Multigram Scale Research Articles

A Robust, Divalent, Phosphaza-bicyclo[2.2.2]octane Connector Provides Access to Cage-Dense Inorganic Polymers and Networks

While polymers containing chain or ring motifs in their backbone are ubiquitous, those containing well-defined molecular cages are very rare and essentially unknown for the inorganic elements. We report that a rigid and dinucleophilic cage (PNSiMe3)2(NMe)6, which is chemically robust and accessible on a multi-gram scale from commercial precursors, serves as a linear and divalent connector that forms cage-dense inorganic materials. Reaction of the cage with various ditopic P(III) dihalide comonomers proceeded via Me3SiCl elimination to give high molecular weight (30 000-70 000 g mol-1), solution-processable polymers that form free-standing films. The end groups of the polymers could be tuned to engender orthogonal reactivity and form block copolymers. Networked cage-dense materials could be accessed by using PCl3 as a tritopic P(III) linker. Detailed mechanistic studies implicate a stepwise polycondensation that proceeds via phosphino-phosphonium ion intermediates, prior to Me3SiCl loss. Thus, metathesis between the dinucleophilic cage and polyhalides represents a general strategy to making cage-dense polymers, setting the stage for systematically understanding the consequences of the three-dimensional microstructure on macroscopic material properties.

Practical and General Alcohol Deoxygenation Protocol

AbstractHerein, we describe a practical protocol for the removal of alcohol functional groups through reductive cleavage of their benzoate ester analogs. This transformation requires a strong single electron transfer (SET) reductant and a means to accelerate slow fragmentation following substrate reduction. To accomplish this, we developed a photocatalytic system that generates a potent reductant from formate salts alongside Brønsted or Lewis acids that promote fragmentation of the reduced intermediate. This deoxygenation procedure is effective across structurally and electronically diverse alcohols and enables a variety of difficult net transformations. This protocol requires no precautions to exclude air or moisture and remains efficient on multigram scale. Finally, the system can be adapted to a one‐pot benzoylation‐deoxygenation sequence to enable direct alcohol deletion. Mechanistic studies validate that the role of acidic additives is to promote the key C(sp3)−O bond fragmentation step.

Practical and General Alcohol Deoxygenation Protocol.

Herein, we describe a practical protocol for the removal of alcohol functional groups through reductive cleavage of their benzoate ester analogs. This transformation requires a strong single electron transfer (SET) reductant and a means to accelerate slow fragmentation following substrate reduction. To accomplish this, we developed a photocatalytic system that generates a potent reductant from formate salts alongside Brønsted or Lewis acids that promote fragmentation of the reduced intermediate. This deoxygenation procedure is effective across structurally and electronically diverse alcohols and enables a variety of difficult net transformations. This protocol requires no precautions to exclude air or moisture and remains efficient on multigram scale. Finally, the system can be adapted to a one-pot benzoylation-deoxygenation sequence to enable direct alcohol deletion. Mechanistic studies validate that the role of acidic additives is to promote the key C(sp3 )-O bond fragmentation step.

Boranes Paving the Way to Anionic Cyclic (Alkyl)(amino)carbenes (Ani-cAACs).

First examples of anionic cyclic (alkyl)(amino)carbenes (Ani-cAACs) that contain borane substituents have been synthesized. The nature of the borane substituents allows a modulation of the σ-donor or π-acceptor abilities compared to their neutral analogues. A B(CN)3 -substituted Ani-cAAC has been generated and used in situ. The corresponding C2 F5 BF2 -Ani-cAAC 6 was obtained in high yield on a multigram scale. First reactions of these novel ligands with elemental selenium and chloro(triphenylphosphine)gold(I) led to the anionic selenium adducts 7 and 8 and the Ani-cAAC gold complex 9. The properties of these compounds and data derived from theoretical calculations provide an insight into the electronic and steric properties of these novel anionic cAACs. Especially the ease of synthesis and the combination of properties such as negative charge, large buried volume, and good σ-donor and π-acceptor ability renders Ani-cAACs unique and promising new building blocks.

General and Scalable Approach to Trifluoromethyl-Substituted Cyclopropanes.

CF3-cyclopropanes with aliphatic, aromatic, and even heteroaromatic substituents were prepared on a multigram scale by deoxyfluorination of cyclopropane carboxylic acids or their salts with sulfur tetrafluoride. For labile α-pyridine acetic acids, only the use of their potassium salts allowed to obtain the needed products. Derivatization of CF3-cyclopropanes into building blocks ready for direct use in medicinal chemistry was performed.

Friedel-Crafts acylation of benzene derivatives in tunable aryl alkyl ionic liquids (TAAILs).

An iron(III) chloride hexahydrate-catalyzed Friedel-Crafts acylation of benzene derivatives in tunable aryl alkyl ionic liquids (TAAILs) has been developed. Through optimization of the metal salt, reaction conditions and ionic liquids, we were able to design a robust catalyst system that tolerates different electron-rich substrates under ambient atmosphere and allows for a multigram scale.

A Scalable Synthesis of Chiral Himbert Diene Ligands for Asymmetric Catalysis

AbstractChiral dienes are important ligands in asymmetric catalysis but they are less accessible than other commonly used ligands such as chiral bisphosphines. Here, we show that intramolecular [4+2] cycloaddition of a simply attained chiral allenecarboxanilide readily affords pseudoenantiomeric bicyclo[2.2.2]octa‐2,5‐dienes containing an alkenyl bromide, which can be readily functionalized to give diverse chiral diene ligands. The synthesis is straightforward and easily conducted on multigram scales. These ligands exhibit high performance in nine types of enantioselective Rh(I)‐catalyzed 1,4‐addition or 1,2‐addition reactions.magnified image

Catalytic Cross-Metathesis Reactions That Afford E- and Z-Trisubstituted Alkenyl Bromides: Scope, Applications, and Mechanistic Insights.

Stereochemically defined trisubstituted alkenes with a bromide and a methyl group at a terminus can be readily and stereoretentively derivatized through catalytic cross-coupling, affording unsaturated fragments found in many bioactive natural products. A direct method for generating such entities would be by stereocontrolled catalytic cross-metathesis (CM). Such methods are scarce however. Here, we present a stereoretentive strategy for CM between tri-, Z- or E-di, or monosubstituted olefins and Z- or E-2-bromo-2-butene, affording an assortment of E- or Z-trisubstituted alkenyl bromides. The majority of the transformations were catalyzed by two Mo monoaryloxide pyrrolide (MAP) complexes, one purchasable and the other accessible by well-established protocols. Substrates, such as feedstock trisubstituted olefins, can be purchased; the alkenyl bromide reagents are commercially available or can be prepared in two steps in a multigram scale. The catalytic process can be used to generate products that contain polar moieties, such as an amine or an alcohol, or sterically hindered alkenes that are α- or β-branched. The utility of the approach is highlighted by a brief and stereocontrolled synthesis of an unsaturated fragment of phomactin A and a concise total synthesis of ambrein. An unexpected outcome of these investigations was the discovery of a new role for the presence of a small-molecule alkene in an olefin metathesis reaction. DFT studies indicate that this additive swiftly reacts with a short-lived Mo alkylidene and probably helps circumvent the formation of catalytically inactive square pyramidal metallacyclobutanes, enhancing the efficiency of a transformation.

Efficient and Scalable Asymmetric Total Synthesis of (−)-Emetine with Pharmaceutical Grade Quality; First Multigram Scale Synthesis

A scalable asymmetric total synthesis of (−)-emetine, a natural product alkaloid from ipecac species and one of the main active ingredients in ipecac syrup used in emetics, has been accomplished. The synthetic route featured a total of 13 steps of highly efficient chemical reactions, including catalytic asymmetric allylation and an industrial deoxygenation of an aliphatic compound, which obviated the need for any chromatographic purification. (−)-Emetine·2HCl was obtained in 12% overall yield and over 93.2% HPLC purity. The synthesis was easily scaled up to 237.1 g and should be amenable to the production of larger quantities for ongoing drug development, while the compound is currently provided as natural ipecac syrup for a clinical use.

Eosin Y as a direct HAT photocatalyst for the synthesis of tetrahydrodipyrazolopyridines under white LED irradiation

A facile and efficient synthetic protocol has been developed for the synthesis of biologically privileged tetrahydrodipyrazolopyridines via visible light mediated one pot pseudo-six component reaction of ethyl acetoacetate, hydrazine hydrate, multifarious aldehydes and ammonium acetate (Knoevenagel condensation-Michael addition) by using metal-free, inexpensive eosin Y organic dye as a direct hydrogen atom transfer (HAT) catalyst at room temperature in open air condition. Mild condition, good yields, environment-friendly, high atom economy and good functional group tolerance of an extensive range of both electron-withdrawing and electron-donating groups are extra features of this approach. Additionally, this methodology is also appropriate for multi-gram scale, which enlighten the potentiality of using this reaction for industrial purposes.

Gambogic acid: Multi-gram scale isolation, stereochemical erosion toward epi-gambogic acid and biological profile.

Extracted from gamboge resin, gambogic acid (GBA) is a natural product that displays a complex caged xanthone structure and exhibits promising antitumor properties. However, efforts to advance this compound to clinical applications have been thwarted by its limited availability that in turn, restricts its pharmacological optimization. We report here an efficient method that allows multigram scale isolation of GBA in greater than 97% diastereomeric purity from various sources of commercially available gamboge. The overall process includes: (a) isolation of organic components from the resin; (b) separation of GBA from the organic components via crystallization as its pyridinium salt; and (c) acidification of the salt to isolate the free GBA. We found that GBA is susceptible to epimerization at the C2 center that produces epi-gambogic acid ( epi-GBA), a common contaminant of all commercial sources of this compound. Mechanistic studies indicate that this epimerization proceeds via an ortho-quinone methide intermediate. Although the observed stereochemical erosion accounts for the chemical fragility of GBA, it does not significantly affect its biological activity especially as it relates to cancer cell cytotoxicity. Specifically, we measured similar levels of cytotoxicity for either pure GBA or an equilibrated mixture of GBA/ epi-GBA in MBA-MB-231 cells with IC50 values at submicromolar concentration and induction of apoptosis after 12 hours of incubation. The results validate the pharmacological promise of gambogic acid and, combined with the multigram-scale isolation, should enable drug design and development studies.

A rapid construction of 1,3,2-benzodiazaborininones [R-B(aam)] from boronic acids and anthranilamides.

A simple, efficient and mild methodology for the synthesis of 1,3,2-benzodiazaborininones [R-B(aam)] from boronic acids and anthranilamides on ethyl acetate is described. A series of 1,3,2-benzodiazaborininones were prepared in moderate to excellent yields at room temperature without dehydrating agents, metal catalysts, corrosive acids or other additives. Meanwhile, a multi-gram scale reaction is also performed to ensure the scalability of the reaction, and the product can be conveniently isolated by simple filtration.

A practical approach for oligopeptide synthesis via synergistic photoredox, cobaloxime and organophosphorus triple catalysis

A catalytic oxidation–reduction condensation strategy for the synthesis of oligopeptides is reported. The triple catalytic system is compatible with all proteinogenic amino acids and applicable for multigram scale peptide synthesis.

Electrochemically enabled oxidative aromatization of pyrazolines.

Pyrazoles are a very important structural motif widely found in pharmaceuticals and agrochemicals. An electrochemically enabled approach for the sustainable synthesis of pyrazoles via oxidative aromatization of pyrazolines is presented. Inexpensive sodium chloride is employed in a dual role as a redox mediator and supporting electrolyte in a biphasic system (aqueous/organic). The method is applicable to a broad scope and can be conducted in the simplest electrolysis set-up using carbon-based electrodes. Hence, the method allows for simple work-up strategies such as extraction and crystallization, which enables application of this green synthetic route on a technically relevant scale. This is underlined by demonstration of a multi-gram scale electrolysis without loss in yield.

Cuprous sulfide intermediate assisted synthesis of PtCu3 intermetallic electrocatalysts in multigram scale for oxygen reduction

PtCu3 intermetallic oxygen reduction electrocatalysts were synthesized via a cuprous sulfide-induced phase transition.

Isolation of high-purity friedelin and 3-hydroxyfriedel-3-en-2-one from cork smoker wash solids

Cork smoker wash solids (black wax) that is obtained in the process of making corkboard by treating the ground cork with superheated steam is useless waste, generating environmental problems. On the other hand, black wax is a rich source of friedelin (1) and 3-hydroxyfriedel-3-en-2-one (3), pentacyclic triterpenoids belonging to the friedelane family. In the present work, a simple, fast, and efficient procedure for the extraction of highly purified friedelin and 3-hydroxyfriedel-3-en-2-one from black wax is presented. Extraction of black wax with hexane or acetone afforded a mixture of friedelin and 3-hydroxyfriedel-3-en-2-one. However, chromatographic separation of 1 and 3, due to their very similar Rf coefficients, is difficult, especially on a multigram scale. Therefore, the conversion of 3-hydroxyfriedel-3-en-2-one to an acetyl derivative 4 was proposed by acetylation of the above mixture. Appropriate selection of the eluent sequence allows for rapid and efficient separation of the resulting mixture of 1 and 4.

Size Control of Iron Oxide Nanoparticles Synthesized by Thermal Decomposition Methods

The controlled synthesis of superparamagnetic iron oxide nanoparticles is crucial for a variety of biomedical applications. Among different synthesis routes, thermal precursor decomposition methods are the most versatile, yielding monodisperse nanoparticles on the multigram scale. Recent in situ kinetic studies of the nucleation and growth processes during thermal decomposition routes revealed nonclassical nucleation and growth paths involving amorphous precursor phases and aggregative growth steps. With the knowledge of this kinetic mechanism, we systematically examined a range of different iron oxide heat-up synthesis routes to understand and conclude which methods allow good and reproducible size control over a range of relevant nanoparticle diameters. Using transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS) for the characterization of the nanoparticle size distribution, we find that a set of solvents (1-octadecene, trioctylamine, docosane) provides access to a temperature range between 300 and 370 °C, allowing us to synthesize monodisperse nanoparticles in a size range of 6–24 nm on a large scale. We confirm that a thermal pretreatment of the iron oxide precursor is essential to achieve reproducible size control. We find that each solvent provides access to a certain temperature range, within which the variation of temperature, heating rate, or precursor concentration allows us to reproducibly control the nanoparticle size.

Experimental assessment of Fe-doped CaMnO3 porous pellets in a bench-scale packed-bed reactor for thermochemical energy storage

Thermodynamic cycles requiring high operating temperatures (≥750 °C up to 1200 °C) are currently being explored to improve the sun-to-electricity conversion efficiency of Concentrating Solar Power (CSP) plants. This is calling for the design of new efficient high-temperature (≥750 °C) Thermochemical Energy Storage (TCES) systems, which are fundamental for supplying power on demand during off-sun periods. Recently, Fe-doped CaMnO3 oxides have been proposed as TCES candidate materials, and the determination of their thermodynamics properties via thermogravimetric (TG) analysis allowed evaluation of their heat storage capacity at a very small scale (mg scale). A 10 % Fe-doped CaMnO3 composition (CaMn0.9Fe0.1O3-δ – CMF91) emerged as optimum candidate material for TCES application due to its large heat storage capacity complemented by enhanced thermal stability over multiple oxidation/reduction cycles. To advance in the thermal characterization of these materials at a multigram scale, here we carried out bench-scale reactor tests using CMF91 under conditions considered representative of future CSP plants. The redox-active material has been extruded in the form of porous pellets through a simple production method that required the use of carboxymethylcellulose as a removable binder and water. With the bench-scale reactor tests, the CMF91 pellets showed fully reversible reduction-oxidation in cycles between 500 and 1100 °C under relevant operating pO2 conditions without any deterioration of the pellet's structural integrity. Remarkably, the material exhibited the same δ(T, pO2) profile at this significantly larger scale (~40 g) than the one derived from thermodynamics. Nevertheless, slight differences in oxygen release/uptake profiles between cooling and heating branches can be tracked down to an excess heat generation in the perovskite bed not efficiently extracted by the carrier gas. These results demonstrate that CMF91 oxide is ideally suited for thermal energy storage applications with a large total (thermochemical and sensible) heat storage capacity (~ 916 kJ/kgABO3 or ~ 400 kWh/m3) and good scalability.

Practical Route for Catalytic Ring-Opening Metathesis Polymerization.

Norbornene derivatives are typical monomers for ring-opening metathesis polymerization (ROMP) for synthesizing highly functional polymers. However, the lack of catalytic methods, that is, the lack of readily available chain transfer agents (CTAs) for these monomers has been a significant cost limitation when large-scale syntheses are required. Here, we report commercially available styrene and its derivatives as efficient regioselective CTAs for the catalytic synthesis of metathesis polymers requiring up to 1000 times less ruthenium than in classical ROMP experiments. The molecular weight of the synthesized polymers was controlled by the monomer-to-CTA ratio. Low molecular weight ROMP polymers known for their antimicrobial properties were also synthesized on a gram scale in this report. Polymers were characterized by SEC, 1H NMR spectroscopy, and isotopically resolved MALDI-TOF MS. This approach describes a greener, more cost-effective, and eco-friendly methodology for the preparation of metathesis-based materials on the multigram scale.

Strychnos alkaloids: total synthesis, characterization, DFT investigations, and molecular docking with AChE, BuChE, and HSA

An efficient five steps, the protection-deprotection synthetic a novel synthetic routes to(±) noruleine (±)-uleine, are reported starting from tetrahydrocarbazole fused monoalkyl nitrile at C-2 position that is prepared on multigram scale from 2-(3-ethyl-1-oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)acetonitrile (1) as well as the key azocino[4,3-b]indole skeleton is constructed via the tetrafluoro-1,4-benzoquinone (TFB)-mediated cyclization of a tetrahydrocarbazole derivative possessing direct amide synthesis from nitrile. As a result, Total synthesis of noruleine and uleine has been developed, which is accomplished in 4 and 5- steps synthesis of the ABCD tetracyclic of the strychnos alkaloids with an overall yield of 44% and 39%, respectively. The DFT computations were performed with B3LYP/6-311g(d,p) level to determine inter and intramolecular interactions and reactivity features of the compound 3–6. Also, TD-DFT computations were performed to characterize the electronic absorption spectra of all compounds. Last, the interactions of compounds 3–6 with selected targets AChE, BuChE, and HSA were evaluated in light of the molecular dockings. The bioactivity and drug-likeness scores revealed that compound 6 3–6 can be proper candidate for future drug-design studies more than the other compounds.