Persistent guaiazulene arylmethylium ions as electrophilic traps for metal enolates.

Guaiazulene-stabilized cations reacted with metal enolates affording carbonyl compounds with an azulene moiety. Metal enolates generated by asymmetric conjugate addition of organometallic reagents led to enantioenriched products. Additionally, guaiazulene-substituted cations efficiently react with silyl enol ethers. DFT calculations allowed estimation of the electrophilicities of the carbocations. Reaction progress was monitored by a decrease in the reactant's Vis-light absorption and an increase in the product's anti-Kasha emission.

Mechanochemical Pd-Catalyzed Amino- and Oxycarbonylations using FeBr2(CO)4 as a CO Source.

Herein, we describe the development of mechanochemical amino- and oxycarbonylation employing FeBr2(CO)4 as a solid CO source. This Pd/XantPhos-catalyzed reaction affords a range of carboxamides and esters from aryl iodides and various amines or phenols. Both primary and secondary amines, including amino acids, can be employed as N-nucleophiles.

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.

Enolates ambushed - asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles.

Metal enolates are useful intermediates and building blocks indispensable in many organic synthetic transformations. Chiral metal enolates obtained by asymmetric conjugate additions of organometallic reagents are structurally complex intermediates that can be employed in many transformations. In this review, we describe this burgeoning field that is reaching maturity after more than 25 years of development. The effort of our group to broaden possibilities to engage metal enolates in reactions with new electrophiles is described. The material is divided according to the organometallic reagent employed in the conjugate addition step, and thus to the particular metal enolate formed. Short information on applications in total synthesis is also given.

Derivatives of benzo-1,4-thiazine-3-carboxylic acid and the corresponding amino acid conjugates.

Herein, we present the synthesis and utilization of derivatives of 4H-benzo[b][1,4]thiazine-3-carboxylic acid. These benzothiazine compounds were assembled via the coupling of aminothiols and bromopyruvates. Oxidative dimerization of these starting materials was also observed and the corresponding benzothiazine dimers were isolated. Moreover, the coupling of benzothiazines with amino acids was realized. In doing so, an enantioselective synthesis of the nonproteinogenic amino acid 2-amino-3-propylhexanoic acid was accomplished.

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.

Diastereoselective Double C-H Functionalization of Chiral Ferrocenes with Heteroaromatics.

Diastereoselective double C-H heteroarylation of chiral ferrocenes provides valuable compounds with multiple functionalities using mild reaction conditions and simple reagents. Pd-Complexes with chiral mono-protected amino acids afforded corresponding heteroarylated ferrocenyl amines in good yields and high diastereomeric purities. In this way, a variety of indole, thiophene, pyrrole, or furan substituents were introduced to the ferrocene moiety. Furthermore, a range of relevant functional groups, for example ketone, ester, chloro, nitro, or silyl, are tolerated by this method. An alternative combination of amino acid and ferrocenyl amine configurations was leveraged to provide the complementary diastereomeric products. The products of C-H heteroarylation can be transformed into corresponding phosphines. Absolute configurations of CH-activation products were confirmed by the combination of X-ray crystallographic analysis and CD spectroscopy. 19 F NMR kinetic study and DFT calculations provided insights into the reaction mechanism and reasons governing stereoinduction.

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.