Cinchona-Based Hydrogen-Bond Donor Organocatalyst Metal Complexes: Asymmetric Catalysis and Structure Determination.

In this study, we describe the synthesis of cinchona (thio)squaramide and a novel cinchona thiourea organocatalyst. These catalysts were employed in pharmaceutically relevant catalytic asymmetric reactions, such as Michael, Friedel-Crafts, and A3 coupling reactions, in combination with Ag(I), Cu(II), and Ni(II) salts. We identified several organocatalyst-metal salt combinations that led to a significant increase in both yield and enantioselectivity. To gain insight into the active catalyst species, we prepared organocatalyst-metal complexes and characterized them using HRMS, NMR spectroscopy, and quantum chemical calculations (B3LYP-D4/def2-TZVP), which allowed us to establish a structure-activity relationship.

A novel recyclable organocatalyst for the gram-scale enantioselective synthesis of (S)-baclofen.

Synthesizing organocatalysts is often a long and cost-intensive process, therefore, the recovery and reuse of the catalysts are particularly important to establish sustainable organocatalytic transformations. In this work, we demonstrate the synthesis, application, and recycling of a new lipophilic cinchona squaramide organocatalyst. The synthesized lipophilic organocatalyst was applied in Michael additions. The catalyst was utilized to promote the Michael addition of cyclohexyl Meldrum's acid to 4-chloro-trans-ß-nitrostyrene (quantitative yield, up to 96% ee). Moreover, 1 mol % of the catalyst was feasible to conduct the gram-scale preparation of baclofen precursor (89% yield, 96% ee). Finally, thanks to the lipophilic character of the catalyst, it was easily recycled after the reaction by replacing the non-polar reaction solvent with a polar solvent, acetonitrile, with 91-100% efficiency, and the catalyst was reused in five reaction cycles without the loss of activity and selectivity.

Cytotoxicity of cinchona alkaloid organocatalysts against MES-SA and MES-SA/Dx5 multidrug-resistant uterine sarcoma cell lines.

Since the first application of natural quinine as an anti-malarial drug, cinchona alkaloids and their derivatives have been exhaustively studied for their biological activity. In our work, we tested 13 cinchona alkaloid organocatalysts, synthesised from quinine. These derivatives were screened against MES-SA and Dx5 uterine sarcoma cell lines for in vitro anticancer activity and to investigate their potential to overcome P-glycoprotein (P-gp) mediated multidrug resistance (MDR). Decorating quinine with hydrogen-bond donor units, such as thiourea and (thio)squaramide, resulted in decreased half-maximal growth inhibition values on both cell lines (1.3-21 µM) compared to quinine and other cinchona alcohols (47-111 µM). Further cytotoxicity studies conducted in the presence of the P-gp inhibitor tariquidar indicated that several analogues, especially cinchona amines and squaramides, but not thiosquaramide, were expelled from MDR cells by P-gp. Similarly to the established P-gp inhibitor quinine, 6 cinchona analogues were shown to inhibit calcein-AM efflux. Interestingly, quinine and didehydroquinine exhibited a marginally increased toxicity against the multidrug resistant Dx5 cells. Collateral sensitivity of the MDR cell line was more pronounced when the cinchona thiosquaramide was complexed with Cu(II) acetate. Based on the results, cinchona derivatives are good anticancer candidates for further drug development.

Synthesis of Novel Crown Ether-Squaramides and Their Application as Phase-Transfer Catalysts.

This work presents the synthesis of six new phase-transfer organocatalysts in which the squaramide unit is directly linked to the nitrogen atom of an aza-crown ether. Four chiral skeletons, namely hydroquinine, quinine, cinchonine (cinchonas), and α-d-glucopyranoside were responsible for the asymmetric construction of an all-carbon quaternary stereogenic center in α-alkylation and Michael addition reactions of malonic esters. We investigated the effects of these different chiral units and that of crown ethers with different sizes on catalytic activity and enantioselectivity. During extensive parameter investigations, both conventional and emerging green solvents were screened, providing valuable α,α-disubstituted malonic ester derivatives with excellent yields (up to 98%).

Synthesis and Applications of Cinchona Squaramide-Modified Poly(Glycidyl Methacrylate) Microspheres as Recyclable Polymer-Grafted Enantioselective Organocatalysts.

This work presents the immobilization of cinchona squaramide organocatalysts on poly(glycidyl methacrylate) solid supports. Preparation of the well-defined monodisperse polymer microspheres was facilitated by comprehensive parameter optimization. By exploiting the reactive epoxy groups of the polymer support, three amino-functionalized cinchona derivatives were immobilized on this carrier. To explore the effect of the amino linker, these structurally varied precatalysts were synthesized by modifying the cinchona skeleton at different positions. The catalytic activities of the immobilized organocatalysts were tested in the Michael addition of pentane-2,4-dione and trans-ß-nitrostyrene with excellent yields (up to 98 %) and enantioselectivities (up to 96 % ee). Finally, the catalysts were easily recovered five times by centrifugation without loss of activity.

Selective Electrocatalytic Oxidation of Biomass-Derived 5-Hydroxymethylfurfural to 2,5-Diformylfuran: from Mechanistic Investigations to Catalyst Recovery.

Invited for this month's cover is the group of Gyorgy Szekely at King Abdullah University of Science and Technology (KAUST). The image shows the efficient TEMPO-based electrocatalytic transformation of biomass-based C6 -platform chemical HMF to DFF using non-precious-metal-based electrodes in green solvents with nanofiltration-enabled catalyst recovery. The Full Paper itself is available at 10.1002/cssc.202000453.

Selective Electrocatalytic Oxidation of Biomass-Derived 5-Hydroxymethylfurfural to 2,5-Diformylfuran: from Mechanistic Investigations to Catalyst Recovery.

The catalytic transformation of bio-derived compounds, specifically 5-hydroxymethylfurfural (HMF), into value-added chemicals may provide sustainable alternatives to crude oil and natural gas-based products. HMF can be obtained from fructose and successfully converted to 2,5-diformylfuran (DFF) by an environmentally friendly organic electrosynthesis performed in an ElectraSyn reactor, using cost-effective and sustainable graphite (anode) and stainless-steel (cathode) electrodes in an undivided cell, eliminating the need for conventional precious metal electrodes. In this work, the electrocatalysis of HMF is performed by using green solvents such as acetonitrile, γ-valerolactone, as well as PolarClean, which is used in electrocatalysis for the first time. The reaction parameters and the synergistic effects of the TEMPO catalyst and 2,6-lutidine base are explored both experimentally and through computation modeling. The molecular design and synthesis of a size-enlarged C3 -symmetric tris-TEMPO catalyst are also performed to facilitate a sustainable reaction work-up through nanofiltration. The obtained performance is then compared with those obtained by heterogeneous TEMPO alternatives recovered by using an external magnetic field and microfiltration. Results show that this new method of electrocatalytic oxidation of HMF to DFF can be achieved with excellent selectivity, good yield, and excellent catalyst recovery.

Comparison of Cinchona Catalysts Containing Ethyl or Vinyl or Ethynyl Group at Their Quinuclidine Ring.

Numerous cinchona organocatalysts with different substituents at their quinuclidine unit have been described and tested, but the effect of those saturation has not been examined before. This work presents the synthesis of four widely used cinchona-based organocatalyst classes (hydroxy, amino, squaramide, and thiourea) with different saturation on the quinuclidine unit (ethyl, vinyl, ethynyl) started from quinine, the most easily available cinchona derivative. Big differences were found in basicity of the quinuclidine unit by measuring the pKa values of twelve catalysts in six solvents. The effect of differences was examined by testing the catalysts in Michael addition reaction of pentane-2,4-dione to trans-ß-nitrostyrene. The 1.6-1.7 pKa deviation in basicity of the quinuclidine unit did not result in significant differences in yields and enantiomeric excesses. Quantum chemical calculations confirmed that the ethyl, ethynyl, and vinyl substituents affect the acid-base properties of the cinchona-thiourea catalysts only slightly, and the most active neutral thione forms are the most stable tautomers in all cases. Due to the fact that cinchonas with differently saturated quinuclidine substituents have similar catalytic activity in asymmetric Michael addition application of quinine-based catalysts is recommended. Its vinyl group allows further modifications, for instance, recycling the catalyst by immobilization.

Biomimetic Synthesis of Drug Metabolites in Batch and Continuous-Flow Reactors.

A medium-throughput screening (MTS) of biomimetic drug metabolite synthesis is developed by using an iron porphyrin catalyst. The microplate method, in combination with HPLC-MS analysis, was shown to be a useful tool for process development and parameter optimization in the production of targeted metabolites and/or oxidation products of forty-three different drug substances. In the case of the biomimetic oxidation of amiodarone, the high quantity and purity of the isolated products enabled detailed HRMS and NMR spectroscopic studies. In addition to identification of known metabolites, several new oxidation products of the drug that was studied were characterized. Fast degradation and poor recovery of the catalyst under batch conditions was overcome by immobilization of 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin iron(III) chloride (FeTSPP) on the surface of 3-aminopropyl-functionalized silica by electrostatic interaction. The supported catalyst was successfully applied in a packed-bed reactor under continuous-flow reaction conditions for the large-scale synthesis of amiodarone metabolites.

Nanofiltration-Enabled In†Situ Solvent and Reagent Recycle for Sustainable Continuous-Flow Synthesis.

Solvent usage in the pharmaceutical sector accounts for as much as 90 % of the overall mass during manufacturing processes. Consequently, solvent consumption poses significant costs and environmental burdens. Continuous processing, in particular continuous-flow reactors, have great potential for the sustainable production of pharmaceuticals but subsequent downstream processing remains challenging. Separation processes for concentrating and purifying chemicals can account for as much as 80 % of the total manufacturing costs. In this work, a nanofiltration unit was coupled to a continuous-flow rector for in situ solvent and reagent recycling. The nanofiltration unit is straightforward to implement and simple to control during continuous operation. The hybrid process operated continuously over six weeks, recycling about 90 % of the solvent and reagent. Consequently, the E-factor and the carbon footprint were reduced by 91 % and 19 %, respectively. Moreover, the nanofiltration unit led to a solution of the product eleven times more concentrated than the reaction mixture and increased the purity from 52.4 % to 91.5 %. The boundaries for process conditions were investigated to facilitate implementation of the methodology by the pharmaceutical sector.

Long-term stability and reusability of molecularly imprinted polymers.

Molecularly imprinted materials are man-made mimics of biological receptors. Their polymer network has recognition sites complementary to a substrate in terms of size, shape and chemical functionality. They have diverse applications in various chemical, biomedical and engineering fields such as solid phase extraction, catalysis, drug delivery, pharmaceutical purification, (bio)sensors, water treatment, membrane separations and proteomics. The stability and reusability of molecularly imprinted polymers (IPs) have crucial roles in developing applications that are reliable, economic and sustainable. In the present article the effect of crosslinkers, functional monomers and conditions for template extraction on the long-term stability and reusability of IPs was systematically investigated. Adsorption capacity, selectivity, morphology and thermal decomposition of eleven different l-phenylalanine methyl ester imprinted polymers were studied to reveal performance loss over 100 adsorption-regeneration cycles. Furthermore, crosslinker and functional monomer specific reversible and irreversible decomposition of imprinted polymers as a result of adsorbent regeneration were investigated through adsorption studies, electron microscopy, N2 adsorption and thermogravimetric analysis. A decomposition mechanism was proposed and revealed using NMR spectroscopy. Solutions to avoid or overcome the limitations of the most common crosslinkers, functional monomers and extraction techniques were proposed and experimentally validated.

Studies of a pyridino-crown ether-based chiral stationary phase on the enantioseparation of biogenic chiral aralkylamines and α-amino acid esters by high-performance liquid chromatography.

This paper reports the enantioseparation ability of a pyridino-18-crown-6 ether-based chiral stationary phase [(S,S)-CSP-1]. The enantiomeric discrimination of chiral stationary phase (S,S)-CSP-1 was evaluated by HPLC using the mixtures of enantiomers of various protonated primary aralkylamines [1-phenylethylamine hydrogen perchlorate (PEA), 2,3-dihydro-1H-inden-1-amine (1-aminoindan), 2,2'-(1,2-diaminoethane-1,2-diyl) diphenol (HPEN)] and perchlorate salts of α-amino acid esters [alanine benzyl ester (Ala-OBn), phenylalanine benzyl ester (Phe-OBn), phenylalanine methyl ester (Phe-OMe), phenylglycine methyl ester (PhGly-OMe), glutamic acid dibenzyl ester (Glu-diOBn), and valine benzyl ester (Val-OBn)]. The best enantioseparation was achieved in the case of PEA. The high enantioselectivity was rationalized by the strong π-π interaction of the extended π system of the aryl-substituted pyridine unit.

Role of chirality and macroring in imprinted polymers with enantiodiscriminative power.

Enantioselective discrimination of chiral amines is of great importance as their biological properties often differ. Therefore, here we report the development of synthetic receptors for their enantioselective recognition and pH-sensitive drug release. This paper reports the preparation of three pyridine and two benzene derivatives containing an allyloxy group [(S,S)-5, 6-9] as well as their evaluation as functional monomer anchors for chiral imprinting of amines. The enantiomeric enriching ability and controlled release of the imprinted polymers (IPs) were evaluated using racemic mixture of 1-(1-naphthyl)ethylamine hydrogen perchlorate (1). The effect of the enantiomeric purity of the template on the enantioseparation performance was investigated. Racemic template in combination with enantiomerically pure macrocyclic anchors and vice versa yields IPs with excellent enantiomeric recognition. In vitro drug delivery, enantiomeric enrichment and pH-sensitive release were investigated through kinetic models.

A novel method for the preparation of a chiral stationary phase containing an enantiopure acridino-18-crown-6 ether selector.

This paper reports a novel method for the preparation of chiral stationary phases (CSPs) using an acridino-18-crown-6 ether selector as a model compound. Chiral stationary phase (R,R)-CSP- 2A: was obtained by in situ continuously recirculating the solution of carboxyl-substituted acridino-18-crown-6 ether (R,R)- 4: , dicyclohexylcarbodiimide and 3-(triethoxysilyl)propylamine through a high-performance liquid chromatography (HPLC) column containing blank silica gel in elevated pressure and temperature. The enantiomer separating ability of chiral stationary phase (R,R)-CSP- 2A: was investigated by HPLC using mixtures of enantiomers of 1-(1-naphthyl)ethylamine hydrogen perchlorate, 1-(2-naphthyl)ethylamine, 1-(4-bromophenyl)ethylamine and 1-(4-nitrophenyl)ethylamine hydrogen chloride. The best results were found for the separation of the mixtures of enantiomers of Br-PEA.

Preparation and studies of chiral stationary phases containing enantiopure acridino-18-crown-6 ether selectors.

The enantiomeric separation ability of the newly prepared chiral stationary phases containing acridino-18-crown-6 ether selectors was studied by high-performance liquid chromatography (HPLC). The chiral stationary phases separated the enantiomers of selected protonated primary aralkylamines efficiently. The best results were found for the separation of the mixtures of enantiomers of NO2 -PEA.