Metal-Catalyzed Enantioconvergent Transformations.

Enantioconvergent catalysis has expanded asymmetric synthesis to new methodologies able to convert racemic compounds into a single enantiomer. This review covers recent advances in transition-metal-catalyzed transformations, such as radical-based cross-coupling of racemic alkyl electrophiles with nucleophiles or racemic alkylmetals with electrophiles and reductive cross-coupling of two electrophiles mainly under Ni/bis(oxazoline) catalysis. C-H functionalization of racemic electrophiles or nucleophiles can be performed in an enantioconvergent manner. Hydroalkylation of alkenes, allenes, and acetylenes is an alternative to cross-coupling reactions. Hydrogen autotransfer has been applied to amination of racemic alcohols and C-C bond forming reactions (Guerbet reaction). Other metal-catalyzed reactions involve addition of racemic allylic systems to carbonyl compounds, propargylation of alcohols and phenols, amination of racemic 3-bromooxindoles, allenylation of carbonyl compounds with racemic allenolates or propargyl bromides, and hydroxylation of racemic 1,3-dicarbonyl compounds.

Catalytic asymmetric synthesis of 1,2-diamines.

The asymmetric catalytic synthesis of 1,2-diamines has received considerable interest, especially in the last ten years, due to their presence in biologically active compounds and their applications for the development of synthetic building blocks, chiral ligands and organocatalysts. Synthetic strategies based on C-N bond-forming reactions involve mainly (a) ring opening of aziridines and azabenzonorbornadienes, (b) hydroamination of allylic amines, (c) hydroamination of enamines and (d) diamination of olefins. In the case of C-C bond-forming reactions are included (a) the aza-Mannich reaction of imino esters, imino nitriles, azlactones, isocyano acetates, and isothiocyanates with imines, (b) the aza-Henry reaction of nitroalkanes with imines, (c) imine-imine coupling reactions, and (d) reductive coupling of enamines with imines, and (e) [3+2] cycloaddition with imines. C-H bond forming reactions include hydrogenation of CN bonds and C-H amination reactions. Other catalytic methods include desymmetrization reactions of meso-diamines.

Phosphine Catalyzed Michael-Type Additions: The Synthesis of Glutamic Acid Derivatives from Arylidene-α-amino Esters.

The reaction of arylidene-α-amino esters with electrophilic alkenes to yield Michael-type addition compounds is optimized using several phosphines as organocatalysts. The transformation is very complicated due to the generation of several final compounds, including those derived from the 1,3-dipolar cycloadditions. For this reason, the selection of the reaction conditions is a very complex task and the slow addition of the acrylic system is very important to complete the process. The study of the variation in the structural components of the starting imino ester is performed as well as the expansion of other electron-poor alkenes. The crude products have a purity higher than 90% in most cases without any purification. A plausible mechanism is detailed based on the bibliography and the experimental results. The synthesis of pyroglutamate entities, after the reduction of the imino group and cyclization, is performed in high yields. In addition, the hydrolysis of the imino group, under acidic media, represents a direct access to glutamate surrogates.

Stabilized Palladium Nanoparticles from Bis-(N-benzoylthiourea) Derived-PdII Complexes as Efficient Catalysts for Sustainable Cross-Coupling Reactions in Water.

Stable palladium (II) complexes, incorporating a double (N-benzoylthiourea) arrangement bonded to a complex heterocyclic scaffold, are used as precursors of catalytic species able to promote Suzuki-Miyaura, Mizoroki-Heck, Hiyama, Buchwald-Hartwig, Hirao and Sonogashira-Hagihara cross-coupling transformations in water. These sustainable processes are chemoselective and very versatile. The nanoparticles responsible for these catalytic reactions were analyzed and studied. Their usefulness is demonstrated after several tests and analyses. The heterogeneous character of this species in water was also confirmed.

Pseudo-multicomponent 1,3-dipolar cycloaddition involving metal-free generation of unactivated azomethine ylides.

The pseudo-multicomponent reaction between propargyl amine, an aldehyde and an electron-deficient alkene is described. The C-H activation takes place thermally and allows the obtaining of cycloadducts in very good yields with high diastereoselectivities. The relative configuration is determined by X-ray diffraction analysis of the chiral molecule, obtained as a single diastereoisomer, using a chiral maleimide. A brief study of the stability of the possible ylides involved in the process is also mentioned, confirming the high diastereoselectivity observed. The high functional group density of these cycloadducts permits the synthesis of complex heterocycles. After allylation or propargylation of the pyrrolidine nitrogen atom, RCM-DA cycloaddition or cyclotrimerization with an alkyne is studied, respectively. In this last example, the resulting tetracyclic structures are of potential interest as drugs for the treatment of cystic fibrosis.

Enantioselective 1,3-Dipolar Cycloaddition Using (Z)-α-Amidonitroalkenes as a Key Step to the Access to Chiral cis-3,4-Diaminopyrrolidines.

The enantioselective 1,3-dipolar cycloaddition between imino esters and (Z)-nitroalkenes bearing a masked amino group in the ß-position was studied using several chiral ligands and silver salts. The optimized reaction conditions were directly applied to the study of the scope of the reaction. The determination of the absolute configuration was evaluated using NMR experiments and electronic circular dichroism (ECD). The reduction and hydrolysis of both groups was performed to generate in an excellent enantiomeric ratio the corresponding cis-2,3-diaminoprolinate.

Biological properties and conformational studies of amphiphilic Pd(II) and Ni(II) complexes bearing functionalized aroylaminocarbo-N-thioylpyrrolinate units.

A series of novel palladium(II) and nickel(II) complexes of multifunctionalized aroylaminocarbo-N-thioylpyrrolinates were synthesized and characterized by analytical and spectroscopic techniques. The biological properties of the freshly prepared compounds were screened against S. aureus, B. subtilis, A. hydrophila, E. coli, and A. baumannii bacteria and antituberculosis activity against M. tuberculosis H37Rv strains. Also, the antifungal activity was studied against C. albicans, C. tropicalis, and C. glabrata standard strains. A deep conformational survey was monitored using DFT calculations with the aim to explain the importance of the final conformation in the biological experimental results.

Stereodivergent routes in organic synthesis: marine natural products, lactones, other natural products, heterocycles and unnatural compounds.

Enantio- and diastereodivergent routes to marine-origin natural products with different sizes of cyclic ethers and lactones have been used in order to assign stereochemical features. Kainoid amino acids such as isodomoic acids have been synthesized using diastereodivergent routes. The bis(indole) alkaloid dragmacidin F has been prepared by enantiodivergent strategies as well as furanoterpenes and the tetracyclic agelastatin A. Natural products containing five-membered lactones like quercus lactones, muricatacins, goniofufuranones, methylenolactocins and frenolicin B have been synthesized using stereodivergent routes. Macrolides are very abundant lactones and have been mainly prepared from the corresponding seco-acids by lactonization, such as lasiodiplodin, zaeralanes, macrosphelides and haloprins, or by ring-closing metathesis, such as aspercyclides, microcarpalides, macrolides FD-891 and 892, and tetradic-5-en-9-olides. Other natural products including cyclic ethers (such as sesamin, asarinin, acetogenins, centrolobines and nabilones), alcohols (such as sulcatol), esters (such as methyl jasmonates), polycyclic precursors of fredericamycin, amino alcohols (such as ambroxol and sphingosines), isoprostanes, isofurans, polyketide precursors of anachelins, brevicomins, gummiferol, shikimic acid and the related compounds, and the pheromone disparlure have been synthesized stereodivergently. Heterocyclic systems such as epoxides, theobroxides and bromoxones, oxetan-3-ones, 5- to 8-membered cyclic ethers, azetidones, γ-lactams, oxazolidinones, bis(oxazolines), dihydropyridoisoindolines and octahydroisoquinolines have been prepared following stereodivergent routes. Stereodivergent routes to unnatural compounds such as alkenes, dienes, allenes, cyclopropanes, alcohols, aldols, amines, amino alcohols, ß-amino acids, carboxylic acids, lactones, nitriles and α-amino nitriles have been considered as well.

Stereodivergent routes in organic synthesis: carbohydrates, amino acids, alkaloids and terpenes.

The natural occurrence of enantiomers and diastereomers is often encountered. In addition, the synthesis of these stereoisomers is important for structure determination and for the study of structure-activity relationships. Stereodivergent routes simplify the access to these molecules starting from a common material. This review is focused on the synthesis of carbohydrates, amino acids, alkaloids and terpenes using this efficient strategy. In the case of carbohydrates, such as monosaccharides, carbasugars, aminosugars and azasugars, carbohydrates are usually employed as common starting materials. As a very common strategy, configurations of hydroxy groups are inverted by SN2 methods playing with protection and deprotection processes. For the synthesis of acyclic α-AAs, diastereoselective methods using mainly Garner's aldehyde have been described. Diastereodivergent routes allowed the synthesis of ß-hydroxy- and ß-amino-α-amino acids, as well as of ß- and γ-amino acids. Heterocyclic and cyclic amino phosphonic acids were synthesized using diastereodivergent routes. Alkaloids containing five- and six-membered saturated azaheterocycles needed multistep stereodivergent routes and other alkaloids, such as enantiomers of balanol, vincamine, anatoxin and codeine, and diastereomeric isochaetominines C and galanthamines. In the terpene field, sesquiterpenes ß-santalene, α-curcumene and α-cuparenone and the diterpene scopadulcic acid A have been synthesized using enantiodivergent routes.

Switching Diastereoselectivity in Catalytic Enantioselective (3+2) Cycloadditions of Azomethine Ylides Promoted by Metal Salts and Privileged Segphos-Derived Ligands.

Catalytic enantioselective 1,3-dipolar cycloaddition between imino esters and electrophilic alkenes, employing chiral metal complexes derived from copper(I) and silver(I) salts and (S)-DM- or (S)-DTBM-Segphos as ligands produces diastereodivergently exo- or endo-cycloadducts, respectively. The effect of the functional group of the dipolarophile and the fine tuning of the catalyst plays an important role in promoting reverse diastereoselectivities. The origins of experimentally observed enantioselectivity and diastereoselectivity data, as well as the origin of the observed switched endo/exo ratios, are also explained by means of density functional theory calculations.

Synthesis of 3-substituted 3-fluoro-2-oxindoles by deacylative alkylation.

The fluorination of 3-acetyl-2-oxindoles with N-fluorobenzenesulfonimide under Lewis acid catalysis using Mg(ClO4)2 gives the starting compounds 3-acetyl-3-fluoro-2-oxindoles. These compounds are subjected to base-promoted deacylative alkylation (DaA) for the in situ generation of 3-fluoro-2-oxindole enolates under very mild reaction conditions using Triton B (1 equiv.) and alkyl halides and Michael acceptors as electrophilic reagents. The corresponding 3-alkylated-3-fluoro-2-oxindoles are obtained in good to very high yields. In addition, the palladium-catalyzed deacylative allylation is carried out with allylic alcohols using LiOtBu as the base and 6 mol% of Pd(OAc)2 and dppp, giving the resulting 3-allylated 3-fluoro-2-oxindoles in good yields. This methodology allows a simple synthesis of 3-alkylated-3-fluoro-2-oxindoles, which are difficult to obtain by other routes.

Cooperative Catalysis with Coupled Chiral Induction in 1,3-Dipolar Cycloadditions of Azomethine Ylides.

1,3-Dipolar cycloadditions (1,3-DC) between imino esters (as precursors of N-metallated azomethine ylides) and π-deficient alkenes are promoted by cooperative asymmetric Lewis acid/Brønsted base catalysis. The components of these catalytic pairs are silver salts derived from enantiopure commercially available BINOL-based phosphoric acids and Cinchona alkaloids. Chiral phosphoric silver(I) salts promote HOMO raising of in situ formed 1,3-dipoles, whereas protonated cinchona alkaloids generate a LUMO lowering for the dipolarophiles resulting in a global acceleration of the 1,3-DC. The best results were obtained with BINOL-derived silver phosphate and hydrocinchonine. Matching between both cooperative metallo- and organocatalyst results in an enhanced enantiomeric excess, superior to that reached by both separate components. NOESY experiments and DFT calculations are compatible with a non-covalent interaction (hydrogen bond) between both catalysts, which results in close contacts and mutually coupled chiral environments.

Deacylative alkylation (DaA) of N-methyl-3-acetyl-2-oxindole for the synthesis of symmetrically 3,3-disubstituted 2-oxindoles. An access gate to anticancer agents and natural products.

The synthesis of 3,3-disubstituted N-methyloxindoles, starting from 3-acetyl-2-hydroxy-1-methyloxindole employing a sequential one-pot synthesis, is studied. The process involves a first alkylation in the presence of 1 equiv. of both organic halide and Triton B and the second one employs another 1.5 equiv. of each in moderate to high yields. This procedure is compared with the results obtained from the direct dialkylation of N-methyloxindole. The metathesis of one of the corresponding diallylated product was also studied obtaining the spiranic oxindole. All these methodologies are directed towards the access to anticancer agents and natural biologically active products.

Diastereoselective [3 + 2] vs [4 + 2] Cycloadditions of Nitroprolinates with α,ß-Unsaturated Aldehydes and Electrophilic Alkenes: An Example of Total Periselectivity.

Diastereoselective multicomponent reactions of enantioenriched 4-nitroprolinates, obtained by enantiocatalyzed 1,3-dipolar cycloaddition (1,3-DC) of imino esters and nitroalkenes, with α,ß-unsaturated aldehydes and electrophilic alkenes proceed with total periselectivity depending on the structure of the aldehyde employed. This process evolves through a [3 + 2] 1,3-DC when cinnamaldehyde is used in the presence of an azomethine ylide, giving the corresponding highly substituted pyrrolizidines with endo selectivity. However, in the case of the α,ß-unsaturated aldehyde, which contains a hydrogen atom at the γ position, an amine-aldehyde-dienophile (AAD) [4 + 2] cycloaddition takes place by formation of an intermediate 1-amino-1,3-diene, affording highly functionalized cyclohexenes with high endo diastereoselectivity. This AAD process only occurred when a nitro group is bonded to the 4-position of the initial enantiomerically enriched pyrrolidine ring. DFT calculations have been carried out with the aim of explaining this different behavior between pyrrolidines with or without a nitro group, demonstrating the strong nitro-group-dependent periselectivity. The results of these computational studies also support the experimentally obtained absolute configuration of the final adducts.

Binap and Phosphoramidites as Privileged Chiral Ligands for the Metal-Catalyzed Enantioselective 1,3-Dipolar Cycloaddition of Azomethine Ylides.

2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (binap) and phosphoramidites are privileged chiral ligands that have been tested in the coinage-metal-catalyzed 1,3-dipolar cycloadditions of metalloazomethine ylides and electrophilic alkenes. Silver(I), copper(II), and gold(I) salts have been evaluated in all of these reactions. Maleimides, acrylates, fumarates, 1,2-bis(phenylsulfonyl)ethylene, and enones reacted with imino esters to give the corresponding endo-prolinates, such as hepatitis C (HCV) inhibitors, in high diastereo- and enantioselectivity using either binap-silver and -gold(I) or phosphoramidite-silver complexes. In the case of nitroalkenes, exo-4-nitroprolinates were obtained using silver or copper(II) phosphoramidite complexes. Azlactones reacted with maleimides and acrylates to give pyrrolines only in the presence of binap-gold(I) complexes. The observed enantioselectivity and mechanism of these 1,3-dipolar cycloadditions were studied for the most relevant examples by means of DFT calculations.

Long-Term Predictors of Thromboembolic Events in Nonvalvular Atrial Fibrillation Patients Undergoing Electrical Cardioversion.

BACKGROUND: Patients with nonvalvular atrial fibrillation (AF) who undergo electrical cardioversion (ECV) tend to be younger and have less comorbidity. Long-term anticoagulation after ECV should be based on thromboembolic risk. We sought to study the long-term incidence of thromboembolic events (TE), factors related to TE and compare the predictive value of the CHADS2and CHA2DS2-VASc scores in this particular population. METHODS AND RESULTS: From January 2008 to June 2012, 571 ECV were performed in 406 consecutive patients with nonvalvular AF. Risk factors for TE and factors related to anticoagulation therapy after ECV were registered. During a follow-up of approximately 2 years, the annual incidence of TE was 1.9%. Factors associated with TE were: poor quality anticoagulation control (hazard ratio [HR]: 2.91; 95% confidence interval [CI]: 1.10-7.80; P=0.03), cessation of anticoagulation after ECV (HR: 8.80; 95% CI: 3.11-25.10; P<0.001), age ≥65 years (HR: 13.65; 95% CI: 1.74-107.16; P=0.01), CHADS2score (HR: 1.59; 95% CI: 1.10-2.29; P=0.01) and CHA2DS2-VASc score (HR: 1.67; 95% CI: 1.30-2.22; P<0.001). Both risk scores predicted TE [c-statistic for CHADS2: 0.68 (95% CI: 0.62-0.74; P=0.005), for CHA2DS2-VASc: 0.75 (95% CI: 0.70-0.80; P<0.001)]. Based on c-statistics, the predictive accuracy of CHA2DS2-VASc was superior (difference between areas: 0.064±0.031; P=0.0403). CONCLUSIONS: Important determinants of long-term occurrence of TE after ECV were related to anticoagulant therapy (poor quality anticoagulation and cessation of this therapy over follow-up). The CHA2DS2-VASc score successfully predicts TE after ECV, having better predictive accuracy than the CHADS2score. (Circ J 2016; 80: 605-612).

1,3-Dipolar cycloadditions of azomethine imines.

Azomethine imines are considered 1,3-dipoles of the aza-allyl type which are transient intermediates and should be generated in situ but can also be stable and isolable compounds. They react with electron-rich and electron-poor olefins as well as with acetylenic compounds and allenoates mainly by a [3 + 2] cycloaddition but they can also take part in [3 + 3], [4 + 3], [3 + 2 + 2] and [5 + 3] with different dipolarophiles. These 1,3-dipolar cycloadditions (1,3-DC) can be performed not only under thermal or microwave conditions but also using metallo- and organocatalytic systems. In recent years enantiocatalyzed 1,3-dipolar cycloadditions have been extensively considered and applied to the synthesis of a great variety of dinitrogenated heterocycles with biological activity. Acyclic azomethine imines derived from mono and disubstituted hydrazones could be generated by prototropy under heating or by using Lewis or Brønsted acids to give, after [3 + 2] cycloadditions, pyrazolidines and pyrazolines. Cyclic azomethine imines, incorporating a C-N bond in a ring, such as isoquinolinium imides are the most widely used dipoles in normal and inverse-electron demand 1,3-DC allowing the synthesis of tetrahydro-, dihydro- and unsaturated pyrazolo[1,5-a]isoquinolines in racemic and enantioenriched forms with interesting biological activity. Pyridinium and quinolinium imides give the corresponding pyrazolopyridines and indazolo[3,2-a]isoquinolines, respectively. In the case of cyclic azomethine imines with an N-N bond incorporated into a ring, N-alkylidene-3-oxo-pyrazolidinium ylides are the most popular stable and isolated dipoles able to form dinitrogen-fused saturated and unsaturated pyrazolopyrazolones as racemic or enantiomerically enriched compounds present in many pharmaceuticals, agrochemicals and other useful chemicals.

Novel magnetic bimetallic AuCu catalyst for reduction of nitroarenes and degradation of organic dyes.

Herein, core-shell magnetic nanoparticles are modified with imidazolium-tagged phosphine and propylene glycol moieties and used for the stabilization of bimetallic AuCu nanoparticles. The structure and morphology of the prepared material are identified with SEM, TEM, XRD, XPS, atomic absorption spectroscopy, Fourier translation infrared spectroscopy, and a vibrating sample magnetometer. This hydrophilic magnetic bimetallic catalyst is applied in the reduction of toxic nitroarenes and reductive degradation of hazardous organic dyes such as methyl orange (MO), methyl red (MR), and rhodamine B (RhB), as well as in the degradation of tetracycline (TC). This magnetic AuCu catalyst indicated superior activity in all three mentioned reactions in comparison with its single metal Au and Cu analogs. This catalyst is recycled for 17 consecutive runs in the reduction of 4-nitrophenol to 4-aminophenol without a significant decrease in catalytic activity and recycled catalyst is characterized.

Preparation of a ruthenium complex covalently bonded to multilayer graphene and its evaluation as a photocatalyst.

Multilayer graphene (MLG), obtained by mild sonication of graphite in NMP, was functionalised via 1,3-dipolar cycloaddition with azomethine ylides generated by thermal 1,2-prototropy from various imino esters. The microwave-assisted functionalisation took place in five hours at 100 °C. The resulting MLG, containing substituted proline-based amine functional groups, was characterized using XPS and showed a nitrogen loading three times that obtained for the same transformation performed for five days using convection-assisted heating. The preparation of the imino ester containing a bipyridine unit at the arylidene position allowed for the preparation of the corresponding functionalised MLG, which incorporated the ruthenium atom to achieve a heterogeneous MLG-Ru complex. This supported complex was tested, as a proof of concept, as a photocatalyst of the aerobic oxidative hydroxylation of 4-methoxyphenylboronic acid.

Design, synthesis, biological evaluation and docking analysis of pyrrolidine-benzenesulfonamides as carbonic anhydrase or acetylcholinesterase inhibitors and antimicrobial agents.

The synthesis and biological assessment of novel multi-functionalized pyrrolidine-containing benzenesulfonamides were reported along with their antimicrobial, antifungal, CAs inhibition, and AChE inhibition as well as DNA-binding effects. The chemical structure of the compounds was elucidated by using FTIR, NMR, and HRMS. Compound 3b, which had Ki values of 17.61 ± 3.58 nM (hCA I) and 5.14 ± 0.61 nM (hCA II), was found the be the most potent CAs inhibitor. Compounds 6a and 6b showed remarkable AChE inhibition effects with Ki values 22.34 ± 4.53 nM and 27.21 ± 3.96 nM in comparison to tacrine. Compounds 6a-6c had moderate antituberculosis effect on M. tuberculosis with a MIC value of 15.62 µg/ml. Compounds had weaker antifungal and antibacterial activity in the range of MIC 500-62.5 µg/ml against standard bacterial and fungal strains. Besides these above, molecular docking studies were performed to examine and evaluate the interaction of the remarkable compounds (3b, 6a and 6b) against the current enzymes (CAs and AChE). Novel compounds gained interest in terms of enzyme inhibitory potencies. Therefore, the most potent enzyme inhibitors may be considered lead compounds to be modified for further research.Communicated by Ramaswamy H. Sarma.