Antiproliferative in Vitro Evaluation of Terpenic Amines Synthesized via a Rhodium-catalyzed Hydroaminomethylation.

Terpene-derived alkaloids show a variety of biological activities, including antioxidant, anti-inflammatory, antimicrobial and cytotoxicity effects. In this work, homologated monoterpene amines have been prepared via a rhodium-catalyzed hydroaminomethylation of biomass-based alkenes, such as (R)-limonene, linalool, myrcene and camphene, in combination with secondary amines of aliphatic and aromatic nature, namely morpholine and N-methylaniline, leading to highly chemo- and regioselective processes. The as-prepared amines were obtained in 50-99 % overall yields, and in vitro tested on a human colon cancer cell line (HCT-116) to evaluate their cytotoxic potential. The lead compound of the series (3 a) showed cytotoxicity in the micromolar range (IC50 52.46 µM) via the induction of cell death by apoptosis, paving the way towards further structure-activity relationship studies.

Palladium Nanoparticles in Polyols: Synthesis, Catalytic Couplings, and Hydrogenations.

Alcohols, in particular polyols, are well-known for the synthesis of metal nanoparticles, often acting as reducing agents, solvents, and stabilizers. Given not only their structural flexibility depending on the number of OH functions and their inherent H bonding interactions, but also the wide range of polyol molecular weights readily available, different physicochemical properties (boiling point, polarity, viscosity) could be exploited toward the synthesis of well-defined nanomaterials. In particular, the relevance of the supramolecular structure of polyols has a fundamental impact on the formation of metal nanoparticles, thereby favoring the dispersion of the nanoclusters. In the field of the metal-based nanocatalysis, palladium occupies a privileged position mainly due to its remarkable versatility in terms of reactivity representing a foremost tool in synthesis. In this review, we describe the controlled synthesis of Pd-based nanoparticles in polyol medium, focusing on the progress in terms of tailoring size, morphology, structure, and surface state. Moreover, we discuss the use of palladium nanoparticles, in a polyol solvent, applied in two of the most relevant Pd-catalyzed processes, i.e., couplings and hydrogenation reactions, including multistep processes.

Understanding Cu(II)-based systems for C(sp3)-H bond functionalization: insights into the synthesis of aza-heterocycles.

Herein we report the synthesis of imidazo[1,5-a]pyridine heterocycles via a Cu(II)-mediated functionalization of α'-C(sp3)-H bonds of pyridinylaldimines and subsequent cyclization. This strategy exploits the inherent directing ability of heteroleptic aldimine and pyridine groups in the substrate yielding the C-H functionalization of α'-methylene groups in a regioselective fashion over distant methyl or methylene groups in ß or γ positions. The observed correlation between the nature of the anionic ligands (halide vs. carboxylate) bonded to copper and the chemoselectivity of the C(sp3)-H activation process points to a concerted metalation-deprotonation pathway prior to cyclization to furnish the corresponding imidazo[1,5-a]pyridine derivative. This copper-mediated C(sp3)-H bond functionalization reaction works for a variety of substrates incorporating linear alkyl chains (from 3 to 12 carbon atoms), and good functional group tolerance (aryl, ether and ester groups). Cu-Catalyzed C(sp2)-H cyanation on the imidazole ring can then take place selectively under oxidative conditions.

Glycerol Boosted Rh-Catalyzed Hydroaminomethylation Reaction: A Mechanistic Insight.

We report a Rh-catalyzed hydroaminomethylation reaction of terminal alkenes in glycerol that proceeds efficiently under mild conditions to produce the corresponding amines in relatively high selectivity towards linear amines, moderate to excellent yields by using a low catalyst loading (1 mol % [Rh], 2 mol % phosphine) and relative low pressure (H2 /CO, 1:1, total pressure 10 bar). This work sheds light on the importance of glycerol in enabling enamine reduction via hydrogen transfer. Moreover, evidence for the crucial role of Rh as chemoselective catalyst in the condensation step has been obtained for the first time in the frame of the hydroaminomethylation reaction by precluding deleterious aldol condensation reactions. The hydroaminomethylation proceeds under a molecular regime; the outcome of catalytically active species into metal-based nanoparticles renders the catalytic system inactive.

Novel Catalyst Composites of Ni- and Co-Based Nanoparticles Supported on Inorganic Oxides for Fatty Acid Hydrogenations.

In the quest to develop nanometrically defined catalytic systems for applications in the catalytic valorization of agri-food wastes, small Ni-based nanoparticles supported on inorganic solid supports have been prepared by decomposition of organometallic precursors in refluxing ethanol under H2 atmosphere, in the presence of supports exhibiting insulating or semi-conductor properties, such as MgAl2O4 and TiO2, respectively. The efficiency of the as-prepared Ni-based nanocomposites has been evaluated towards the hydrogenation of unsaturated fatty acids under solvent-free conditions, with high selectivity regarding the hydrogenation of C=C bonds. The influence of the support on the catalytic performance of the prepared Ni-based nanocomposites is particularly highlighted.

Copper nanocatalysts applied in coupling reactions: a mechanistic insight.

Copper-based nanocatalysts have seen great interest for use in synthetic applications since the early 20th century, as evidenced by the exponential number of contributions reported (since 2000, more than 48 000 works published out of about 81 300 since 1900; results from SciFinder using "copper nanocatalysts in organic synthesis" as keywords). These huge efforts are mainly based on two key aspects: (i) copper is an Earth-abundant metal with low toxicity, leading to inexpensive and eco-friendly catalytic materials; and (ii) copper can stabilize different oxidation states (0 to +3) for molecular and nanoparticle-based systems, which promotes different types of metal-reagent interactions. This chemical versatility allows different pathways, involving radical or ionic copper-based intermediates. Thus, copper-based nanoparticles have become convenient catalysts, in particular for couplings (both homo- and hetero-couplings), transformations that are involved in a remarkable number of processes affording organic compounds, which find interest in different fields (medicinal chemistry, natural products, drugs, materials, etc.). Clearly, this richness in reactivity makes understanding the mechanisms more complex. The present review focuses on the analysis of reported contributions using monometallic copper-based nanoparticles as catalytic precursors applied in coupling reactions, paying attention to those shedding light on the reaction mechanism.

Design of Glycerol-Based Solvents for the Immobilization of Palladium Nanocatalysts: A Hydrogenation Study.

Twenty-one green solvents, including glycerol-derived ethers, and their eutectic mixtures with two renewable ammonium salts, were used for the straightforward synthesis, stabilization, and immobilization of palladium nanoparticles (Pd NPs). The nature of the solvent allows tuning of the characteristics and properties of resulting catalytic systems in terms of particle size and morphology, stability, reactivity, and recoverability. Pd NPs immobilized in glycerol-based solvents were applied in the catalytic hydrogenation of alkenes, alkynes, and carbonyl compounds, as well as in the selective semihydrogenation of alkynes to alkenes. The optimal experimental parameters and the influence on the reactivity of the physicochemical properties of solvent, mainly the viscosity, were studied. Moreover, the most active and recoverable catalytic system, Pd NPs/N00Cl-100, was fully characterized both in the liquid phase and in the solid state, and its deactivation upon recovery was analyzed.

Isolation, structural assignment, and total synthesis of barmumycin.

Barmumycin was isolated from an extract of the marine actinomycete Streptomyces sp. BOSC-022A and found to be cytotoxic against various human tumor cell lines. On the basis of preliminary one- and two-dimensional (1)H and (13)C NMR spectra, the natural compound was initially assigned the structure of macrolactone-type compound 1, which was later prepared by two different routes. However, major spectroscopic differences between isolated barmumycin and 1 led to revision of the proposed structure as E-16. On the basis of the synthesis of this new compound, and subsequent spectroscopic comparison of it to an authentic sample of barmumycin, the structure of the natural compound was indeed confirmed as that of E-16.

Lamellarin D bioconjugates I: Synthesis and cellular internalization of PEG-derivatives.

Herein is reported the design and synthesis of poly(ethylene glycol) derivatives of Lamellarin D with the aim of modulating their physicochemical properties and improving the biological activity. Mono-, di-, and tri-PEG conjugates with improved solubility were obtained in 18-57% overall yields from the corresponding partially protected phenolic derivatives of Lamellarin D. Conjugates 1-9 were tested in a panel of three human tumor cell lines (MDA-MB-231 breast, A-549 lung, and HT-29 colon) to evaluate their cytotoxicity. Several compounds exhibited enhanced cellular internalization, and more than 85% of the derivatives showed a lower GI(50) than Lam-D. Furthermore, cell cycle arrest at G2 phase and apoptotic cell-death pathways were determined for Lamellarin D and these derivatives.

Lamellarin D bioconjugates II: Synthesis and cellular internalization of dendrimer and nuclear location signal derivatives.

The design and synthesis of Lamellarin D conjugates with a nuclear localization signal peptide and a poly(ethylene glycol)-based dendrimer are described. Conjugates 1-4 were obtained in 8-84% overall yields from the corresponding protected Lamellarin D. Conjugates 1 and 4 are 1.4- to 3.3-fold more cytotoxic than the parent compound against three human tumor cell lines (MDA-MB-231 breast, A-549 lung, and HT-29 colon). Besides, conjugates 3 and 4 showed a decrease in activity potency in BJ skin fibroblasts, a normal cell culture. Cellular internalization was analyzed, and a nuclear distribution pattern was observed for 4, which contains a nuclear localization signaling sequence.

Synthesis and structure-activity relationship study of potent cytotoxic analogues of the marine alkaloid Lamellarin D.

The marine alkaloid, Lamellarin D (Lam-D), has shown potent cytotoxicity in numerous cancer cell lines and was recently identified as a potent topoisomerase I inhibitor. A library of open lactone analogues of Lam-D was prepared from a methyl 5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate scaffold (1) by introducing various aryl groups through sequential and regioselective bromination, followed by Pd(0)-catalyzed Suzuki cross-coupling chemistry. The compounds were obtained in a 24-44% overall yield, and tested in a panel of three human tumor cell lines, MDA-MB-231 (breast), A-549 (lung), and HT-29 (colon), to evaluate their cytotoxic potential. From these data, the SAR study concluded that more than 75% of the open-chain Lam-D analogues tested showed cytotoxicity in a low micromolar GI50 range.

[18F]-Fluoride capture and release: azeotropic drying free nucleophilic aromatic radiofluorination assisted by a phosphonium borane.

[18F]-Fluoride ready for aromatic nucleophilic substitution was prepared according to a simple process including trapping of aqueous [18F]-fluoride on a cartridge pre-loaded with the phosphonium borane [(Ph2MeP)C6H4(BMes2)]+, then releasing by elution of TBACN in dry acetonitrile. Subsequent radiofluorination was successfully applied to a model reaction and to the radiosynthesis of [18F]-setoperone.

Naphthylaminoborane: from structural switches to frustrated Lewis pair reactivity.

A series of naphthyl-bridged amino-borane derivatives, namely 1-(dimethylamino)-8-naphthylboranes (1, 3, 5, 7) and 5-(dimethylamino)-6-acenaphthylboranes (2, 4, 6, 8, 10, 11), differing in the steric and electronic properties of the boryl moiety, have been synthesized and fully characterized by spectroscopic and crystallographic means. Structural X-ray analysis of the peri-atom displacement and ring torsion angles served to experimentally assess the presence and magnitude of the B-N interactions. The reversible quaternarization of nitrogen has been explored and was found to provide an efficient switch corresponding to different molecular organizations. The electronic characteristics of the nature of B-N interactions were further studied by Natural Bonding Orbital analysis derived from the theoretically calculated electron densities. This real-space bonding indicator discriminates the bonding B-N contact in 5 from the nonbonding in 8, which correlates with the flexibility of the naphthyl scaffold to respond to the Lewis acidity of boron allowing shorter peri interactions. Whereas, the steric shielding imposed by the two mesityl groups, and/or the rigidity of the acenaphthene framework disrupt B-N interaction. Thus, this communication reports on the modulation of the B-N bonding continuum by means of structural tuning leading to a molecular switch, as well as its implications towards revealing FLP reactivities through the isolation of intermediates of a stepwise mechanism.

A steric tethering approach enables palladium-catalysed C-H activation of primary amino alcohols.

Aliphatic primary amines are a class of chemical feedstock essential to the synthesis of higher-order nitrogen-containing molecules, commonly found in biologically active compounds and pharmaceutical agents. New methods for the construction of complex amines remain a continuous challenge to synthetic chemists. Here, we outline a general palladium-catalysed strategy for the functionalization of aliphatic C-H bonds within amino alcohols, an important class of small molecule. Central to this strategy is the temporary conversion of catalytically incompatible primary amino alcohols into hindered secondary amines that are capable of undergoing a sterically promoted palladium-catalysed C-H activation. Furthermore, a hydrogen bond between amine and catalyst intensifies interactions around the palladium and orients the aliphatic amine substituents in an ideal geometry for C-H activation. This catalytic method directly transforms simple, easily accessible amines into highly substituted, functionally concentrated and structurally diverse products, and can streamline the synthesis of biologically important amine-containing molecules.

5-(Methylthio)tetrazoles as Versatile Synthons in the Stereoselective Synthesis of Polycyclic Pyrazolines via Photoinduced Intramolecular Nitrile Imine-Alkene 1,3-Dipolar Cycloaddition.

A key thioether substituent in readily accessible 2-alkyl-5-(methylthio)tetrazoles enables facile photoinduced denitrogenation and intramolecular nitrile imine 1,3-dipolar cycloaddition to afford a wide range of polycyclic pyrazoline products with excellent diastereoselectivity. The methylthio group red-shifts the UV absorbance of the tetrazole, obviating the requirement in all previous substrate systems for at least one aryl substituent, and can subsequently be converted into a variety of other functionalities. This synthetic platform has been applied to the concise total syntheses of the alkaloid natural products (±)-newbouldine and withasomnine.

Total synthesis and antiproliferative activity screening of (+/-)-aplicyanins A, B and E and related analogues.

The first total synthesis of the indole alkaloids (+/-)-aplicyanins A, B, and E, plus 17 analogues, all in racemic form, is reported. Modifications to the parent compound included changing the number of bromine substituents on the indole, the nature of the substituents on the indole nitrogen (H, Me, or OMe), and/or the oxidation level of the heterocyclic core tetrahydropyrimidine. Each compound was screened against three human tumor cell lines, and 14 of the newly synthesized compounds showed considerable cytotoxicity. The assay results were used to establish structure-activity relationships. These results suggest that the presence of the bromine at position 5 of the indole is critical to activity, as well as the acetyl group on the imine nitrogen does in some compounds.

Modular total synthesis of lamellarin D.

[Chemical reaction: see text] A modular total synthesis of lamellarin D, a marine alkaloid with potent cytotoxic as well as topoisomerase I inhibition properties, has been accomplished. A sequential and regioselective bromination/Suzuki cross-coupling procedure was applied for the introduction of aryl groups at positions 1 and 2 of scaffold 1. Microwave-assisted 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) oxidation to yield pyrroloisoquinoline 15, followed by phenol group deprotection and subsequent lactonization, gave lamellarin D (18% in eight steps from 1).