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A divergent synthesis of skeletally distinct arboridinine and arborisidine was achieved. The central divergent strategy was inspired by the divergent biosynthetic cyclization mode of arboridinine and arborisidine and their hidden topological connection. The branch point was reached through a Michael and Mannich cascade process. A site-selective intramolecular Mannich reaction was developed to construct the tetracyclic core of arboridinine, while a site-selective intramolecular α-amination of ketone was used to access the tetracyclic core of arborisidine. A strategic Peterson olefination through intramolecular nucleophile delivery was able to set up the exocyclic olefin of arboridinine.

ConspectusNatural products are constructed by organisms in impressive ways through various highly selective enzyme-catalyzed chemical reactions. Over the past century, there has been considerable interest in understanding and emulating the underlying biosynthetic logic for the target molecule. The successful implementation of a biomimetic strategy usually has some uniquely valuable benefits over other abiotic routes in total synthesis by (1) corroborating the chemical feasibility of a given biogenetic hypothesis and further unraveling some insightful implications for future biosynthetic studies and (2) providing remarkably more concise access to not only the original synthetic target but also diversified biogenetically related congeners, which may result in either the structural reassignment of previously disclosed natural products or the anticipation of undiscovered natural products. However, for the devised essential biomimetic transformation, fine-tuning the optimization of the substrates and the reaction conditions can sometimes be painstakingly challenging. Turning to nature for inspiration can provide additional impetus for methodological innovations.Previously used as oral veterinary drugs, lankacidins have potential as next-generation antibiotics to tackle the problems caused by multidrug-resistant bacteria with novel modes of action (MoAs). The hypersensitive and densely functionalized lactonic core within this family of macrocyclic polyketides poses a formidable challenge for chemical total synthesis and derivatization. In this account, we summarized the evolution of a unified biomimetic approach toward 10 lankacidin antibiotics and their linear biosynthetic intermediates in the longest linear 7-12 steps from readily available starting materials. Our endeavor commenced with an intermolecular bioinspired amido sulfone-based Mannich reaction approach to assemble 2 advanced fragments under mild biphasic organocatalytic conditions. It successfully gave rise to stereodivergent access to 4 C2/C18-isomeric lankacyclinols but failed to efficiently deliver lactone-containing congeners through Stille macrocyclization. Facilitated by the thermolysis chemistry of N,O-acetal to generate the requisite N-acyl-1-azahexatriene species, we realized the projected Mannich macrocyclization and eight macrocyclic lankacidins can be produced by orchestrated desilylative manipulations. In this process, we were able to perform structural reassignments of isolankacidinol (7 to 50) and isolankacyclinol (104 to 83) and, for the first time, elucidate the natural occurrence of 2,18-bis-epi-lankacyclinol (84). Moreover, the inability of the current biomimetic route to cofurnish the reported structure of 2,18-seco-lankacidinol A (15) triggered a proposed structural revision that is rooted in reconsidered biogenesis and was confirmed by a divergent synthesis that enabled us to identify the correct isomer (116). Finally, the modular, diversity-oriented design also provided streamlined entries to acyclic 2,18-seco-lankacidinol B (120) and the biosynthetic intermediate LC-KA05 (17) together with its C7-O-deacetylated congeners in all C4/C5-stereochemical variations (18, 127-129), culminating in a need for structural revision to the six-membered lactonic segment in LC-KA05-2. The selection and execution of biomimetic strategies in lankacidin total synthesis give rise to all the previously mentioned advantages at the current stage. The modular-based, late-stage diversified complex construction offers an exceptionally high level of synthetic flexibility for future synthetic forays toward newly isolated or chemically modified congeners within the lankacidin family.

KYNAs, a compound with endogenous neuroprotective functions and an indole that is a building block of many biologically active compounds, such as a variety of neurotransmitters, are reacted in a transformation building upon Mannich bases. The reaction yields triarylmethane derivatives containing two biologically potent skeletons, and it may contribute to the synthesis of new, specialised neuroprotective compounds. The synthesis has been investigated via two procedures and the results were compared to those of previous studies. A possible alternative reaction route through acid catalysis has been established.

A series of 3-substituted-2-hydroxy-1,4-naphthoquinone derivatives with a variety of side chains were successfully synthesized by Mannich reaction of 2-hydroxy-1,4-naphthoquinone (lawsone) with selected amines and aldehydes. All substances (1-16) were evaluated for in-vitro antimalarial activity against strains of Plasmodium falciparum by microculture radioisotope technique. Bioassay data revealed that ten derivatives (1-8, 11 and 13) displayed significantly good activity with values of IC50 ranging from 0.77 to 4.05 µg/mL. The best biological profile (IC50 = 0.77 µg/mL) was observed in compound 1, possessing a n-butyl substituted aminomethyl group. Experimental results support the potential use of our active Mannich components as promising antimalarial agents in the fight against malaria infections and multidrug resistance problems.

The antitumor indole–indoline alkaloids of the evergreen Catharanthus roseus—namely vinblastine and vincristine—are widely used in chemotherapy of cancer. Many efforts were made to synthesize more efficient derivatives with less side-effect. The 14,15-cyclopropane derivative of vinblastine was synthesized successfully by a five-step procedure starting from vindoline. Vincristine, vinorelbine and several derivatives condensed with a cyclopropane ring were synthesized. Various hybrid molecules were prepared by the coupling reaction of vindoline and methyl ester of tryptophan, which were conjugated by carrier peptides of octaarginine. Studying the halogenation reactions of vindoline and catharanthine some fluorine derivatives were obtained which showed promising antitumor activity on various tumor types. The synthesis of the Aspidospermane alkaloid bannucine and 5′-epibannucine were carried out using N-acyliminium intermediates. The same intermediate was also applied in the first synthesis of sessiline. The research group have synthesized of flavonoid alkaloids: dracocephins A and B. Further three flavonoid alkaloids, namely 8-(2”-pyrrolidinon-5′′-yl)quercetin, 6-(2′′-pyrrolidinon-5′′-yl)-(−)- and 8-(2′′-pyrrolidinon-5′′-yl)-(−)-epicatechin were prepared by acid-catalyzed regioselective Mannich reaction starting from the corresponding flavonoid precursor. Vindoline was also coupled to synthetic pharmacophores, such as triphenylphosphine and various N-heterocycles. Some of these hybrid molecules showed significant antitumor activity. Furthermore, 7-OH and 7-NH modified flavonoid derivatives were synthesized by a regioselective alkylation followed by Smiles rearrangement and hydrolysis.

We report 8‐step syntheses of (−)‐minovincine and (−)‐aspidofractinine using easily available and inexpensive reagents and catalyst. A key element of the strategy was the utilization of a sequence of cascade reactions to rapidly construct the penta‐ and hexacyclic frameworks. These cascade transformations included organocatalytic Michael‐aldol condensation, a multistep anionic Michael‐SN2 cascade reaction, and Mannich reaction interrupted Fischer indolization. To streamline the synthetic routes, we also investigated the deliberate use of steric effect to secure various chemo‐ and regioselective transformations., Concise syntheses of (−)‐minovincine and (−)‐aspidofractinine were achieved using easily available and inexpensive reagents and catalyst. A key element of the strategy was the use of a sequence of cascade reactions to rapidly construct the penta‐ and hexacyclic frameworks. To streamline the synthetic routes, the steric effect was used to secure various chemo‐ and regioselective transformations.

Lysozyme, a type of natural enzyme, has been widely used for bacteriostatic functionalization of various materials due to its efficient and selective antibacterial properties. Herein, we report the preparation and characterization of an eco-friendly antibacterial textile based on the immobilization of lysozyme from chicken egg white onto wool fibers. Tris(hydroxymethyl)phosphine (THP) was employed as the cross-linker for the immobilization of lysozyme on the surface of wool fiber. The mechanism of THP cross-linking was investigated via phosphorus test, energy-dispersive spectroscopy (EDX) and Fourier transform infrared spectroscopy (FT-IR). The surface staining, optimization of immobilization parameters, morphology, antibacterial properties, and durability of wool fibers with immobilized lysozyme were also assessed. The results show that hydroxymethyl groups of THP reacted with amino groups of wool fiber and lysozyme through Mannich reaction, which successfully immobilized lysozyme on the wool fiber. The wool fibers incorporated with lysozyme had better antibacterial properties and durability compared with the untreated wool fabric. This facile immobilization approach of lysozyme provides an effective strategy for environmentally benign modification and functionalization of keratin and keratin-containing materials.

In this present study, a detailed study of metal chelates of Mannich base derived from barbituric acid have been carried out with particular reference to the structural aspects of the ligand moieties in the metal complexes. The ligand and its complexes of ZnII, CdII and HgII were characterized by elemental analysis, 1H NMR, IR and Mass spectral techniques. Conductance measurements of the complexes, anticorrosion study and antimicrobial study of ligand and its complexes were also analysed.

Mannich bases are compounds bearing a β-amino carbonyl moiety. They are formed in the Mannich reaction that consists of an amino alkylation of an acidic proton placed next to a carbonyl functional group by formaldehyde and a primary or secondary amine. Mannich base products are known for their curative properties such as anti-inflammatory, antibacterial, anticancer, antifungal, anthelmintic, anticonvulsant, analgesic, anti-HIV, antipsychotic, antiviral, and antimalarial activities. Further, thiazolidinedione derivatives have shown to be efficacious in inflammatory diseases as wide-ranging as psoriasis, ulcerative colitis and non-alcoholic steatohepatitis. In light of the above observations, new series of thiazolidine-2,4-dione based Mannich base derivatives were synthesized via a simple and catalyst-free procedure involving the condensation of thiazolidine-2,4-dione, formaldehyde and secondary amines in DMF solvent. The structures of the newly synthesized compounds were confirmed by their IR, 1H-NMR, and Mass spectra. The synthesized compounds were tested for their in silico anti-inflammatory activity by Docking studies against COX-2 enzyme (PDB: 1CX2). Compounds 4a and 4b showed good in silico anti-inflammatory properties comparable to that of standard drug Diclofenac and may be considered as promising candidates for the development of new anti-inflammatory agents.

The part of the influenza polymerase PA subunit featuring endonuclease activity is a target for anti-influenza therapies, including the FDA-approved drug Xofluza. A general feature of endonuclease inhibitors is their ability to chelate Mg2+ or Mn2+ ions located in the enzyme’s catalytic site. Previously, we screened a panel of flavonoids for PA inhibition and found luteolin and its C-glucoside orientin to be potent inhibitors. Through structural analysis, we identified the presence of a 3′,4′-dihydroxyphenyl moiety as a crucial feature for sub-micromolar inhibitory activity. Here, we report results from a subsequent investigation exploring structural changes at the C-7 and C-8 positions of luteolin. Experimental IC50 values were determined by AlphaScreen technology. The most potent inhibitors were C-8 derivatives with inhibitory potencies comparable to that of luteolin. Bio-isosteric replacement of the C-7 hydroxyl moiety of luteolin led to a series of compounds with one-order-of-magnitude-lower inhibitory potencies. Using X-ray crystallography, we solved structures of the wild-type PA-N-terminal domain and its I38T mutant in complex with orientin at 1.9 Å and 2.2 Å resolution, respectively.

Talatisamine (1) is a member of the C19 -diterpenoid alkaloid family, and exhibits K+ channel inhibitory and antiarrhythmic activities. The formidable synthetic challenge that 1 presents is due to its highly oxidized and intricately fused hexacyclic 6/7/5/6/6/5-membered-ring structure (ABCDEF-ring) with 12 contiguous stereocenters. Here we report an efficient synthetic route to 1 by the assembly of two structurally simple fragments, chiral 6/6-membered AE-ring 7 and aromatic 6-membered D-ring 6. AE-ring 7 was constructed from 2-cyclohexenone (8) through fusing an N-ethylpiperidine ring by a double Mannich reaction. After coupling 6 with 7, an oxidative dearomatization/Diels-Alder reaction sequence generated fused pentacycle 4 b. The newly formed 6/6-membered ring system was then stereospecifically reorganized into the 7/5-membered BC-ring of 3 via a Wagner-Meerwein rearrangement. Finally, Hg(OAc)2 induced an oxidative aza-Prins cyclization of 2, thereby forging the remaining 5-membered F-ring. The total synthesis of 1 was thus accomplished by optimizing and orchestrating 33 transformations from 8.

Low-cost natural polymer lignin has been widely used to remove heavy metal ions from polluted water. But it still has some shortcomings, such as poor removal performance, and weak selective adsorption. Thus, in this study, the lignin prepared by Mannich reaction with black liquor was activated with triethylenetetramine (TETA) to achieve a novel adsorbent with high adsorption rates and a strong selectivity for specific oxygen-containing anions. The adsorption capacity of activated lignin (a-CL) on three oxygen-containing anions (i.e. As(V), P(V) and Cr(VI)) was investigated systematically. The adsorption mechanism of a-CL was elucidated theoretically by the density functional theory (DFT) method. Under the same conditions, the selectivity toward oxygen-containing anions by a-CL followed P(V) Cr(VI) As(V). Both FT-IR and DFT simulation results revealed that the hydrogen bond between HAsO

A new catalytic system comprising chiral Ag complex and Li aryloxide/bisphosphine oxide is developed for the synthesis of β2,2-amino acids via direct asymmetric Mannich-type reaction of 4-subsituted isoxazolidin-5-ones. The Mannich adduct is a direct precursor of β-peptidic compounds otherwise difficult to obtain.

For its unique role in developing and designing new bioactive materials and healthcare products, fluoro-organic compounds have attracted remarkable interest. Along with ever-increasing demand for a wider availability of fluorine-containing structural units, a large diversity of methods has been introduced to incorporate fluorine atoms specially in a stereoselective fashion. Among them, catalytic Mannich reaction can proceed with a broad variety of reactants and open clear paths for the synthesis of versatile amine synthons in the synthesis of natural product and pharmaceutical molecules. This review provides an overview of the employment of catalytic asymmetric Mannich reactions in the synthesis of fluorine-containing amine compounds and highlights the conceivable distinct mechanisms.

In this short review we will concentrate on the newest methods for the synthesis of this type of important heterocyclic compounds...

Kopsinitarines A-E are complex octacyclic caged Kopsia alkaloids with strained cage skeletons and a unique cyclic hemiaminal bridge that makes total synthesis challenging. Herein, we disclose the first total synthesis of kopsinitarine E. The key synthetic features include a SmI2 -mediated radical cascade cyclization and a subsequent semi-pinacol rearrangement to install the key carbocyclic skeleton, a chemoselective hydrosilyl amide reduction to construct the hemiaminal ether bridge, and an intramolecular Mannich reaction to establish the highly strained cage system.

BACKGROUND The benzimidazole ring is an important pharmacophore in modern drug discovery. Mannich reaction is one of the versatile reaction widely used in organic synthesis. Mannich base derivatives play an important role in medical field with diverse biological actions. OBJECTIVE A series of N-(benzimidazol-1-ylmethyl)-4-chlorobenzamide derivatives (3a- 3m) were synthesized and evaluated for anti-inflammatory and antimicrobial potential. METHOD Mannich reaction was used to synthesize N-(benzimidazol-1-ylmethyl)-4- chlorobenzamide analogues. The structures of novel target compounds were elucidated by spectral and analytical techniques and screened for in vivo anti-inflammatory activity and ulcerogenic activity. In addition, the prepared derivatives were also evaluated for in vitro antimicrobial activity against gram negative, gram positive and fungal strains. Further, in silico studies were carried out to define the interaction of the title compounds with COX-2 enzyme and microbial protein. RESULTS The results revealed that out of thirteen molecules, compound 3a (containing chloromethyl substituent at 2-position of benzimidazole) showed significant antiinflammatory effect at a dose of 100 mg/kg p.o. and the experimental data was statistically significant at p≤0.05 level. Diclofenac sodium was taken as standard drug for antiinflammatory activity. Furthermore, derivative 3e (containing 2-chlorophenyl moiety at 2- position of benzimidazole scaffold) was found to be the most effective antimicrobial compound among the synthesized derivatives. Ciprofloxacin and clotrimazole were used as reference antimicrobial agents. Results from in vivo and in vitro studies of synthesized analogues were found to be in good correlation with in silico study. CONCLUSION These results designate that N-(Benzimidazol-1-ylmethyl)-4-chlorobenzamide analogues, substituted with halogen functionality, could be used as potential lead for designing more potent anti-inflammatory and antimicrobial agents.

The Chlorella vulgaris harvesting was explored by magnetic separation using Fe3O4 particles coated with the plant polyphenol chemically modified by a Mannich reaction followed by quaternization (Fe3O4@Q-PP). The -N(R)4+ and Cl-N+-C perssad of the Q-PP were linked to the Fe3O4 particles by N-O bonds, as suggested by the X-ray photoelectron spectroscopy spectra. The thermogravimetric analysis displayed the mass percentage of the Q-PP coated on the Fe3O4 surface was close to ~ 5%. Compared with the naked Fe3O4 particles, zeta potentials of the Fe3O4@Q-PP particles were improved from the range of - 17.5~- 25.6 mV to 1.9~36.3 mV at pH 2.1~13.1. A 70.2 G coercive force was obtained for the Fe3O4@Q-PP composite, which demonstrated its ferromagnetic behavior. The use of Fe3O4@Q-PP resulted in a harvesting efficiency of 90.9% of C. vulgaris cells (3.06 g/L). The Fe3O4 particles could be detached from the cell flocs by ultrasonication leading to a recovery efficiency of 96.1% after 10 cycles. The recovered Fe3O4 could be re-coated with Q-PP and led to a harvesting efficiency of 80.2% after 10 cycles. The magnetic separation using Fe3O4@Q-PP included charge neutralization followed by bridging and then colloid entrapment.

Tannin extracts from the bark of Acacia mearnsii and wood of Schinopsis balansae, commonly known as Quebracho, were employed. These were modified at laboratory sale via the Mannich aminomethylation with formaldehyde and dimethylamine hydrochloride. Some reaction conditions were varied, namely the formaldehyde dosage and reaction time, while keeping the Mannich solution activation time constant, and their influence on the shear viscosity of the created bio-coagulants was evaluated. The effect of the final pH of the products on their shear viscosity was also analyzed. Up-scaling of the Mannich reaction for tannin from South Africa was performed and the procedure developed at 1-L scale was reproducible in upscaled conditions. One example of a modified South Africa tannin and the modified Quebracho tannin was subsequently selected for the treatment of an industrial wastewater and tested for color and turbidity reduction in jar tests. The effluent treatment was carried out in a single and dual system with cationic synthetic flocculation agents of different charge degree. Good turbidity and decoloration results (93 and 89% reduction, respectively) were obtained with the simultaneous introduction of a cationic, 40% charged polyacrylamide, with minimal dosage (5 ppm) of the latter additive. The tannin-based coagulant from Acacia mearnsii was successfully applied in dual system with cationic polyacrylamide flocculant for industrial wastewater treatment at pilot plant scale. It was shown to satisfactorily treat the water and generate less sludge.

A new diastereoselective route to 2-aminotetrahydrofurans has been developed from N,O-dialkenylhydroxylamines. These intermediates undergo a spontaneous C-C bond-forming [3,3]-sigmatropic rearrangement followed by a C-O bond-forming cyclization. A copper-catalyzed N-alkenylation of an N-Boc-hydroxylamine with alkenyl iodides, and a base-promoted addition of the resulting N-hydroxyenamines to an electron-deficient allene, provide modular access to these novel rearrangement precursors. The scope of this de novo synthesis of simple nucleoside analogues has been explored to reveal trends in diastereoselectivity and reactivity. In addition, a base-promoted ring-opening and Mannich reaction has been discovered to covert 2-aminotetrahydrofurans to cyclopentyl β-aminoacid derivatives or cyclopentenones.

One-bead-one-compound (OBOC) libraries constructed by solid-phase split-and-pool synthesis are a valuable source of protein ligands. Most OBOC libraries are comprised of oligoamides, particularly peptides, peptoids, and peptoid-inspired molecules. Further diversification of the chemical space covered by OBOC libraries is desirable. Toward this end, we report here the efficient proline-catalyzed asymmetric Mannich reaction between immobilized aldehydes and soluble ketones and anilines. The reaction conditions do not compromise the amplification of DNA by the PCR. Thus, this chemistry will likely be useful for the construction of novel DNA-encoded libraries by solid-phase synthesis.

Novel nontoxic derivatives of SN38 with favorable antineoplastic properties were characterized in water solution using NMR. The phenomena observed by NMR were linked to basic pharmacological properties, such as solubility, bioavailability, chemical and stereochemical stability, and binding to natural DNA oligomers through the terminal G-C base pair, which is commonly considered a biological target of Topo I inhibitors. Compound 1, with bulky substituents at both C5(R) and C20(S) on the same side of a camptothecin core, manifests self-association, whereas diastereomers 2, with bulky C5(S) and C20(S) substituents are mostly monomeric in solution. The stereogenic center at C5 is stable in water solution at pH 5–6. The compound with an (N-azetidinyl)methyl substituent at C9 can undergo the retro Mannich reaction after a prolonged time in water solution. Both diastereomers exhibit different abilities in terms of binding to DNA oligomers: compound 1 is strongly bound, whereas the binding of compound 2 is rather weak. Molecular modeling produced results consistent with NMR experiments. These complementary data allow linking of the observed phenomena in NMR experiments to basic preliminary information on the pharmacodynamic character of compounds and are essential for planning further development research.

A simple and highly efficient procedure for the synthesis of novel thiazol-2-amines, via Mannich reaction with secondary amines, is described. The newly synthesized derivatives 8(a-e) and 9(a-e) were characterized by 1H NMR, 13C NMR, IR, Mass spectroscopy and elemental analysis. All the derivatives were evaluated for their in-vitro anti-microbial activity against a panel of pathogenic strains of bacteria and fungi. The SAR showed that the secondary amines had a significant impact on the in-vitro antimicrobial activity of this class of agents. The most potent analogue N-((1H-benzo[d]imidazol-1-yl)methyl)-N-(2(trifluoromethyl)phenyl)-4,5-dihydrothiazol-2-amine (8c) showed excellent inhibition with MIC (zoi) 6.25 (22.5), 25 (21.5) and 25 (18) µg/mL against E. coli, S. typhi and P. aeruginosa respectively as compared to the standard drug. Molecular docking results suggest that compound exhibited inhibitory activity by binding of the title compound within the active sites of the inhibiting Enoyl ACP reductase, Lipid A, Pyridoxal kinase and type I DHQase enzymes. The compound exhibited promising anti-microbial activity which can be further explored as potential lead for the development of cheaper, safe, effective and potent drugs against resistant microbial parasites.

In order to extend the application of black liquor (BL), amino group was introduced in lignin through Mannich reaction. The structure of the aminated black liquor (ABL) was characterized with FT-IR, elemental analysis, the zeta potential and the inherent viscosity. The foam generated by ABL was more stable, for the surface tension was lower. The results of the mortar test indicated that the water-retention rate of the fresh mortar incorporated with 0.3 wt% ABL was 89.1%; the consistency loss was about 39.7% after 4 h. When the dosage was less than 0.3 wt%, ABL could increase the bond strength of the hardened mortars. The results showed that ABL could be used as an effective ready-mixed wet mortar admixture. This study not only provided a new method to develop new mortar admixture, but also alleviated the pollution of BL.

An artificial system of substrate-induced dimerization assembly of chiral macrocycle catalysts enables a highly cooperative hydrogen-bonding activation network for efficient enantioselective transformation. These macrocycles contain two thiourea and two chiral diamine moieties and dimerize with sulfate to form a sandwich-like assembly. The macrocycles then adopt an extended conformation and reciprocally complement the hydrogen-bonding interaction sites. Inspired by the guest-induced dynamic assembly, these macrocycles catalyze the decarboxylative Mannich reaction of cyclic aldimines containing a sulfamate heading group. The imine substrate can be activated toward nucleophilic attack of β-ketoacid by a cooperative hydrogen-bonding network enabled by sulfamate-induced dimerization assembly of the macrocycle catalysts. Highly efficient (>95 % yield in most cases) and enantioselective (up to 97.5:2.5 er) transformation of a variety of substrates using only 5 mol % macrocycle was achieved.

The denitrification of bio-oil remains an important challenge in bio-oil quality upgrading. Microalgae (MA) and sweet potato waste (SPW) were co-liquefied to investigate the denitrification of Mannich reaction. The influence of interaction reaction between MA and SPW on products qualities was explored. The results showed that the N contents of bio-oils from co-liquefaction (4.44–7.19%) were lower than that from microalgae (7.60%). Besides, the ester contents from MA&SPW (60.31–73.17%) were higher than that from MA (56.11%) and SPW (17.55%).The addition of SPW decreased the lubricating oil and fuel oil content. The experimental energy recovery efficiency (66.82–70.16%) was higher than the calculated energy recovery efficiency (65.68–66.69%) during co-liquefaction processes. Based on chemical compositions of products, a possible reaction pathway of Mannich reaction during co-liquefaction process was proposed. The current study suggested that co-liquefaction of microalgae and sweet potato waste was a feasibility way to improve the bio-oil quality and energy recovery efficiency.

[EN] Hydrogels are widely studied as drug delivery system. In this work we propose the employment of tetrakis (hydroxymethyl)phosphonium chloride as crosslinking agent to obtain covalent hydrogels based on chitosan. These hydrogels are obtained by Mannich reaction between the amino groups of chitosan with the hydroxymethyl groups of the crosslinker molecule. They show a pH sensitive second order swelling kinetic, have low toxicity, are biocompatible, mucoadhesive and allow a modified release of the encapsulated drug, camptothecin, for 48 h. This antitumor drug has been studied as a drug of interest to develop oral chemotherapy administration strategies. According to the obtained results, oral administration of camptothecin through hydrogels would provide low concentrations of drug at the absorption site, avoiding carrier saturation and reducing its intestinal toxicity., Authors acknowledge partial financial support to project SAF2016-78756 from MINECO (Spanish Ministry of economy, industry and competitivity). Mayte Martinez-Martínez received a grant from the Ministry of Education and Science of Spain (FPU13-01105).

Microalgae (MA) was co-liquefied with sweet potato waste (SPW) to improve bio-oil and bio-char qualities via Mannich reaction. The influence of Mannich reaction on combustion performances of bio-oil and bio-char were investigated. Results suggested that the addition of SPW decrease the ignition temperature of bio-oil from 186.6 °C to 165.0 °C. In addition, the denitrification effect of Mannich reaction can decrease the HCN and NO emission of bio-oil, contributing to reducing pollutant emission. As for bio-char, Mannich reaction improved the combustible material content in bio-char, which decreased the risk of slagging problem. The comprehensive combustion indexes of bio-oil (1.23 × 10−6 × min−2×°C−3) and bio-char (4.79 × 10−8 × min−2×°C−3) from co-liquefaction were higher than those from liquefaction of MA (0.91 × 10−6 × min−2×°C−3 for bio-oil and 1.24 × 10−8 × min−2×°C−3 for bio-char), indicating that the combustion performance was promoted by adding SPW. Overall, Mannich reaction can be applied to improve the combustion performance of bio-oil and bio-char.

The first example of organocatalyzed γ'-selective functionalization of cyclic enones with 3-substituted maleimides results in the stereoselective construction quaternary carbon center is presented. The reactions provided γ'-functionalized cyclic enones and β-functionalized cyclopentenones in good to excellent yields with excellent diastereo- and enantioselectivities. DFT calculations indicated that the reaction might proceed as a [4+2] cycloaddition/retro-Mannich reaction which could explain the unexpected product with a chiral quaternary carbon center and the excellent stereoselectivity.

A chiral-NHC-catalyzed highly diastereo- and enantioselective dearomatizing double Mannich reaction of isoquinolines was developed that provides a powerful and straightforward synthetic route toward substituted tropane derivatives with four contiguous stereocenters. A unique feature of this strategy is the use of readily available isoquinolines to provide two reactive sites for dearomatization, thus opening up an unprecedented approach to tropane derivatives with excellent stereoselectivity. The four-component reactions proceeded smoothly with good results. Thus, the present method is suitable for the diversity-oriented synthesis of useful tropane derivatives with high efficiency.

In this study, dithiomalonates (DTMs) were demonstrated to be exceptionally efficient Mannich donors in terms of reactivity and stereoselectivity in cinchona-based-squaramide-catalyzed enantioselective Mannich reactions of diverse imines or α-amidosulfones as imine surrogates. Owing to the superior reactivity of DTMs as compared to conventional malonates, the catalyst loading could be reduced to 0.1 mol % without the erosion of enantioselectivity (up to 99 % ee). Furthermore, by the use of a DTM, even some highly challenging primary alkyl α-amidosulfones were smoothly converted into the desired adducts with excellent enantioselectivity (up to 97 % ee), whereas the use of a malonate or monothiomalonate resulted in no reaction under identical conditions. The synthetic utility of the chiral Mannich adducts obtained from primary alkyl substrates was highlighted by the organocatalytic, coupling-reagent-free synthesis of the antidiabetic drug (-)-(R)-sitagliptin.

A highly efficient asymmetric ring-opening/cyclization/retro-Mannich reaction of cyclopropyl ketones with aryl 1,2-diamines has been realized using a chiral N,N'-dioxide/Sc(III) catalyst. Benzimidazoles containing chiral side chains were generated under mild reaction conditions in excellent outcomes (up to 99 % yield and 97 % ee). This method also provides efficient access to chiral benzimidazole-substituted amide and cycloheptene derivatives.

The concept of noncovalent organocatalysis by means of networks of cooperative hydrogen bonds (NCHB organocatalysis) has been explored. Arylideneureas were chosen as ideal substrates because of their powerful donor-acceptor properties. We have examined their uncatalyzed, direct Mannich reaction with acetoacetates in comparison with that catalyzed by a number of salan derivatives capable of providing a network of cooperative hydrogen bonds. Catalyst D [(R,R)-N,N'-bis(salicyl)cyclohexane-1,2-diamine] was found to drive the above direct Mannich reaction in an enantioselective manner, thereby allowing the synthesis of several Biginelli dihydropyrimidinones with high enantioselectivity. DFT calculations (B3LYP-D-PCM/6-31+G*//B3LYP/6-31+G*) revealed that the NCHB organocatalyst lowers the energy barrier of the reaction. The NCHB organocatalysts appear to function as biomimetic catalysts.

The synthesis of novel coumarin[8,7-e][1,3]oxazine derivatives through a microwave-assisted three-component one-pot Mannich reaction is described in this study. All the target compounds were evaluated in vitro for their antifungal activity against Botrytis cinerea, Colletotrichum capsici, Alternaria solani, Gibberella zeae, Rhizoctonia solani, and Alternaria mali. The preliminary bioassays showed that 5e, 5m, and 5s exhibited good antifungal activity and the most active compound was 5m with an [Formula: see text] value as low as 2.1 nM against Botrytis cinerea.

The Ti(II) -mediated formation of cyclopropylamines from alkenes and amides, the Kulinkovich-de Meijere reaction, involves two carbon-carbon bond-forming steps. Strategic use of a tricyclic intermediate can arrest the process if the second step requires formation of a bridgehead double bond. Use of this Bredt's rule constraint results in the production of carbocyclic amino ketones, key alkaloid building blocks.

Two amino acids play a key role in the first total synthesis of lycopalhine A. l-glutamic acid serves as a convenient chiral starting material for the 13-step synthesis, and l-proline promotes an unusual 5-endo-trig Mannich cyclization that generates the central pyrrolidine ring of the Lycopodium alkaloid. The bicyclo[3.3.0]octanol moiety of the molecule is formed through an intramolecular aldol addition that may occur spontaneously in nature.

By manipulating the reactivity of spiroindolenine species, a sequential Michael/retro-Mannich/Mannich reaction of ω-indol-3-yl α,β-unsaturated ketones was developed. In the presence of 10 mol % of a chiral phosphoric acid as the catalyst, a series of 3-(indol-3-yl)-pyrrolidines were synthesized in high yields (up to 91 %) with excellent stereoselectivities (up to 92 % ee, >19:1 d.r.). The products obtained here undergo diverse functional-group transformations. The mechanistic proposal of this reaction is supported by DFT calculations.

To develop a novel lignin-based highly efficient nitrogen fertilizer, the amination of the biorefinery technical lignin was conducted by Mannich reaction synergy with phenolation pretreatment. Subsequently, the structural transformations of lignin samples and the reaction mechanism were investigated in detail. The soil column leaching experiment was also performed to research the nitrogen release behavior of aminated lignin in soil. The results indicated that the amounts of active sites in lignin were significantly increased to 8.26 mmol/g from the original 2.91 mmol/g by phenolation. In addition, the Mannich reaction was highly selective for occurring at ortho- and para-positions of phenolic hydroxyl groups in the phenolated lignin, in which the latter was favored. Moreover, the nitrogen content in the aminated lignin was highly depended on the types of amination reagent instead of the proportion of reactants in this study. Under an optimal condition, aminated lignin with a high nitrogen content (10.13%) and low C/N ratio (6.08) could be obtained. Besides, it was especially noteworthy that the prepared APL in this study has a favorable nitrogen release behavior in soil. Thus, it is believed that these aminated lignin derivatives could be used for the preparation of various lignin-based highly efficient nitrogen fertilizer.

Background Heliomycin (resistomycin), an antibiotic with broad spectra of biological activities including antimicrobial, antifungal, antiviral, and antiproliferative. However, an extremely low solubility in aqueous media and in the majority of organic solvents limits its practical application. Objective Due to a high practical potential of heliomycin, new routes of structural modification are strongly required to improve its solubility. Conclusion The patent claims a series of 4-aminomethyl derivatives of heliomycin as well as a pharmaceutical composition based on it. Application of Mannich aminomethylation allowed to diversify the structure of initial antibiotic and to obtain the derivatives with significantly improved water solubility and a potent antiproliferative efficacy.

A series of novel Mannich base derivatives of flavone containing benzylamine moiety was synthesized using the Mannich reaction. The results of antifungal activity are not ideal, but its antifungal effect has a certain increase compared to flavonoids. After that, four bacteria were used to test antibacterial experiments of these compounds; compound 5g (MIC = 0.5, 0.125 mg/L) showed significant inhibitory activity against Staphylococcus aureus and Salmonella gallinarum compared with novobiocin (MIC = 2, 0.25 mg/L). Compound 5s exhibited broad spectrum antibacterial activity (MIC = 1, 0.5, 2, 0.05 mg/L) against four bacteria. The selected compounds 5g and 5s exhibit potent inhibition against Topo II and Topo IV with IC50 values (0.25–16 mg/L). Molecular docking model showed that the compounds 5g and 5s can bind well to the target by interacting with amino acid residues. It will provide some valuable information for the commercial antibacterial agents.

We report a Zn-ProPhenol catalyzed asymmetric Mannich reaction between butenolides and polyfluorinated alkynyl ketimines to obtain vinylogous products featuring two contiguous tetrasubstituted stereogenic centers. Notably, this is the first successful use of ketimines in the ProPhenol Mannich process, and the reaction offers a new approach for the preparation of pharmaceutically relevant products possessing trifluoromethylated tetrasubstituted alkylamines. The reaction can be performed on large scale with reduced catalyst loading without impacting its efficiency. Moreover, the acetylene moiety can be further elaborated using various methods.

New derivatives of two isomeric types of azaphenothiazines, 1,8- and 2,7-diazaphenothiazine, containing the triple bond substituents and additionally tertiary cyclic and acyclic amine groups, were synthesized and tested for their anticancer activity. The compounds exhibited differential inhibitory activities. Better results were obtained when the acetylenic group was transformed via the Mannich reaction to the dialkylaminobutynyl groups. The most active was 2,7-diazaphenothiazine with the N-methylpiperazine-2-butynyl substituent against the human ductal breast epithelial tumor cell line T47D, more potent than cisplatin. The 2,7-diazaphenothiazine system turned out to be more active than isomeric 1,8-diaza one. For the most active compound, the expression of TP53, CDKN1A, BCL-2 and BAX genes was detected by the RT-QPCR method. The gene expression ratio BACL-2/BAX suggests the mitochondrial apoptosis in T47D cells. The synthesis makes possible to obtain many new bioactive phenothiazines with the dialkylaminoalkynyl substituents inserting various tertiary cyclic and acyclic amine moieties to the substituents.

Fourteen novel pterostilbene (1) and $$3^\prime $$ -methoxy pterostilbene (2) Mannich base derivatives (3–16) were synthesized via the microwave-assisted Mannich reaction of 1 or 2 with various secondary amines and formaldehyde. The regioselectivity of the reaction occurred preferentially at $$\hbox {C-3}^\prime (\hbox {and /or C-5}^\prime )$$ position of the B-ring of stilbene. The biological testing results showed that all the target compounds exhibit antiproliferative activity against Hela cells from $$\hbox {IC}_{50}=22.5$$ – $$65.3\,\upmu \hbox {M}$$ . Compounds 1–3, 7, 11–13, and 16 displayed higher (lower $$\hbox {IC}_{50}$$ values) activity than the positive control cisplatin $$(\hbox {IC}_{50}= 41.3\,\upmu \hbox {M})$$ .

Phosphonopeptides are important phosphorus analogs of natural peptides and have been widely applied as enzyme inhibitors and antibacterial agents. A series of phosphonodipeptides containing C-terminal α-aminoalkylphosphonic acids was synthesized in satisfactory to good yields conveniently from 2-(N-benzyloxycarbonylamino)alkanamides, aldehydes, and phosphorus trichloride via Mannich-type reaction and subsequent sequential hydrolysis. The reaction mechanism was proposed and verified by (31)P NMR tracing experiments. The current method is an efficient and convenient method for preparation of phosphonopeptides containing C-terminal α-aminoalkylphosphonic acids.

A synthesis of potentially biologically active heterocyclic amino alcohols of acetylene (Piperidine and Morpholine) under the conditions of Mannich reaction accomplished and received their acyl derivatives. Pharmacological activity (antibacterial and antispasmotic) of synthesized compounds, also acute toxicological characteristics studied. The study showed that the combination of DMAE-4 has antispasmodic activity with low toxicity.

Various substituted dibenzo[ b,f ][ 1,4 ]oxazepines as seven-membered cyclic imines underwent a highly enantioselective direct Mannich reaction with acetone when catalyzed by proline. These reactions gave a range of optically active β-carbonyl seven-membered N -heterocycles with excellent enantioselectivity (93%–98% ee). With 2-butanone as a Mannich donor, the single regioselective product was obtained with 96%–97% ee. The absolute configuration of the product was assigned to be R by X-ray single crystal analysis of its derivative.

Cationic polyacrylamide is a derivative of polyacrylamide, a cationic polymer flocculant which has an excellent effect on sewage treatment. Our existing cationic polyacrylamide are mostly prepared by the Mannich reaction ,which has the shortcomings of more unreacted material, low cationic degree, poor stability, short validity, etc. Therefore, a cationic polyacrylamide has been prepared by aqueous solution.P(DAC-AM) was synthesized by aqueous copolymerization of acrylamide (AM) and DAC using complex initiated system consisted of (NH4)2S2O8,NaHSO3 and V-50. Mass percent of monomer, amount of initiator, content of cation monomer, pH, reaction time et al on the effect of intrinsic viscosity of polymer were discussed. The suitable conditions of synthesis were concluded. Mass concentration of monomers:35%, initiator amount 0.06 %,V-50 amount 0.005%,pH:5.5~6.5,urea concentration 0.1%,EDTA 0.02%,β-dimethylaminopropionitrile concentration 0.03%,reaction time 5~6h,the intrinsic viscosity of product is 13.95dL·g-1.

The alcoholic depolymerization and Mannich reaction were conducted to improve the chemical activity of biorefinery technical lignins and introduce amino groups into lignins, respectively. To understand the chemical structural transformations and examine the reaction mechanism, GPC and solution-state NMR techniques were performed. Element analysis was also used to quantify the amount of amine groups. The NMR characterization the depolymerized lignins indicated of the depolymerization, demethoxylation, and bond cleavage of linkages occurred during the depolymerization process. Results showed that the depolymerization temperature instead of the addition of capping reagents was the main factor for improving the reactivity of lignin under the given conditions. The Mannich reaction was very selective, primarily occurred at H3,5 and G5 positions, and the H units present a higher chemical reactivity. It is believed that the understanding of the fundamental chemistry of lignin during depolymerization and Mannich reaction process will contribute to the extension of high value-added applications of biorefinery lignin.

N,O-acetals (NOAcs) were developed as bench stable surrogates for N-carbamoyl, (Boc, Cbz and Fmoc) formaldehyde and glyoxylate imines in asymmetric Mannich reactions. The NOAcs can be directly utilized in the chiral primary amine catalyzed Mannich reactions of both acyclic and cyclic β-ketocarbonyls with high yields and excellent stereoselectivity. The current reaction offers a straightforward approach in the asymmetric synthesis of α- or β-amino carbonyls bearing chiral quaternary centers in a practical and highly stereocontrolled manner.