenyl or pyridine propyl ketene derivatives were designed and synthesized. The biological activities of these derivatives were then evaluated as potential antitumour agents. These compounds were assayed for growth-inhibitory activity against HCT116, MCF-7 and HepG2 cell lines in vitro. The IC50 values of compounds A1 and A7 against the cancer cells were 0.06–3.64 μM and 0.04–9.80 μM, respectively. Their antiproliferative activities were significantly better than that of 5-Fluorouracil (IC50: 56.96–174.50 μM) and were close to that of Paclitaxel (IC50: 0.026–1.53 μM). The activity of these derivatives was over 100 times more effective than other reported structures of chalcone analogues (licochalcone A). A preliminary mechanistic study suggested that these compounds inhibit p53-MDM2 binding. Compounds A1, A7 and A9 effectively inhibited tumour growth in BALB/c mice with colon carcinoma HCT116 cells. The group administered 200 mg/kg of compound A7 showed a 74.6% tumour growth inhibition with no signs of toxicity at high doses that was similar to the inhibition achieved with the 12.5 mg/kg irinotecan positive control (70.2%). Therefore, this class of benzimidazole-2-subsituted phenyl or pyridine propyl ketene derivatives represents a promising lead structure for the development of possible p53-MDM2 inhibitors as new antitumour agents.

Exploration of Novel Botanical Insecticide Leads: Synthesis and Insecticidal Activity of β-Dihydroagarofuran Derivatives.

The discovery of novel leads and new mechanisms of action is of vital significance to the development of pesticides. To explore lead compounds for botanical insecticides, 77 β-dihydroagarofuran derivatives were designed and synthesized. Their structures were mainly confirmed by (1)H NMR, (13)C NMR, DEPT-135°, IR, MS, and HRMS. Their insecticidal activity was evaluated against the third-instar larvae of Mythimna separata Walker, and the results indicated that, of these derivatives, eight exhibited more promising insecticidal activity than the positive control, celangulin-V. Particularly, compounds 5.7, 6.6, and 6.7 showed LD50 values of 37.9, 85.1, and 21.1 μg/g, respectively, which were much lower than that of celangulin-V (327.6 μg/g). These results illustrated that β-dihydroagarofuran ketal derivatives can be promising lead compounds for developing novel mechanism-based and highly effective botanical insecticides. Moreover, some newly discovered structure-activity relationships are discussed, which may provide some important guidance for insecticide development.

Gas-Phase Amidation of Carboxylic Acids with Woodward's Reagent K Ions.

Gas-phase amidation of carboxylic acids in multiply-charged peptides is demonstrated via ion/ion reactions with Woodward's reagent K (wrk) in both positive and negative mode. Woodward's reagent K, N-ethyl-3-phenylisoxazolium-3'-sulfonate, is a commonly used reagent that activates carboxylates to form amide bonds with amines in solution. Here, we demonstrate that the analogous gas-phase chemistry occurs upon reaction of the wrk ions and doubly protonated (or doubly deprotonated) peptide ions containing the carboxylic acid functionality. The reaction involves the formation of the enol ester intermediate in the electrostatic complex. Upon collisional activation, the ethyl amine on the reagent is transferred to the activated carbonyl carbon on the peptide, resulting in the formation of an ethyl amide (addition of 27 Da to the peptide) with loss of a neutral ketene derivative. Further collision-induced dissociation (CID) of the products and comparison with solution-phase amidation product confirms the structure of the ethyl amide.

Organobase catalyzed 1,4-conjugate addition of 4-hydroxycoumarin on chalcones: Synthesis, NMR and single-crystal X-ray diffraction studies of novel warfarin analogues

The synthesis of a new series of warfarin analogues by convenient organobase catalyzed 1,4-conjugate addition of 4-hydroxycoumarin to chalcone derivatives is described. 1H NMR spectroscopy evidenced the presence of a predominant acyclic open-form together with the cyclic hemiketal tautomers of the resulting Michael adducts. The acyclic open-form has been unequivocally proved by single-crystal X-ray diffraction analysis. The use of the B ring ortho-hydroxychalcone synthons in this reaction has led to a diastereoselective synthesis of warfarin bicyclo[3.3.1]nonane ketal derivatives.

Convenient Synthesis of Ketal Derivatives from Cubebin Using Amberlite as Heterogeneous Catalyst

Eleven ketal derivatives were prepared from the natural product cubebin using Amberlite IR-120AR as heterogeneous catalyst and ROH as the source of the alkyl group.

Reactions of Boroles Formed by 1,1-Carboboration

The borole 2, obtained by 1,1-carboboration of phenylbis(trimethylsilylethynyl)borane with B(C6F5)3, undergoes [4 + 2] cycloaddition reactions with 1-pentyne and with ethene to give the 7-borabicyclo[2.2.1]heptadiene and -heptene derivatives, respectively. The borole 2 reacts with pyridine at room temperature to give a pyridine-stabilized borolium ion. The reaction proceeds by phenyl migration and Me3SiF elimination. Carbon monoxide reacts rapidly with the borole 2 at room temperature to give the unusual ketene derivative 19 with Me3Si migration across the ring system.

Dual pH-responsive and CD44 receptor targeted multifunctional nanoparticles for anticancer intracellular delivery

In this article, we prepared a multifunctional oligosaccharides of hyaluronan (oHA) conjugates, oHA-histidine-menthone 1,2-glycerol ketal (oHM). The oHM conjugates possess pH-sensitive menthone 1,2-glycerol ketal (MGK) as hydrophobic moieties and oHA as the target of CD44 receptor. The polymeric mPEG-Chitosan-Ketal (PCK) carrying pH-sensitive ketal group as hydrophobic moieties and PEG group as hydrophilic moieties were synthesized. The two pH-sensitive ketal derivatives were employed to fabricate nanoparticles for anti-tumor drug delivery. The oHM-PCK nanoparticles (oHPN) can spontaneously self-assemble into mixed micellar structure with nano-sized spherical shape of 100–200 nm at pH 7.4 PBS conditions. The oHPN could release encapsulated curcumin with 92.6 % at pH 5.0 compared with 55.3 % at pH 7.4. The results of cytotoxicity assay indicated that encapsulated curcumin in oHPN (Cur-oHPN) have less toxicity compared to curcumin suspension. The anti-tumor efficacy in vivo suggested that Cur-oHPN suppressed tumor growth most efficiently. These results present the promising potential of oHPN as an effective nano-sized pH-sensitive drug delivery system for intracellular delivery.