Heterogeneous Organocatalysts for Light-Driven Reactions in Continuous Flow.

Within the realm of organic synthesis, photocatalysis has blossomed since the beginning of the last decade. A plethora of classical reactivities, such as selective oxidation of alcohol and amines, redox radical formation of reactive species in situ, and indirect activation of an organic substrate for cycloaddition by EnT, have been revised in a milder and more sustainable fashion via photocatalysis. However, even though the spark of creativity leads scientists to explore new reactions and reactivities, the urgency of replacing the toxic and critical metals that are involved as catalysts has encouraged chemists to find alternatives in the branch of science called organocatalysis. Unfortunately, replacing metal catalysts with organic analogues can be too expensive sometimes; however, this drawback can be solved by the reutilization of the catalyst if it is heterogeneous. The aim of this review is to present the recent works in the field of heterogeneous photocatalysis, applied to organic synthesis, enabled by continuous flow. In detail, among the heterogeneous catalysts, g-CN, polymeric photoactive materials, and supported molecular catalysts have been discussed within their specific sections, rather than focusing on the types of reactions.

Modulable Photocatalyzed Strategies for the Synthesis of α-C-Glycosyl Alanine Analogues via the Giese Reaction with Dehydroalanine Derivates.

Herein, we present the α-selective Giese reaction between pyranosyl/furanosyl bromides and dehydroalanine analogues, which provides access to a library of highly valuable α-C-glycosyl alanines. The key C-glycosyl radical is generated through photocatalysis by either the new generation copper(I) complex [(DPEPhos)(bcp)Cu]PF6 or [Ru(bpy)3](BF4)2. The reactions proceed smoothly, affording the desired α-C-glycosyl alanines in up to 99% yield when diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate [Hantzsch ester (HE)] is used as an additive. N,N-Diisopropylethylamine (DIPEA) has been selected as a reductant in both protocols. A mechanistic study by means of transient absorption spectroscopy unveils a halogen-atom transfer (XAT) process in C-glycosyl radical formation.

Oxidative NHC Catalysis: An Unconventional Tool for Macrocyclic Oligoesters Synthesis.

The application of N-heterocyclic carbene (NHC) catalysis under highly diluted oxidative condition to the polycondensation of dialdehydes and diols is herein presented as an alternative, atom-economical synthetic route to macrocyclic oligoesters (MCOs). The disclosed protocol paves the way to the straightforward access to MCOs, starting from commercial dialdehydes, avoiding the use of toxic diacyl chlorides, commonly employed in traditional MCOs synthetic processes. The method is totally metal-free, takes place in the green Me-THF solvent and requires the use of a fully recyclable quinone oxidant. The protocol versatility is confirmed by the employment of fossil-based and bio-based monomers such as 2,5-diformylfuran (DFF), 2,5-bis(hydroxymethyl)furan (BHMF), and isomannide, synthesizing a series of novel and known synthetically relevant macrocyclic oligoesters, fully characterized by NMR and MALDI-TOF MS analysis, with product yields (51-86 %) comparable to those obtained by traditional synthetic routes. Finally, to emphasize the synthetic relevance of the target macrocycles, an entropically-driven ring opening polymerization (ED-ROP) key study has been performed, optimizing the organocatalyzed synthesis of poly(2,5-furan-dimethylene 2,5 furandicarboxylate) (PBHMF) with number-average molecular weight up to 8200 g mol-1 and 66 % isolated yield.

Oxidative N-Heterocyclic Carbene Catalysis.

N-Heterocyclic carbene (NHC) catalysis is a by now consolidated organocatalytic platform for a number of synthetic (asymmetric) transformations via diverse reaction modes/intermediates. In addition to the typical umpolung processes involving acyl anion/homoenolate equivalent species, implementation of protocols under oxidative conditions greatly expands the possibilities of this methodology. Oxidative NHC-catalysis allows for oxidative and oxygenative transformations through specific manipulations of Breslow-type species depending upon the oxidant used (external oxidant or O2 /air), the derived NHC-bound intermediates paving the way to non-umpolung processes through activation of carbon atoms and heteroatoms. This review is intended to update the state of the art in oxidative NHC-catalyzed reactions that appeared in the literature from 2014 to present, with a strong focus to crucial intermediates and their mechanistic implications.

Exploring the Synergy Between HPTLC and HPLC-DAD for the Investigation of Wine-Making By-Products.

Both environmental and economic issues are increasingly pushing for the revalorization of agri-food by-products, including those arising from wine industry. Wastes produced from wine-making processes are important sources of biologically active compounds, mainly phenolic acids and flavonoids, which could be re-used for several applications, for example as additive surrogates or new ingredients in foodstuffs and/or pharmaceuticals. Therefore, the development of methods aimed at isolating, characterizing and quantifying molecules present in winery by-products acquires considerable importance in view of their re-utilization on a large scale. In this connection, this study demonstrated that high-performance thin-layer chromatography (HPTLC) and high-performance liquid chromatography with diode array detection (HPLC-DAD) can operate in synergy for the investigation of pomace and seed materials arising from both white and red cultivars of Vitis Vinifera. By virtue of fingerprint profiling, mass spectrometry (MS) interfacing and band comparison method, HPTLC enabled detection and identification of phenolic acids, non-anthocyanic flavonoids and anthocyanins. On the contrary, only anthocyanins could be identified by HPLC-DAD, and their subsequent quantification showed that malvidin-3-O-glucoside (oenin) was the most abundant one. In parallel, HPTLC has allowed to detect and quantify proanthocyanidins (PAC), showing that only catechin was present in the test samples. Both quantitative analytical methods were validated in terms of linearity, detection and quantification limits and precision.

Synthesis of functionalized imidazolidine-2-thiones via NHC/base-promoted aza-benzoin/aza-acetalization domino reactions.

A strategy for the synthesis of biologically relevant 5-hydroxy-imidazolidine-2-thione derivatives is presented. A novel class of α-sulfonylamines have been suitably prepared (46-81% yield) as precursors of formal benzylidenethiourea acceptors; these are generated in situ and intercepted by N-heterocyclic carbene (NHC)-activated aldehydes affording open-chain aza-benzoin-type adducts, which in turn undergo an intramolecular aza-acetalization reaction in a one-pot fashion. A thiazolium salt/triethylamine couple proved to be the more effective system to trigger the domino sequence giving the target heterocycles in good yields (45-97%) and diastereoselectivities (up to 99 : 1 dr). The multigram scale synthesis and elaboration of a selected 5-hydroxy-imidazolidine-2-thione compound is also described.

Research Progress in the Modification of Quercetin Leading to Anticancer Agents.

The flavonoid quercetin (3,3',4',5,7-pentahydroxyflavone) is widely distributed in plants, foods, and beverages. This polyphenol compound exhibits varied biological actions such as antioxidant, radical-scavenging, anti-inflammatory, antibacterial, antiviral, gastroprotective, immune-modulator, and finds also application in the treatment of obesity, cardiovascular diseases and diabetes. Besides, quercetin can prevent neurological disorders and exerts protection against mitochondrial damages. Various in vitro studies have assessed the anticancer effects of quercetin, although there are no conclusive data regarding its mode of action. However, low bioavailability, poor aqueous solubility as well as rapid body clearance, fast metabolism and enzymatic degradation hamper the use of quercetin as therapeutic agent, so intense research efforts have been focused on the modification of the quercetin scaffold to obtain analogs with potentially improved properties for clinical applications. This review gives an overview of the developments in the synthesis and anticancer-related activities of quercetin derivatives reported from 2012 to 2016.

Recent Developments in General Methodologies for the Synthesis of α-Ketoamides.

The α-ketoamide motif is widely found in many natural products and drug candidates with relevant biological activities. Furthermore, α-ketoamides are attractive candidates to synthetic chemists due to the ability of the motif to access a wide range of functional group transformations, including multiple bond-forming processes. For these reasons, a vast array of synthetic procedures for the preparation of α-ketoamides have been developed over the past decades, and the search for expeditious and efficient protocols continues unabated. The aim of this review is to give an overview of the diverse methodologies that have emerged since the 1990s up to the present. The different synthetic routes have been grouped according to the way the α-ketoamide moiety has been created. Thus, syntheses of α-ketoamides proceeding via C(2)-oxidation of amide starting compounds are detailed, as are amidation approaches installing the α-ketoamide residue through C(1)-N bond formation. Also discussed are the methodologies centered on C(1)-C(2) σ-bond construction and C(2)-R/Ar bond-forming processes. Finally, the literature regarding the synthesis of α-ketoamide compounds by palladium-catalyzed double-carbonylative amination reactions is discussed.

Electron-transfer-initiated benzoin- and Stetter-like reactions in packed-bed reactors for process intensification.

A convenient heterogeneous continuous-flow procedure for the polarity reversal of aromatic α-diketones is presented. Propaedeutic batch experiments have been initially performed to select the optimal supported base capable to initiate the two electron-transfer process from the carbamoyl anion of the N,N-dimethylformamide (DMF) solvent to the α-diketone and generate the corresponding enediolate active species. After having identified the 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine on polystyrene (PS-BEMP) as the suitable base, packed-bed microreactors (pressure-resistant stainless-steel columns) have been fabricated and operated to accomplish the chemoselective synthesis of aroylated α-hydroxy ketones and 2-benzoyl-1,4-diones (benzoin- and Stetter-like products, respectively) with a good level of efficiency and with a long-term stability of the packing material (up to five days).

One-Pot, Four-Step Organocatalytic Asymmetric Synthesis of Functionalized Nitrocyclopropanes.

The asymmetric synthesis of functionalized nitrocyclopropanes has been achieved by a one-pot, four-step method catalyzed by (S)-diphenylprolinol TMS ether, which joins two sequential domino reactions, namely a domino sulfa-Michael/aldol condensation of α,ß-unsaturated aldehydes with 1,4-dithiane-2,5-diol, and a domino Michael/α-alkylation reaction of the derived chiral dihydrothiophenes with bromonitromethane. The title compounds were obtained in 27-45% yields, with high levels of diastereoselectivity (93:7 to 100:0 dr) and generally good enantioselectivities (up to 95:5 er).

Efficient synthesis and biological evaluation of two modafinil analogues.

Non classical bioisosters of modafinil featuring interesting biological profile have been easily produced through replacement of the sulfoxide function with a carbonyl group and modification of the carboxylic acid amide functionality.

Proteasome inhibitors; synthesis and activity of arecoline oxide tripeptide derivatives.

We describe the synthesis and biological activities of a series of methyl 3,4-epoxypiperidine-3-carboxylate tripeptide derivatives that inhibit the chymotryptic and tryptic active sites of the 20S proteasome. Of the series, compound 2 which contains 3-hydroxy-2-methylbenzoyl group at its N-terminal position, displayed the greatest inhibitory potency (IC(50) <1 microM). All derivatives showed favourable pharmacokinetic properties.

Pharmacological profiles of presynaptic nociceptin/orphanin FQ receptors modulating 5-hydroxytryptamine and noradrenaline release in the rat neocortex.

1 The pharmacological profiles of presynaptic nociceptin/orphanin FQ (N/OFQ) peptide receptors (NOP) modulating 5-hydroxytryptamine (5-HT) and noradrenaline (NE) release in the rat neocortex were characterized in a preparation of superfused synaptosomes challenged with 10 mM KCl. 2 N/OFQ concentration-dependently inhibited K(+)-evoked [(3)H]-5-HT and [(3)H]-NE overflow with similar potency (pEC(50) approximately 7.9 and approximately 7.7, respectively) and efficacy (maximal inhibition approximately 40%). 3 N/OFQ (0.1 micro M) inhibition of [(3)H]-5-HT and [(3)H]-NE overflow was antagonized by selective NOP receptor antagonists of peptide ([Nphe(1)]N/OFQ(1-13)NH(2) and UFP-101; 10 and 1 microM, respectively) and non-peptide (J-113397 and JTC-801; both 0.1 microM) nature. Antagonists were routinely applied 3 min before N/OFQ. However, a 21 min pre-application time was necessary for J-113397 and JTC-801 to prevent N/OFQ inhibition of [(3)H]-NE overflow. 4 The NOP receptor ligand [Phe(1)psi(CH(2)-NH)Gly(2)]N/OFQ(1-13)NH(2) ([F/G]N/OFQ(1-13)NH(2); 3 microM) did not affect K(+)-evoked [(3)H]-NE but inhibited K(+)-evoked [(3)H]-5-HT overflow in a UFP-101 sensitive manner. [F/G]N/OFQ(1-13)NH(2) antagonized N/OFQ actions on both neurotransmitters. 5 The time-dependency of JTC-801 action was studied in CHO cells expressing human NOP receptors. N/OFQ inhibited forskolin-stimulated cAMP accumulation and JTC-801, tested at different concentrations (0.1-10 microM) and pre-incubation times (0, 40 and 90 min), antagonized this effect in a time-dependent manner. The Schild-type analysis excluded a competitive type of antagonism. 6 We conclude that presynaptic NO receptors inhibiting 5-HT and NE release in the rat neocortex have similar pharmacological profiles. Nevertheless, they can be differentiated pharmacologically on the basis of responsiveness to [F/G]N/OFQ(1-13)NH(2) and time-dependent sensitivity towards non-peptide antagonists.

[Arg(14),Lys(15)]nociceptin, a highly potent agonist of the nociceptin/orphanin FQ receptor: in vitro and in vivo studies.

The nociceptin (NC)/orphanin FQ analog, [Arg(14),Lys(15)]NC, has been recently demonstrated to behave as a potent agonist at the human recombinant NC receptors (OP(4)). In this study, we evaluated the pharmacological profile of [Arg(14),Lys(15)]NC in vitro on the native OP(4) receptors expressed in isolated tissues and in vivo in the locomotor activity and the tail-withdrawal assays in mice. On isolated tissues, [Arg(14),Lys(15)]NC mimicked the effects of NC, showing similar maximal effects but higher potencies (17-fold in the mouse vas deferens, 10-fold in the rat vas deferens, and about 5-fold in the guinea pig ileum and mouse colon). In these preparations, the effects of [Arg(14),Lys(15)]NC were not modified by 1 microM naloxone, although antagonized by the OP(4) receptor antagonists [Nphe(1)]NC(1-13)NH(2) (pA(2) congruent with 6) and (+/-)trans-1-[1-cyclooctylmethyl-3hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) (pA(2) congruent with 8). In the rat vas deferens, a cocktail of peptidase inhibitors increased the maximal effects of NC, its analog, and the pEC(50) of NC (by 4-fold); the potency of [Arg(14),Lys(15)]NC was not significantly modified by peptidase inhibitors. In in vivo experiments, [Arg(14),Lys(15)]NC mimicked the effects of NC, producing, after intracerebroventricular administration, pronociceptive effects in the tail-withdrawal assay and inhibiting the locomotor activity of the mice. In both assays, [Arg(14),Lys(15)]NC was about 30-fold more potent than NC and produced longer lasting effects. Taken together, the present data demonstrate that [Arg(14),Lys(15)]NC behaves as a highly potent agonist of the OP(4) receptor and is able to produce long-lasting effects in vivo, compared with the natural ligand NC.