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Biomimetic oxidation of primary amines to carboxylic acids has been developed where the copper-containing amine oxidase (CuAO)-like o-NQ-catalyzed aerobic oxidation was combined with the aldehyde dehydrogenase (ALDH)-like TBHP-mediated imine oxidation protocol. Notably, the current tandem oxidation strategy provides a new mechanistic insight into the imine intermediate and the seemingly simple TBHP-mediated oxidation pathways of imines. The developed metal-free amine oxidation protocol allows the use of molecular oxygen and TBHP, safe forms of oxidant that may appeal to the industrial application.

The generation of aminium radical cation species from N-nitrosoamines is disclosed for the first time through visible-light excitation at 453 nm. The developed visible-light-promoted photoaddition reaction of N-nitrosoamines to alkenes was combined with the o-NQ-catalyzed aerobic oxidation protocol of amines to telescope the direct handling of harmful N-nitroso compounds, where the desired α-amino oxime derivatives were obtained in a one-pot tandem N-nitrosation and photoaddition sequence.

The nitroso group served as a traceless directing group for the C–H functionalization of N-alkylanilines, ultimately removed after functioning either as an internal oxidant or under subsequent redu...

A facile access to fused pyrimidin-4(3H)-one derivatives has been established by using the metal-free ortho-naphthoquinone-catalyzed aerobic cross-coupling reactions of amines. The utilization of two readily available amines allowed a direct coupling strategy to quinazolinone natural product, bouchardatine, as well as sildenafil (Viagra™) in a highly convergent manner.

A combination of CuCl and DM-SEGPHOS catalyst system has allowed the development of highly enantioselective and diastereoselective conjugate addition of bis(pinacolato)diboron to α-alkylidene-γ-lactams. The key structural feature of conjugate acceptors, α-alkylidene-γ-lactams, was identified as the carbamate group such as N-Boc and N-Cbz, where the typical low reactivity and stereoselectivity issues associated with α,β-unsaturated lactams as conjugate acceptors were resolved.

Two distinctive transition-metal-promoted aerobic oxidation protocols have been developed for the synthesis of isoquinolones from 2-vinylbenzaldehydes and aniline derivatives. Thus, the one-pot tandem reaction sequence of imine formation, thermal 6π-electrocyclization, followed by either Cu(OAc)2-mediated or Pd(OAc)2-catalyzed aerobic oxidation protocol allowed the ready access to isoquinolone derivatives. The control experiments revealed that the 1,2-dihydroisoquinoline intermediates from the 6π-electrocyclization of 1-azatrienes were aerobically oxidized to isoquinolones in the presence of either Cu(OAc)2 or Pd(OAc)2 catalyst.

The synthesis of isoxazoles has been achieved in a continuous flow system composed of two reaction units: the Friedel-Crafts acylation of alkynes and the azide conjugate addition to the resulting β-chlorovinyl ketones followed by a photochemical-thermal reaction sequence. The salient feature of the current flow system includes the safe handling of potentially explosive organic azide species as well as the rapid conversion of batch reactions into flow conditions with the integration of multiple reactor units.

Background: Nuclear protein-1 (NUPR1, also known as p8/Com-1) is a transcription factor involved in the regulation of cellular stress responses, including serum starvation and drug stimulation. Methods: We investigated the mechanism of NUPR1 nuclear translocation involving karyopherin β1 (KPNB1), using a single-molecule binding assay and confocal microscopy. The cellular effects associated with NUPR1–KPNB1 inhibition were investigated by gene expression profiling and cell cycle analysis. Results: The single-molecule binding assay revealed that KPNB1 bound to NUPR1 with a binding affinity of 0.75 nM and that this binding was blocked by the aminothiazole ATZ-502. Following doxorubicin-only treatment, NUPR1 was translocated to the nucleus in more than 90% and NUPR1 translocation was blocked by the ATZ-502 combination treatment in MDA-MB-231 with no change in NUPR1 expression, providing strong evidence that NUPR1 nuclear translocation was directly inhibited by the ATZ-502 treatment. Inhibition of KPNB1 and NUPR1 binding was associated with a synergistic anticancer effect (up to 19.6-fold) in various cancer cell lines. NUPR1-related genes were also downregulated following the doxorubicin–ATZ-502 combination treatment. Conclusion: Our current findings clearly demonstrate that NUPR1 translocation into the nucleus requires karyopherin β1 binding. Inhibition of the KPNB1 and NUPR1 interaction may constitute a new cancer therapeutic approach that can increase the drug efficacy while reducing the side effects.

In this study, the effect of particle size of genistein-loaded solid lipid particulate systems on drug dissolution behavior and oral bioavailability was investigated. Genistein-loaded solid lipid microparticles and nanoparticles were prepared with glyceryl palmitostearate. Except for the particle size, other properties of genistein-loaded solid lipid microparticles and nanoparticles such as particle composition and drug loading efficiency and amount were similarly controlled to mainly evaluate the effect of different particle sizes of the solid lipid particulate systems on drug dissolution behavior and oral bioavailability. The results showed that genistein-loaded solid lipid microparticles and nanoparticles exhibited a considerably increased drug dissolution rate compared to that of genistein bulk powder and suspension. The microparticles gradually released genistein as a function of time while the nanoparticles exhibited a biphasic drug release pattern, showing an initial burst drug release, followed by a sustained release. The oral bioavailability of genistein loaded in solid lipid microparticles and nanoparticles in rats was also significantly enhanced compared to that in bulk powders and the suspension. However, the bioavailability from the microparticles increased more than that from the nanoparticles mainly because the rapid drug dissolution rate and rapid absorption of genistein because of the large surface area of the genistein-solid lipid nanoparticles cleared the drug to a greater extent than the genistein-solid lipid microparticles did. Therefore, the findings of this study suggest that controlling the particle size of solid-lipid particulate systems at a micro-scale would be a promising strategy to increase the oral bioavailability of genistein.

A tandem aerobic oxidation protocol has been developed for the facile synthesis of indole-3-carboxylates. Two readily available starting materials, anilines and benzylamines, were efficiently cross-coupled under the o-naphthoquinone-catalyzed aerobic oxidation conditions to the corresponding 2-arylmethyleneaminophenylacetates that in turn smoothly underwent the Cu(II)-catalyzed intramolecular Mannich reaction. The resulting indoline derivatives were aerobically oxidized to indole-3-carboxylates, providing a ready access to indole derivatives from two simple amine derivatives.

A tandem three-component reaction has been developed for the synthesis of spirocyclic 2-indolinylformamidines through a cooperative action of palladium and copper catalysts. The Pd-catalyzed benzylation of α-isocyano lactams with 2-bromobenzyl bromides allows efficient formation of α-substituted α-isocyano lactams. A subsequent in situ Cu-catalyzed amine addition to the isocyanide moiety provides amidine intermediates that readily undergo intramolecular N-arylation via the cooperative action of Pd/Cu catalysis, allowing a facile chiral resolution of the spirocyclic 2-indolines.

With the increasing prevalence of obesity, the use of counterfeit drugs for weight loss is widespread owing to their easy and rapid availability. Since counterfeit weight-loss drugs are not prepared under the rigorous standard of Good Manufacturing Practice (GMP), they pose a risk to public health and cause significant side effects. To counteract the risk posed by counterfeit drugs, we investigated counterfeit weight-loss drugs seized by the Incheon Customs Services using UHPLC-PDA. Five of 23 confiscated samples with distinctive pink-coloured coating contained levothyroxine, sennoside A and B, and phenolphthalein in amounts ranging from 0.03–132.40 mg/g. In addition, three unknown compounds in one of the adulterated samples containing phenolphthalein were structurally elucidated by several analytical techniques. Their accurate masses corresponded to molecular formula of C34H22O7, C34H20O6, and C20H12O3, respectively. These compounds were identified as impurities, possibly produced during the synthesis of phenolphthalein or by improper removal during purification. These impurities were detected for the first time in counterfeit drugs.

The direct regioselective synthesis of highly functionalized pyrroles with two different electron-withdrawing groups has been developed using an angle strain-induced 1,2-shift of an electron-withdrawing group in 2H-pyrroles. The preferential migration aptitude of an electron-withdrawing group over alkyl and aryl groups is believed to be the result of the orbital overlap between the internal alkene and the electron-withdrawing group. The newly developed regioselective synthesis of pyrroles features a wide substrate scope, simple reaction set-up, and high yields (60–82%), capturing the essence of alkyne-isocyanide “click” reactions.

Enantiodivergent catalyst systems were developed using metals with different ionic radii and a multifunctional brucine diol (BD) ligand. The catalytic use of purported 1:1 Cu-BD complexes in the 1,3-dipolar cycloaddition of azomethine ylides with chalcones resulted in the selective formation of endo-pyrrolidines in 87–96% ees with an absolute stereochemical outcome of (2R,3S,4R,5S). In contrast, an opposite absolute stereochemical outcome was observed by using the catalysts derived from Ag(I) salts and BD. The demonstration of enantiodivergent approaches to a broad class of substrates/reaction types underlines their synthetic value in asymmetric synthesis.

A facile approach to spirocyclic pyrrolidinonylformimidamides has been developed via three-component reactions of isocyanides, alkenes, and amines. The reaction proceeds through a sequence of two distinct reaction pathways; the base-catalyzed conjugate addition of α-isocyano lactams to electron-deficient alkenes and the Ag(I)-catalyzed amine insertion to the isocyanide moiety. Both reactions display markedly different reaction kinetics, allowing the one-pot three-component reactions to be performed in the presence of respective catalysts, a Bronsted base and a silver salt. The formation of spirocyclic pyrrolidin-2-ones represents an unusual use of α-isocyano lactam as a two-atom unit in a formal [3 + 2] cycloaddition reaction. The successful identification of ways to defy the typical three-atom unit role of α-isocyano carbonyl compounds in the [3 + 2] cycloaddition pathways manifests a rapid assembly of medicinally important spirocyclic scaffolds from readily available starting materials.

A highly selective and practical asymmetric Ag(I) catalyst system has been developed for the [3 + 2] cycloaddition reactions between isocyanoacetates and cyclopentenediones. The current Ag(I) catalyst system tolerates moisture and air and readily utilizes class III solvents such as EtOAc and acetone. The development of on demand generation of an active chiral catalyst in the presence of isocyanides paves a way to the efficient asymmetric preparation of bicyclic pyrrolidines with four stereogenic centers, including two quaternary centers in 80–97% ee.

A mechanism-driven enantiodivergent approach to chiral 1,1′-bi-2-naphthols via catalytic asymmetric oxidative coupling of 2-naphthol derivatives is described for the first time. By utilizing 2-naphthol derivatives with low oxidation potential, the substrates were activated by either chiral mononuclear or dinuclear vanadium(V) catalyst to promote distinctively different asymmetric reaction pathways: single versus dual substrate activation mechanisms.

The facile synthesis of 6- to 8-membered pyrrololactams has been developed using a ring expansion of spiro-2H-pyrroles, the products of intermolecular alkyne–isocyanide click reactions. The key to successful ring expansion of spiro-2H-pyrroles to pyrrololactams is the enforced orbital overlap between the internal alkene and the amide carbonyl group through the conformationally locked bicyclic structures. The newly disclosed α-isocyano lactams, substrates for click reactions, should find their utility in the synthesis of pharmaceutically important heterocyclic compounds.

Treatment of the title compounds with NEt3 generates novel vinyl anion synthons which undergo aldol reaction with aldehydes to give aldol-type allene structures.

A facile synthetic method to chromenones and thiochromenones has been developed using a one-pot Friedel–Crafts acylation of alkynes with suitably substituted benzoyl chlorides. This unified approach to (thio)chromenones is readily applicable to aryl- and alkylalkynes where the stereochemically well-defined β-chlorovinyl ketone intermediates undergo distinctively different cyclization pathways. The ready availability of both starting materials, alkynes and benzoyl chlorides, coupled with the experimental simplicity makes the current synthetic method to (thio)chromenones fast, efficient, and practical.

Catalyst-dependent divergent pathways of 2-naphthol derivatives have been investigated. A readily available CuCl2–DMAP catalyst system promotes the aerobic oxidation of 2-naphthol derivatives to ortho-naphthoquinones whereas switching the catalyst system to Cu(OAc)2–DBN under an argon atmosphere allows the oxidative coupling of 2-naphthols to 1,1′-bi-2-naphthols (BINOLs) in good to excellent yields.

Catalyst-dependent divergent pathways of 2-naphthol derivatives have been investigated. A readily available CuCl2–DMAP catalyst system promotes the aerobic oxidation of 2-naphthol derivatives to ortho-naphthoquinones whereas switching the catalyst system to Cu(OAc)2–DBN under an argon atmosphere allows the oxidative coupling of 2-naphthols to 1,1′-bi-2-naphthols (BINOLs) in good to excellent yields.

Enantiodivergent catalyst systems were developed using metals with different ionic radii and a multifunctional brucine diol (BD) ligand. The catalytic use of purported 1:1 Cu-BD complexes in the 1,3-dipolar cycloaddition of azomethine ylides with chalcones resulted in the selective formation of endo-pyrrolidines in 87–96% ees with an absolute stereochemical outcome of (2R,3S,4R,5S). In contrast, an opposite absolute stereochemical outcome was observed by using the catalysts derived from Ag(I) salts and BD. The demonstration of enantiodivergent approaches to a broad class of substrates/reaction types underlines their synthetic value in asymmetric synthesis.

The use of the Broensted base, Et3N, along with a catalytic amount of Lewis base, PPh3, leads to the isomerization of chlorovinyl ketones affording 1,3-dienones.

Stereodivergent catalytic asymmetric conjugate reactions of glycine (ket)imines with nitroalkenes have been achieved using various chiral catalyst systems derived from a multidentate amino alcohol (1). The stepwise nature of the [3 + 2] cycloaddition reactions of N-metalated azomethine ylides has also been demonstrated by highly enantio- and diastereoselective syntheses of exo-5 and endo-8 from the respective syn-4 and anti-7 conjugate addition products in a one-pot tandem fashion.

The Morita-Baylis-Hillman (MBH) reaction of aryl vinyl ketones has been achieved for the first time through cooperative catalysis of proline and brucine N-oxide. A unique mode of activation of the aldehydes through proline iminium intermediates has been identified as a key reaction parameter for the successful MBH reaction of aryl vinyl ketones. The reaction pathways leading to 1:2 MBH products under typical nucleophilic catalysis conditions were investigated. A systematic study revealed two different reaction pathways leading to 1:2 MBH products: (1) the second reaction of normal MBH products with aryl vinyl ketones as a dominating reaction pathway at the initial stage of the reaction, and (2) the aldol reaction pathway of Rauhut-Currier products with aldehydes (auto-catalysis by alcohol products) as a major reaction pathway during the later stage of reaction.

A mild and operationally simple deoxygenation of epoxides, sulfoxides, and amine N -oxides is described using a sub-stoichiometric amount of low-valent niobium complexes generated in situ from commercially available NbCl 5 and zinc dust. The deoxygenation proceeds by a reductive cleavage of polarized O–C/O–N/O–S bonds through a single electron transfer from zinc metal to the niobium–substrate complex due to the high oxophilic nature of the niobium species. The presence of adjacent radical-stabilizing groups is beneficial to epoxide substrates; however the similar prerequisite does not apply to sulfoxides and amine N -oxides, where a broad range of substrates are efficiently deoxygenated in excellent yields.

Chiral tertiary amine N-oxides have been shown to undergo stereoselective oxygen transfer reaction in the epoxidation of chalcone derivatives with modest to good enantioselectivity.

Reduction of biotin sulfone derivatives leads to 2-epi-biotin analogs. The stereochemistry of the side chain at C2 can be simply deduced from the diagnostic chemical shift pattern of the benzylic protons, rather than through the conventional analysis of the coupling constants using the empirical Karplus equation.

This account summarizes the recent efforts in the Oh group toward the development of stereodivergent asymmetric catalysis using a single chiral source, namely brucine diol. Enantiodivergent catalytic approaches are discussed in the context of [3+2]-cycloaddition reactions, aldol-type reactions, and Friedel–Crafts alkylation reactions. Expansion of the brucine diol catalyzed asymmetric reactions is also detailed in diastereodivergent conjugate addition reactions as well as in a cooperative catalysis approach to the aldol reactions of methyl isocyanate. Collectively, the research presented in this account demonstrates the important mechanistic as well as practical significance of single ­chiral-source-based asymmetric catalysis. 1 Introduction 2 Enantiodivergent Approaches 2.1 [3+2]-Cycloaddition Reactions 2.2 Nitro-Aldol Reactions 2.3 Friedel–Crafts Alkylation Reactions 3 Diastereodivergent Approaches 3.1 Conjugate Addition Reactions 3.2 endo-Selective [3+2]-Cycloaddition Reactions 4 Cooperative Catalysis Approaches 5 Outlook

Enantio- and diastereodivergent approaches to pyrrolidines are described by using catalyst- and substrate-controlled reaction pathways. A concerted endo-selective [3 + 2]-cycloaddition pathway is developed for the reaction of methyl imino ester, whereas endo-pyrrolidines with an opposite absolute stereochemical outcome are prepared by using the stepwise reaction pathway of tert-butyl imino ester. The development of catalyst- and substrate-controlled stereodivergent approaches highlights the inherent substrate–catalyst interactions in the [3 + 2]-cycloaddition reactions of metalated azomethine ylides.

The synthesis of heterocyclic amides containing pyrrole, pyrrolidinone, and piperidone fragments is described and these are tested together with a wide range of previously prepared analogous derivatives for their binding activity at the urokinase receptor.

The synthesis of 5- to 8-memebered cyclic thioethers 4 has been achieved through a simple two-step sequence. The present methodology utilizes the facile Friedel-Crafts acylation of terminal alkynes 1 with acid chlorides 2 followed by tandem C(sp(3))-S and C(sp(2))-S bond formations with NaSH.xH(2)O.

A biotin core has been assembled in a short and efficient sequence utilizing a tandem intramolecular Michael reaction/fragmentation/Michael reaction from vinyl sulfoxide and sulfone alcohols (12 and 13).

Reaction of trimethylaluminium, dimethyllithium cuprate and lithium tetramethylaluminate with the homochiral epoxide 8 has been studied. Intermolecular epoxide ring-opening was observed with dimethyllithium cuprate and lithium tetramethylaluminate, but acetal ring-opening followed by intramolecular epoxide ring-opening was observed with trimethylaluminium.

[reaction: see text] Addition of diverse nucleophiles to the unsaturated lactone 2 that results from hetero Diels-Alder reaction of Brassard's diene 1 with aldehydes leads to an efficient and general approach to the synthesis of 2,3-dihydro-4H-pyran-4-ones 3.

The urokinase receptor (uPAR) is a cell-surface protein that is part of an intricate web of transient and tight protein interactions that promote cancer cell invasion and metastasis. Here, we evaluate the binding and biological activity of a new class of pyrrolidinone and piperidinone compounds, along with derivatives of previously-identified pyrazole and propylamine compounds. Competition assays revealed that the compounds displace a fluorescently labeled peptide (AE147-FAM) with inhibition constant (Ki ) values ranging from 6 to 63 μM. Structure-based computational pharmacophore analysis followed by extensive explicit-solvent molecular dynamics (MD) simulations and free energy calculations suggested the pyrazole-based and piperidinone-based compounds adopt different binding modes, despite their similar two-dimensional structures. In cells, pyrazole-based compounds showed significant inhibition of breast adenocarcinoma (MDA-MB-231) and pancreatic ductal adenocarcinoma (PDAC) cell proliferation, but piperidinone-containing compounds exhibited no cytotoxicity even at concentrations of 100 μM. One pyrazole-based compound impaired MDA-MB-231 invasion, adhesion, and migration in a concentration-dependent manner, while the piperidinone inhibited only invasion. The pyrazole derivative inhibited matrix metalloprotease-9 (gelatinase) activity in a concentration-dependent manner, while the piperidinone showed no effect suggesting different mechanisms for inhibition of cell invasion. Signaling studies further highlighted these differences, showing that pyrazole compounds completely inhibited ERK phosphorylation and impaired HIF1α and NF-κB signaling, while pyrrolidinones and piperidinones had no effect. Annexin V staining suggested that the effect of the pyrazole-based compound on proliferation was due to cell killing through an apoptotic mechanism. The compounds identified represent valuable leads in the design of further derivatives with higher affinities and potential probes to unravel the protein-protein interactions of uPAR.

Glycine imine (I) undergoes syn-selective conjugate addition with nitroalkenes (II) in the presence of chiral catalyst systems consisting of a copper(I) salt and a ligand derived from a multidentate amino alcohol.

The novel protocol for the successful reaction includes a combined catalyst of L-proline and brucine N-oxide.

Either enantiomeric alkylated indole (III) can be selectively obtained in the presence of a copper catalyst derived from dihydroxylated brucine.

A new approach to both enantioenriched Henry products is developed by use of different molecularities of metal−ligand complexes generated from Cu(I) and Zn(II) metals with readily available chiral amino alcohol 1.

A new approach to both enantioenriched Henry products is developed by use of different molecularities of metal−ligand complexes generated from Cu(I) and Zn(II) metals with readily available chiral amino alcohol 1.

A mild and operationally simple deoxygenation of epoxides, sulfoxides, and amine N -oxides is described using a sub-stoichiometric amount of low-valent niobium complexes generated in situ from commercially available NbCl 5 and zinc dust. The deoxygenation proceeds by a reductive cleavage of polarized O–C/O–N/O–S bonds through a single electron transfer from zinc metal to the niobium–substrate complex due to the high oxophilic nature of the niobium species. The presence of adjacent radical-stabilizing groups is beneficial to epoxide substrates; however the similar prerequisite does not apply to sulfoxides and amine N -oxides, where a broad range of substrates are efficiently deoxygenated in excellent yields.

Chiral tertiary amine N-oxides have been shown to undergo stereoselective oxygen transfer reaction in the epoxidation of chalcone derivatives with modest to good enantioselectivity.

[481047-13-6] C11H19NOS (MW 213.34) InChI = 1S/C11H19NOS/c1-3-11(2)10(13)12-7-4-5-9(12)6-8-14-11/h9H,3-8H2,1-2H3/t9-,11-/m0/s1 InChIKey = GGNLYDGKZKRGPC-ONGXEEELSA-N (highly stereoselective chiral auxiliary for quaternary carbon center generation) Solubility: soluble in THF. Form Supplied in: not commercially available. Preparative Methods: successive alkylation of (7S)-1-aza-4-thiabicyclo[5.3.0]-2-decanone with ethyl iodide and methyl iodide (eq 1). Purification: flash column chromatography on silica gel, eluted with 20% ethyl acetate in hexanes.

[7758-89-6] ClCu (MW 99.00) InChI = 1S/ClH.Cu/h1H;/q;+1/p-1 InChIKey = OXBLHERUFWYNTN-UHFFFAOYSA-M (catalyst for diazo and diazonium chemistry; for use with Grignard reagents1) Alternate Name: cuprous chloride. Physical Data: mp 430 °C; d 4.140 g cm−3. Solubility: insol H2O and most organic solvents; partially sol dimethyl sulfide (DMS). Form Supplied in: light green-tinged white solid; 99.99% grade available commercially. Handling, Storage, and Precautions: maintenance of a dry N2 or Ar atmosphere is recommended.

[125928-78-1] C10H14BNO2 (MW 191.04) InChI = 1S/C10H14BNO2/c1-3-12(4-2)11-13-9-7-5-6-8-10(9)14-11/h5-8H,3-4H2,1-2H3 InChIKey = SXGVJVOSHXGJNN-UHFFFAOYSA-N (an efficient iminium ion generator) Physical Data: bp 72 °C/0.1 mmHg. Solubility: soluble in pentane. Form Supplied in: not commercially available. Preparative Methods: the reagent is prepared from diethylamine and o-phenylene chloroboronate in pentane at −80 °C (eq 1).1, 2 (1) Purification: distillation.

This account summarizes the recent efforts in the Oh group toward the development of stereodivergent asymmetric catalysis using a single chiral source, namely brucine diol. Enantiodivergent catalytic approaches are discussed in the context of [3+2]-cycloaddition reactions, aldol-type reactions, and Friedel–Crafts alkylation reactions. Expansion of the brucine diol catalyzed asymmetric reactions is also detailed in diastereodivergent conjugate addition reactions as well as in a cooperative catalysis approach to the aldol reactions of methyl isocyanate. Collectively, the research presented in this account demonstrates the important mechanistic as well as practical significance of single ­chiral-source-based asymmetric catalysis. 1 Introduction 2 Enantiodivergent Approaches 2.1 [3+2]-Cycloaddition Reactions 2.2 Nitro-Aldol Reactions 2.3 Friedel–Crafts Alkylation Reactions 3 Diastereodivergent Approaches 3.1 Conjugate Addition Reactions 3.2 endo-Selective [3+2]-Cycloaddition Reactions 4 Cooperative Catalysis Approaches 5 Outlook