Active Amines Research Articles

Development of Teaching Materials and Concept Maps About the Relationship Between Sustainability and Chitosan for Water Treatment: Qualitative Content Analysis

Chitosan is formed by deacetylation of chitin using strong alkali at high temperatures. The content of the active amine groups in chitosan is widely used as an alternative natural coagulant that is environmentally friendly. So, it can be included in learning materials about the concept of sustainability. This study aimed to produce concept maps and Teaching Learning Sequences (TLS) based on scientists’ conceptions of sustainability on the topic of water treatment using natural coagulants. The method used in this research was qualitative content analysis. The research instruments included content analysis formats and sustainability aspects. The content analysis process included literature collection, descriptive analysis, category selection, and material evaluation with didactic aspects. This research produced concept maps and TLS that described the relationship between water treatment using natural coagulants and colloid content. Additionally, TLS related to sustainability education in the form of learning about water treatment using natural coagulants from chitosan was also developed. The concept map and TLS that have been compiled show the relationship between mapping aspects of scientific literacy and environmentally friendly water treatment using natural coagulants. The research results can be used as a basis for developing teaching materials and didactic designs. Keywords: concept maps, sustainability, chitosan

Microwave assisted synthesis of ion-imprinted polyacrylonitrile fibre via one-step phosphorylation for selective recovery of Dy(III) from wastewater

The selective recovery of Dy(III) from wastewater is highly desirable. Ion imprinted fibers are considered as attractive adsorbents due to their low flow resistance, high selectivity and ease of recovery. Phosphate groups with strong affinity to rare earth ions are widely used to construct ion imprinted polymers. However, current approaches for introducing phosphate groups into fibers suffer from the low grafting percentage and long reaction time because of the complicated procedures. Herein, a simple one-step phosphorylation method was explored to simultaneously introduce highly active primary amine and phosphate groups into polyacrylonitrile fiber (PANF) under microwave assisted conditions. Additionally, an unique Dy(III) ion-imprinted fibrous adsorbent (IIF-3) was fabricated by cross-linking of the aminated and phosphorylated PANF for selective capture of Dy(III) from wastewater. The advantages of this innovative technology in synthesizing fibrous adsorbent include: short reaction time, high phosphonic content and good mechanical property. In addition, batch sorption tests reveal that the uptake of Dy(III) onto IIF-3 is well described by the Langmuir isotherm and pseudo-second order models. Besides, IIF-3 exhibits a high adsorption selectivity for Dy(III) in multi-component system with different types of interfering ions. Importantly, benefiting from the protective effect of surface imprinting layer, the IIF-3 not only achieves enhanced mechanical property, but also shows satisfied reusability in six times application. This work opens a novel path to prepare phosphorylated ion-imprinted fibers and sheds light on their applications for selective capture of Dy(III) from wastewater.

A synergistic strategy based on active hydroxymethyl amine compounds and fucoidan for bioprosthetic heart valves with enhancing anti-coagulation and anti-calcification properties

With an aging population, the patients with valvular heart disease (VHD) are growing worldwide, and valve replacement is a primary choice for these patients with severe valvular disease. Among them, bioprosthetic heart valves (BHVs), especially BHVs trough transcatheter aortic valve replacement, are widely accepted by patients on account of their good hemodynamics and biocompatibility. Commercial BHVs in clinic are prepared by glutaraldehyde cross-linked pericardial tissue with the risk of calcification and thrombotic complications. In the present study, a strategy combines improved hemocompatibility and anti-calcification properties for BHVs has been developed based on a novel non-glutaraldehyde BHV crosslinker hexakis(hydroxymethyl)melamine (HMM) and the anticoagulant fucoidan. Besides the similar mechanical properties and enhanced component stability compared to glutaraldehyde crosslinked PP (G-PP), the fucoidan modified HMM-crosslinked PPs (HMM-Fu-PPs) also exhibit significantly enhanced anticoagulation performance with a 72 % decrease in thrombus weight compared with G-PP in ex-vivo shunt assay, along with the superior biocompatibility, satisfactory anti-calcification properties confirmed by subcutaneous implantation. Owing to good comprehensive performance of these HMM-Fu-PPs, this simple and feasible strategy may offer a great potential for BHV fabrication in the future, and open a new avenue to explore more N-hydroxymethyl compound based crosslinker with excellent performance in the field of biomaterials.

Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) – Current literature review of diagnostics and therapy. What has changed in the management?

Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) are malignancies originating from cells of the diffuse endocrine system. They are rare and localize in the upper and lower parts of gastrointestinal tract and in the pancreas. Despite such varied localization, GEP-NENs are considered a common group of neoplasms due to the fact of their similar morphology and ability to secrete peptide hormones and biologically active amines. They are associated with clinical manifestations specific to the substances produced by a particular neoplasm. The classification of GEP-NENs is constantly systematized and updated based on their differentiation and grading. The development of available diagnostic and treatment methods for these tumors has made significant progress over the past 10 years and is improved all the time. In the following paper, we review the diagnosis and treatment of GEP-NENs, taking into account the latest molecular, immunological or gene-based methods. Imaging methods using markers for receptors allow for high diagnostic sensitivity. Surgical management is still the method of choice in the treatment of GEP-NENs, but over the years it has been supplemented by selective pharmacotherapy for complete resolution and prevention of metastases. Numerous new substances are still in clinical trials, which offers prospects for the future of GEP-NENs diagnostics and therapy.

Ion Exchanger‐Based Electrodes for Determination of Highly Lipophilic Physiologically Active Amines: Peculiarities of Functioning and Ways for Improving Analytical Characteristics

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Chiral Aldehyde Catalysis-Enabled Asymmetric α-Functionalization of Activated Primary Amines.

ConspectusThe development of catalytic activation modes provides a reliable and effective platform for designing new enantioselective reactions and preparing chiral molecules with diverse structures. Chiral aldehyde catalysis is an attractive concept in asymmetric catalysis, which utilizes a chiral aldehyde catalyst to promote the asymmetric hydroamination of allylic amines, the asymmetric α-functionalization of primary amines, or the asymmetric transamination of α-keto esters. Typically, the chiral aldehyde-catalyzed asymmetric α-functionalization of primary amines provides an efficient and straightforward method for the synthesis of α-functionalized chiral amines, which does not require any additional protection or deprotection manipulations of the amine group. However, achieving catalytic stereoselective transformations with high efficiency and enantioselectivity by this strategy has remained an intractable challenge.This Account summarizes our endeavors in the development and application of chiral aldehyde catalysis. Using a chiral aldehyde as a catalyst, we reported the catalytic asymmetric α-C alkylation of 2-aminomalonate with 3-indolylmethanol in 2014, which represents the first chiral aldehyde-catalyzed asymmetric α-functionalization of an activated primary amine. Subsequently, several axially chiral aldehyde catalysts were continuously prepared by using chiral BINOL as the starting material, and their applications in asymmetric synthesis were explored. On the one hand, they were used as organocatalysts to realize the various transformations of α-amino acid esters, such as asymmetric 1,4-addition toward conjugated enones/α,β-unsaturated diesters and cyclic 1-azadienes as well as asymmetric α-arylation/allylation and benzylation with corresponding halohydrocarbons. Notably, taking advantage of the difference in the distribution of catalytic sites between two chiral aldehyde catalysts, we disclosed chiral aldehyde-catalyzed diastereodivergent 1,6-conjugated addition and Mannich reactions. On the other hand, the potential for the cooperative catalysis of a chiral aldehyde with a transition metal has also been demonstrated. Enabled by the combination of a chiral aldehyde, a palladium complex, and a Lewis acid, the enantioselective α-allylation of amino acid esters with allyl alcohol esters was established. Moreover, the ternary catalytic system has been successfully used for the α-functionalization of amino acid esters with 1,3-dienes, allenes, allenylic alcohol esters, 1,3-disubstituted allyl alcohol esters, and arylmethanol esters as well as the asymmetric cascade Heck-alkylation reaction. The combination of a chiral aldehyde and nickel complex allows for the asymmetric α-propargylation of amino acid esters with propargylic alcohol esters and provides excellent enantioselectivities. These transformations provide a large library of optically active amines and amino acids. With those chiral amino acid esters as key building blocks, the synthesis or formal synthesis of multiple natural products and biologically significant unnatural molecules was accomplished. This includes the stereodivergent synthesis of natural pyrrolizidine alkaloid NP25302 and the formal synthesis of natural product (S)-hypoestestatin 1 and manzacidin C, clinical candidate compound (+)-AG-041R, and somatostatin mimetics. It is fully anticipated that chiral aldehyde catalysis will soon witness rapid expansion both in the development of novel asymmetric transformations and in innovative applications for constructing optically active nitrogen-containing molecules with significant values.

Biocatalytic reductive aminations with NAD(P)H-dependent enzymes: enzyme discovery, engineering and synthetic applications.

Chiral amines are pivotal building blocks for the pharmaceutical industry. Asymmetric reductive amination is one of the most efficient and atom economic methodologies for the synthesis of optically active amines. Among the various strategies available, NAD(P)H-dependent amine dehydrogenases (AmDHs) and imine reductases (IREDs) are robust enzymes that are available from various sources and capable of utilizing a broad range of substrates with high activities and stereoselectivities. AmDHs and IREDs operate via similar mechanisms, both involving a carbinolamine intermediate followed by hydride transfer from the co-factor. In addition, both groups catalyze the formation of primary and secondary amines utilizing both organic and inorganic amine donors. In this review, we discuss advances in developing AmDHs and IREDs as biocatalysts and focus on evolutionary history, substrate scope and applications of the enzymes to provide an outlook on emerging industrial biotechnologies of chiral amine production.

Melatonin as a master regulatory hormone for genetic responses to biotic and abiotic stresses in model plant Arabidopsis thaliana: a comprehensive review.

Melatonin is a naturally occurring biologically active amine produced by plants, animals and microbes. This review explores the biosynthesis of melatonin in plants, with a particular focus on its diverse roles in Arabidopsis thaliana, a model species. Melatonin affects abiotic and biotic stress resistance in A. thaliana. Exogenous and endogenous melatonin is addressed in association with various conditions, including cold stress, high light stress, intense heat and infection with Botrytis cinerea or Pseudomonas, as well as in seed germination and lateral root formation. Furthermore, melatonin confers stress resistance in Arabidopsis by initiating the antioxidant system, remedying photosynthesis suppression, regulating transcription factors involved with stress resistance (CBF, DREB, ZAT, CAMTA, WRKY33, MYC2, TGA) and other stress-related hormones (abscisic acid, auxin, ethylene, jasmonic acid and salicylic acid). This article additionally addresses other precursors, metabolic components, expression of genes (COR, CBF, SNAT, ASMT, PIN, PR1, PDF1.2 and HSFA) and proteins (JAZ, NPR1) associated with melatonin and reducing both biological and environmental stressors. Furthermore, the future perspective of melatonin rich agri-crops is explored to enhance plant tolerance to abiotic and biotic stresses, maximise crop productivity and enhance nutritional worth, which may help improve food security.

Asymmetric Hydrogenation of Phenanthridines with Chiral Boranes

Comprehensive SummaryThe asymmetric hydrogenation of N‐heteroarenes provides an efficient method for the synthesis of optically active cyclic secondary amines. In this paper, we described an asymmetric hydrogenation of phenanthridines using a chiral mono‐alkene‐derived borane. A variety of dihydrophenanthridines were furnished in high yields with up to 93% ee. The current catalytic system was very sensitive for the steric hindrance of phenanthridines. Bulky substituents at one phenyl group of phenanthridines were required to obtain the high enantioselectivity. But large substituents on the carbon of the C=N bonds would diminish the reactivity sharply.

Distinctive Features of 3‐Acetyl‐ and 3‐Benzoyl‐Isocoumarins’ Interaction with Active Primary Amines

AbstractIsoquinolones and isoquinolines are crucial natural and synthetic heterocyclic compounds exhibiting a range of biological activities. A less explored strategy for the recyclization of isocoumarins to isoquinolones involves the transformation of 1H‐isochromen‐1‐ones with a carbonyl group at position 3 using primary amines. This study presents a straightforward one‐pot protocol for the recyclization of 3‐acetyl‐ and 3‐benzoylisocoumarins into their corresponding isoquinolone derivatives using structurally diverse primary amines. This provides versatile and scalable routes for accessing a variety of 2‐R‐isoquinolin‐1(2H)‐ones. Interestingly, the acyl group also reacted with the hydroxyl group of 2‐aminoethanol, leading to the simultaneous formation of 3,4‐dihydro[1,4]oxazino[4,3‐b]isoquinolin‐6(1H)‐ones alongside lactone recyclization. Moreover, the recyclization process was accompanied by more complex alternative cyclizations, including an oxidative‐reductive stage. For instance, the recyclization of isocoumarins with benzylamine resulted in the formation of isochromeno[3,4‐c]pyrroles, whereas with glycine derivatives, 1,2‐dihydro‐6H‐pyrazino[1,2‐b]isoquinolin‐3,6(4H)‐diones were obtained.

Ultraviolet Light Responsive N-Nitroso Polymers for Antibacterial Nitric Oxide Delivery.

This study investigates the incorporation of active secondary amine moieties into the polymer backbone by co-polymerizing 2,4,6-tris(chloromethyl)-mesitylene with three diamines, namely 1,4-diaminobutane, m-phenylenediamine, and p-phenylenediamine. This process results in the stabilization of the amine moieties and the subsequently introduced nitroso groups. Charging bioactive nitric oxide (NO) into the polymers is accomplished by converting the amine moieties into N-nitroso groups. The ability of the polymers to store and release NO depends on their structures, particularly the amount of incorporated active secondary amines. With grafting photosensitive N-nitroso groups into the polymers, the derived NO@polymers exhibit photoresponsivity. NO release is completely regulated by adjusting UV light irradiation. These resulting polymeric NO donors demonstrate remarkable bactericidal and bacteriostatic activity, effectively eradicating E. coli bacteria and inhibiting their growth. The findings from this study hold promising implications for combining NO delivery with phototherapy in various medical applications.

Study and Characterization of Tribofilm based on Activated Carbon-Nanochitosan Modified with Silicone Oil for Application of Self-Healing Coatings on Metal Surfaces

A tribofilm material based on activated carbon and nanochitosan modified with silicone oil has been prepared using the sol gel method with variations in the composition of activated carbon at a mass ratio of 40% wt – 60% wt at 5% wt intervals. Sampling was carried out in two stages. The first stage of the synthesis of activated carbon from palm shells using activation of 7% H3PO4 and nanochitosan derived from shrimp shells using the ionic gelation method. The second stage was mixing the tribofilm material of activated carbon, nanochitosan and silicone oil using the sol gel method to produce a film-forming solution which was then characterized including: physical, chemical, mechanical and thermal properties. The characterization results showed that the most optimum composition was the tribofilm material of activated carbon/nanochitosan/silicone oil in S1 with a mass ratio of 40%wt activated carbon which produced a density of 0.94 x 103 kg/m3, a viscosity of 28.42 cP, and a liquid surface tension of 63.5 mN/m. While the performance characteristics of the metal surface coating produce a surface roughness of 0.162 µm for aluminum metal and 0.156 µm for copper metal, friction coefficient 0.024, wear rate 0.19 mm, thermal conductivity 0.092 W/m.K, corrosion properties 1a (slight tarnish), rate corrosion rate of 2.34 mm/yr in 3.5% NaCl medium, 4.33 mm/yr in seawater medium and 11,476 mm/yr in 3% H2SO4 medium and has good self-healing properties for 3 days on carbon steel metal surfaces with corrosion scratch treatment on 3.5% NaCl media, namely almost all the scratches/cracks covered due to frictional force from galvanic corrosion with active carboxyl, amine and hydroxyl groups with the healing agent aminopropyl siloxane (NH2-R-NH-Si-O-R) which reacts with metal ion particles (M-OH) in the formation of polymer chains for new network layers.

Penurunan Cr6+ dari Limbah Batik dengan Menggunakan Kitosan dari Cangkang Kupang Putih

Chitosan is a biological material that has the potential as an environmentally friendly coagulant. Because based on its chemical structure, chitosan has an active amine group (NH2). The presence of a lone pair of electrons from the nitrogen atom in the amine group causes the group to be electronegative and very reactive to increase metal ions so that it is very good to be used to absorb metal ions. At the c-3 and c-6 atoms of the chitosan sugar group. This aims to reduce the levels of cr6+ in waste using an adsorption process where adsorption is a process that occurs when a fluid (liquid or gas) is bound to a solid and eventually forms a film (thin layer) on the surface of the solid. The adsorption uses chitosan media made from the white shell of mussel which has a weight of 3 grams, 5 grams, 7 grams, 9 grams and 11 grams with temperatures of 30 C, 45 C, 60 C, 75 C and 90 C. After making chitosan The weight of chitosan will be mixed with batik waste with a certain temperature and a rotation of 150 RPM. The best results are obtained at 11 grams at a temperature of 90 C, with the ability to reduce it to 94.62% with an initial concentration of 2.473 mg/l. at 11 grams with a temperature of 90 C, it is in accordance with SNI with group 2 where the cr6+ content is 0.5 mg/L.

Actinide Ion (Americium-241 and Uranium-232) Interaction with Hybrid Silica-Hyperbranched Poly(ethylene imine) Nanoparticles and Xerogels.

The binding of actinide ions (Am(III) and U(VI)) in aqueous solutions by hybrid silica-hyperbranched poly(ethylene imine) nanoparticles (NPs) and xerogels (XGs) has been studied by means of batch experiments at different pH values (4, 7, and 9) under ambient atmospheric conditions. Both materials present relatively high removal efficiency at pH 4 and pH 7 (>70%) for Am(III) and U(VI). The lower removal efficiency for the nanoparticles is basically associated with the compact structure of the nanoparticles and the lower permeability and access to active amine groups compared to xerogels, and the negative charge of the radionuclide species is formed under alkaline conditions (e.g., UO2(CO3)34- and Am(CO3)2-). Generally, the adsorption process is relatively slow due to the very low radionuclide concentrations used in the study and is basically governed by the actinide diffusion from the aqueous phase to the solid surface. On the other hand, adsorption is favored with increasing temperature, assuming that the reaction is endothermic and entropy-driven, which is associated with increasing randomness at the solid-liquid interphase upon actinide adsorption. To the best of our knowledge, this is the first study on hybrid silica-hyperbranched poly(ethylene imine) nanoparticle and xerogel materials used as adsorbents for americium and uranium at ultra-trace levels. Compared to other adsorbent materials used for binding americium and uranium ions, both materials show far higher binding efficiency. Xerogels could remove both actinides even from seawater by almost 90%, whereas nanoparticles could remove uranium by 80% and americium by 70%. The above, along with their simple derivatization to increase the selectivity towards a specific radionuclide and their easy processing to be included in separation technologies, could make these materials attractive candidates for the treatment of radionuclide/actinide-contaminated water.

Hypoxia-Responsive T2-to-T1 Dynamically Switchable Extremely Small Iron Oxide Nanoparticles for Sensitive Tumor Imaging In Vivo.

To realize the accurate diagnosis of tumors by magnetic resonance imaging (MRI), switchable magnetic resonance contrast agents (CAs) between T1 and T2 contrast enhancement that are constructed based on extremely small iron oxide nanoparticles (ESIONPs) have been developed in recent years. We herein report, for the first time, a novel ESIONP-based nanocluster (named EAmP), which exhibited hypoxia responsiveness to the tumor microenvironment and offered a T2-to-T1-switchable contrast enhancement function, effectively distinguishing between the normal tissue and tumor tissue. In detail, active perfluorophenyl ester-modified ESIONPs with a diameter of approximately 3.6 nm were initially synthesized, and then 4,4'-azodianiline was used as a cross-linker to facilitate the formation of nanoclusters from ESIONPs through the reaction between the active ester and amine. Finally, poly(ethylene glycol) was further modified onto nanoclusters by utilizing the remaining active ester residues. The resulting EAmP demonstrated satisfactory colloidal stability and favorable biosafety and exhibited a desired T2-to-T1-switchable function, as evidenced by conversion from nanocluster to the dispersed state and a significant decrease in the r2/r1 ratio from 14.86 to 1.61 when exposed to a mimical hypoxic environment in the solution. Moreover, EAmP could decompose into dispersed ESIONPs at the tumor region, resulting in a switch from T2 to T1 contrast enhancement. This T2-to-T1-switchable contrast agent offers high sensitivity and signal-to-noise ratio to realize the accurate diagnosis of tumors. In conclusion, hypoxia-responsive EAmP is a potential MRI nanoprobe for improving the diagnostic accuracy of solid tumors.

Highly active primary amine ligated Ru(II)-arene complexes as selective catalysts for solvent-free N-alkylation of Anilines

Efficient Ru(II) catalysts with substituted aniline based ligands were synthesized having chemical formula [Ru(η6-p-cymene)Cl2(L1)] [Ru-1] and [Ru(η6-p-cymene)Cl2(L2)] [Ru-2] (where, L1 = 3,5-bis(trifluoromethyl)aniline and L2 = 3,4,5- trimethoxy aniline). The structural features of both the complexes were authenticated by ESI-MS, 1H and 13C NMR, FT-IR, elemental analyses, and single-crystal X-ray diffraction studies. Catalytic performance of both [Ru-1] and [Ru-2] was investigated for conversion of primary amine to secondary amine using alcohols under milder and solvent-free conditions and compared with the reported aniline-based Ru(II)-arene complex [Ru-3]. Among them, [Ru-1] could achieve 100% selectivity towards mono N-alkylated amines with > 99% conversion without formation of any imine derivatives. The results suggested that the lone pair of electrons of benzyl alcohol binds easily to the electron-deficient Ru(II) center of [Ru-1] catalyst making it more effective compared to electron-rich [Ru-2] and [Ru-3] catalysts. The catalytic performance of [Ru-1] demonstrates that it is one of the most active primary amine ligated Ru(II) based catalytic systems for N-alkylation of anilines under milder and solvent-free conditions.

An Updated Review Summarizing the Anticancer Efficacy of Melittin from Bee Venom in Several Models of Human Cancers.

Apitherapy (using bee products) has gained broad recognition in cancer therapeutics globally. Honeybee venom has a broad range of biological potential, and its utilization is rapidly emerging in apitherapy. Bee products have significant potential to strengthen the immune system and improve human health. Thus, this review is targeted toward recapitulating the chemo-preventive potential of melittin (MEL), which constitutes a substantial portion of honeybee venom. Honeybee venom (apitoxin) is produced in the venom gland of the honeybee abdomen, and adult bees utilize it as a primary colony defense mechanism. Apitoxin comprises numerous biologically active compounds, including peptides, enzymes, amines, amino acids, phospholipids, minerals, carbohydrates, and volatile components. We are mainly focused on exploring the potential of melittin (a peptide component) of bee venom that has shown promising potential in the treatment of several human cancers, including breast, stomach, lung, prostate, ovary, kidney, colon, gastric, esophageal, cervical cancers, melanoma, osteosarcoma, and hepatocellular carcinoma. This review has summarized all potential studies related to the anticancerous efficacy of melittin (apitoxin), its formulations, conjugates, and nano-formulations against several human carcinomas, which would further pave the way for future researchers in developing potent drugs for cancer management.

A High-Efficient DOPO-Based Flame Retardant as a Co-Curing Agent for Simultaneously Enhancing the Fire Safety and Mechanical Properties of Epoxy Resin.

Simultaneously enhancing the fire safety and mechanical properties of epoxy resin (EP) remains a persistent challenge. Herein, a high-efficient phosphaphenanthrene-based flame retardant (FNP) is synthesized using 3,5-diamino-1,2,4-triazole, 4-formylbenzoic acid, and 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide. Due to the presence of active amine groups, FNP is employed as a co-curing agent for fabricating EP composites with outstanding fire safety and mechanical properties. EP containing 8 wt% FNP (EP/8FNP) achieves a vertical burning (UL-94)V-0 rating with a limiting oxygen index of 31%. Meanwhile, FNP declines the peak heat release rate, total heat release, and total smoke release of EP/8FNP by 41.1%, 31.8%, and 16.0%, respectively, compared to those of unmodified EP. The increased fire safety of EP/FNP composites is because FNP promotes the formation of an intumescent, compact, and cross-linking char layer for EP/FNP composites, and releases P-containing substances and noncombustible gases in the gas phase during combustion. In addition, EP/8FNP exhibits 20.3% and 5.4% increase in the flexural strength and modulus compared with those of pure EP. Furthermore, FNP enhances the glass transition temperature of EP/FNP composites from 141.6 °C for pure EP to 147.3 °C for EP/8FNP. Therefore, this work is conducive to the future development of fabricating fire-safe EP composites with enhanced mechanical properties.

W-Phos Ligand Enables Copper-Catalyzed Enantioselective Alkylation of N-Sulfonyl Ketimines with Grignard Reagents

Catalytic asymmetric addition of reactive Grignard reagents to ketimines poses a considerable challenge. Herein, a PNP-type W-Phos ligand developed recently by our group showed a unique effect toward this end, paving the way to a Cu(I)-catalyzed asymmetric alkylation reaction of N-sulfonyl ketimines, delivering optically active α-tertiary amines in high enantioselectivities. This catalytic protocol shows an unprecedented substrate scope with more than 80 examples, not only compatible with benzo five- and six-membered cyclic N-sulfonyl ketimines but also suitable for geometrically unstable (E or Z) acyclic N-sulfonyl ketimines. The application potential of the protocol is featured by the extensive presence of α-tertiary amines in natural products and pharmaceutical compounds and also demonstrated by downstream transformations with maintenance of the enantioselectivity.

Computational design and molecular modeling of morphine derivatives for preferential binding in inflamed tissue.

The opioid epidemic has impacted over 10million Americans in 2019. Opioids, like morphine, bind non-selectively in both peripheral tissue, leading to effective pain relief, and central tissue, resulting in dangerous side effects and addiction. The inflamed conditions of injured tissues have a lower pH (pH=6-6.5) environment than healthy tissue (pH=7.4). We aim to design a morphine derivative that binds selectively within inflamed tissue using molecular extension and dissection techniques. Morphine binds to the μ-opioid receptor (MOR) when the biochemically active amine group is protonated. Fluorination of a β-carbon from the tertiary amine group led to a reduced pKa of the derivative through induction. Through a decrease in the pKa, protonation is still statistically favored in lower pH environments of inflamed tissue but primarily deprotonated in healthy tissue. The cyclohexenol and N-methyl-piperidine rings of morphine are removed to increase conformational flexibility when binding while still maintaining the interactions required for analgesia. Electronic structure calculations were performed with Gaussian16 using the Keck Computational Research Cluster at Chapman University to determine the pKa. The theoretical pKa values are determined at the M06-2X(SMD)/aug-cc-pVDZ level of theory to calculate the ΔG°aq values for the amine deprotonation reactions. Fluoromorphine β-C2 was designed computationally and modeled within the MOR using Maestro: Schrödinger. This derivative exhibits a pKa reduction and enhanced ligand-protein interactions within the MOR. β-fluorination decreased the overall pKa values of the morphine derivatives (pKa: 6.1-7.83) relative to morphine, reducing binding within healthy, central tissue.