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Kinetically controlled cyclocondensation of stereoisomeric and ring-chain tautomeric mixture of (±)-hydroxylactone 1 and 0.5 equiv of (R)-phenylglycinol provided tricyclic oxazoloisoindolone lactam (3R,5aS,9aR,9bS)-2a, a versatile intermediate for further stereocontrolled transformations to access enantiopure cis-fused octahydroisoindolones. An extension of this methodology was successfully applied to the synthesis of the 5,6-dihydroxy derivative (3aR,5R,6S,7aS)-17.

The potential of “customizable units” to generate structural diversity for biological screenings is highlighted in this proof‐of‐concept synthesis of new peptides related to the potent antitumoral Sansalvamide A. Using L‐4‐hydroxyproline (Hyp) as a customizable unit in a linear parent peptide, an improved procedure for selective peptide modification was developed. A divergent Hyp scission‐reductive amination process was carried out, affording five linear peptides with cationic residues, and notably, an N‐alkyl moiety that affected the conformation of the peptide. After two steps (saponification and macrocyclization), sixteen differently N1‐substituted linear and cyclic peptides were obtained. For the first time, the activity of the linear and cyclic compounds was compared. Not only some linear analogs but also cyclic compounds with scarcely studied cationic residues were active against MCF7 breast cancer line. Thus, the structural diversity generated from customizable units can be valuable in drug discovery., This work was partly financed by the Consejo Nacional de Ciencia y Tecnología (CONACYT, Mexico) through project 2015‐01‐807, and by MINECO‐MCIU (Spain) with European Social Funds (ESF), through Programme Plan Estatal I+D‐RETOS (project SAF‐2013‐48399‐R). C. J. S. received a postdoctoral contract from the Torres Quevedo Programme (PTQ15‐07923) by MINECO/Min. Science and Innovation, cofinanced by BIOSIGMA SL. Finally, I.R−E. and F.C. thank CONACYT for Catedra contract 942 and predoctoral grant 305283 respectively.

An expedient synthetic entry to cis-4-hydroxyphosphonic and cis-4-hydroxyphosphinic analogs of cis-4-hydroxypipecolic acid is presented in this paper. The main feature of this methodology is the highly regioselective addition of silyl phosphites or phosphonites to cyclic 1-benzyloxycarbonyl enaminones. Interestingly, the hydride reduction of the resulting 2-phospho-4-oxopiperidine proceeds with high diastereofacial preference using NaBH

Kinetically controlled cyclocondensation of stereoisomeric and ring-chain tautomeric mixture of (±)-hydroxylactone

Two new strategies for the efficient synthesis of racemic 1,2,3,4-tetrahydroisoquinoline-3-phosphonic acid (TicP) (±)-2 have been developed. The first strategy involves the electron-transfer reduction of the easily obtained α,β-dehydro phosphonophenylalanine followed by a Pictet–Spengler cyclization. The second strategy involves a radical decarboxylation–phosphorylation reaction on 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic). In both strategies, the highly electrophilic N-acyliminium ion is formed as a key intermediate, and the target compound is obtained in good yield using mild reaction conditions and readily available starting materials, complementing existing methodologies and contributing to the easy accessibility of (±)-2 for further research., This work was supported by Consejo Nacional de Ciencia y Tecnología (CONACYT) through projects 286614 and 256985, and Gobierno de Aragon-FEDER (Grupo Aminoacidos y Peptidos E19-17R; FEDER 2014-2020 “Construyendo Europa desde Aragon”).

Quarantines may exacerbate the presence of emotional symptoms or anxiety.To explore the relation between time spent in lockdown and development of depressive and anxiety symptoms.A survey including the GAD anxiety and PHQ-9 depression scores was answered online by 1,488 subjects aged 36 ± 14 years (74% women), invited to participate through social networks. Both scores are validated for the Chilean population.Most responders had a private health insurance system. Sixty seven percent had clinically significant depressive symptoms and 39% had anxiety symptoms. Spending four or more weeks of lockdown (quarantine) was associated with 1.6 times higher risk of developing depressive symptoms and 2.9 times higher risk of developing anxiety symptoms. Difficulties in access to health care increased 3.3 times the risk of developing depression. Suffering a respiratory disease increased 2.39 times the risk of developing anxiety.There was a direct association between depressive and anxious symptoms, and the time spent of quarantine.

A new series of oligomethylene bis(nitrophenylureylbenzamide) receptors were synthesized varying the relative position of the urea and amide groups (ortho 4 and meta 8) and the length of the oligomethylene chain (C2 to C8). An anion recognition study was performed with TBAX salts (X = AcO−, BzO−, F−, H2PO4−, and HP2O73−) by UV-vis and 1H NMR. The flexibility of these receptors allows a cooperative effect of both ureylbenzamide units in the receptors. Noteworthy, the ortho position favored the 1 : 1 stoichiometry in the complexes with the carboxylates. The formation of 2 : 1 receptor–anion complexes with both types of receptors 4 and 8 and with hydrogen pyrophosphate and high log K values obtained were very significant in this work. The NMR studies evidenced the formation of supramolecular complexes, even in a competitive solvent, such as DMSO.

We report the first stereoselective synthesis of (2R,3aR,7aR)- and (2S,3aS,7aS)-octahydroindole-2-phosphonic acid 2 (OicP derivatives). The key points are the highly diastereoselective synthesis of cis-fused bicyclic (3aR,7aR)- and (3aS,7aS)-pyrrolidin-2-ones 4 through a dynamic kinetic resolution of racemic γ-keto acid (±)-5 with (R)- and (S)-phenylglycinol via Meyers' bicyclic lactams, and the highly diastereoselective addition of trimethyl phosphite to the N-acyliminium ions 3 obtained from 4.

We report here an alternative and practical method for the preparation of 1,2,3,4-tetrahydroisoquinoline-1-phosphonic acid and the first synthesis of 1,2,3,4-tetrahydroisoquinoline-1-H-phosphinic and 1,2,3,4-tetrahydroisoquinoline-1-phenylphosphinic acids through Kabachnik–Fields and aza-Pudovik reaction. This methodology does not require any metallic catalyst and proceeds under mild reaction conditions., The authors thank the Consejo Nacional de Ciencia y Tecnología (CONACyT) for financial support through projects 286614, 807, and Cátedra contract 942, and Gobierno de Aragón-FEDER (Grupo Aminoácidos y Péptidos E19_17R; FEDER 2014-2020 ‘Construyendo Europa desde Aragón’). J.T.H.-M. also wishes to thank CONACyT for Graduate Scholarship 335029.

In this work, the interaction of three different pyridylalkyl mono-core substituted naphthalenedimides (NDIs) with metal ions was studied by UV-Vis and fluorescence spectroscopy. The influence of pyridine substituents position, the spacer length, and solvent over the metal ion recognition was investigated. The most sensible responses observed were with Cu2+ and Fe3+ ions, showing a remarkable change in their colorimetric and fluorescent properties. The prior formation of NDI-Cu2+ (2a and 2b) complexes generates a unique response towards Fe2+ and Mg2+, promoting an OFF/ON response and a colorimetric change, acting as a dual probe for Cu2+ and Fe2+ or Cu2+ and Mg2+. Finally, NDIs 2b and 2c show a specific and selective response towards Hg2+ions in water, forming a solid complex removing the Hg2+ from the aqueous media achieving a removal efficiency up to 92%. NDIs 2b and 2c have potential as probes and removal of Hg2+ ions.

Both experimental and theoretical methods were used in order to study the fluorescent properties of nine new compounds based on phthalimides, isoindolin-1-ones and isoindolines bearing aminobenzoic acids (2-aminobenzoic acid, 3-aminobenzoic acid and 4-aminobenzoic acid), which were obtained under mild reaction conditions. The photophysical properties of all the compounds were studied by electronic absorption and fluorescence spectroscopy in methanol solutions. All compounds exhibited fluorescence emission and high quantum yields. Additionally, it was found that the intramolecular charge in these donor-acceptor systems is significantly depending on electron-withdrawing substituents at the carboxylic acid position.

This review outlines the most recent papers describing the stereoselective synthesis of γ-amino acids. In this update, the γ-amino acids have been classified according to the type of compounds, position and number of substituents, and depending on the type of substrate, acyclic, carbocyclic or azacyclic derivatives, following in the first case an order related to the strategy used, whereas in the second and third cases the classification is based on the ring size., The authors thank CONACYT-Mexico for financial support via projects 181816 and 248868. Ministerio de Ciencia e Innovación–FEDER-Spain (grant CTQ2010-17436) and Gobierno de Aragón–FSE (research group E40).

We report here a practical and efficient synthesis of diethyl 1,2,3,4-tetrahydroisoquinoline-3-phosphonate derivatives. The target compounds were prepared in good yield using a Pictet-Spengler reaction involving α-amino phosphonates that were easily obtained. We have paid special attention to the synthesis of (R)- and (S)-1,2,3,4-tetrahydroisoquinoline-3-phosphonic acid (Tic) 2a, a conformationally constrained analogue of phosphophenylalanine Phe. The procedure is based on the preparation of racemic phosphophenylalanine (Phe) diethyl ester followed by chiral chromatographic separation and subsequent Pictet-Spengler chemistry., The authors thank Consejo Nacional de Ciencia y Tecnología (CONACYT) for financial support through projects 181816 and 248868, the Ministerio de Ciencia e Innovación – FEDER (grant CTQ2010-17436), and the Gobierno de Aragón-FSE (research group E40).

In this paper, we report the synthesis of a new series of α-aminophosphonates derivatives based in an efficient three-component reaction. All compounds prepared showed significant anti-inflammatory activity, being the compounds 1a, 1c, 1d, 1f, 2b and 2c the most promising ones, in terms of maximal efficacy (over 95%), potency (ED50 range between 0.7 and 10.1 mg/ear) and relative potency (range from 0.04 to 0.67). Compounds 1a, 1c, 1d and 1f significantly decrease the number of neutrophils (range from 46.7 to 63.0%) and monocytes (18.9–34.1%) in blood samples from the orbital sinus. Additionally, QSAR model revealed that the spherical molecular shape and the location of the HOMO on the phenyl ring improves the anti-inflammatory activity of the compounds. The values of R2, Q2, s and F statistical parameters and the QUIK, asymptotic Q2 and Overfitting rules validate the descriptive and predictive ability of the QSAR model. Altogether these results suggest that these new α-aminophosphonates are potential agents for the treatment of inflammation.

Practical and convenient method for the synthesis of novel phosphonopeptides 8a-h and 10a-f incorporating the quaternary α-aminophosphonate 6 is reported. The target compounds were prepared in moderate to good yield based on the preparation of the quaternary α-aminophosphonate 6 followed by the formation of the α-bromoamide 7 and subsequent nucleophilic substitution reaction with several amines or by peptide bond formation with several amino acids and with the quaternary α-aminophosphonate 6, using isobutyl chloroformate as activating agent under racemization-free condition.

The alkylation reaction of diethyl N-(diphenylmethylene)aminomethylphosphonate (6) with alkyl dihalides under phase-transfer catalysis followed by hydrolysis of the benzophenone imine moiety and subsequent cyclization provides a simple and convenient method for the synthesis of known and new cyclic α-aminophosphonates 1–5 in moderate to good yields.

Optically active α-aminoalkylphosphonic acids 1 are structural analogues of α-amino acids 2, obtained by isosteric substitution of the planar and less bulky carboxylic acid (CO2H) by a tetrahedral phosphonic acid functionality (PO3H2). Several α-aminoalkylphosphonic acids and derivatives have been isolated from natural sources, either as free amino acids or as constituents of more complex molecules. These classes of compounds are currently attracting interest in organic and medicinal chemistry, as well as in agriculture, due to their important biological and pharmacological properties. Additionally, the α-aminophosphonates have been used as key synthetic intermediates for the preparation of more complex compounds1b, and as organocatalysts., We gratefully acknowledge CONACyT of Mexico (grant 181816), Ministerio de Economía y Competitividad (grant CTQ2013-40855-R), and Gobierno de Aragón -FSE (research group E40).

The bis(silyl)triazene compound 2,6-(Me3Si)2-4-Me-1-(NNNC4H8)C6H2 (4) was synthesized by double lithiation/silylation of 2,6-Br2-4-Me-1-(NNNC4H8)C6H2 (1). Furthermore, 2,6-bis[3,5-(CF3)2-C6H3]-4-Me-C6H2-1-(NNNC4H8)C6H2 derivative 6 can be easily synthesized by a C,C-bond formation reaction of 1 with the corresponding aryl-Grignard reagent, i.e., 3,5-bis[(trifluoromethyl)phenyl]magnesium bromide. Reactions of compound 4 with KI and 6 with I2 afforded in good yields novel phenyl derivatives, 2,6-(Me3Si)2-4-MeC6H2I and 2,6-bis[3,5-(CF3)2C6H3]-4-MeC6H2I (5 and 7, resp.). On the other hand, the analogous m-terphenyl 1,3-diphenylbenzene compound 2,6-bis[3,5-(CF3)2C6H3]C6H3I (8) could be obtained in moderate yield from the reaction of (2,6-dichlorophenyl)lithium and 2 equiv. of aryl-Grignard reagent, followed by the reaction with I2. Different attempts to introduce the tBu (Me3C) or neophyl (PhC(Me)2CH2) substituents in the central ring were unsuccessful. All the compounds were fully characterized by elemental analysis, melting point, IR and NMR spectroscopy. The structure of compound 6 was corroborated by single-crystal X-ray diffraction measurements.

Shikimic acid (SA) pathway is the common route used by bacteria, plants, fungi, algae, and certain Apicomplexa parasites for the biosynthesis of aromatic amino acids and other secondary metabolites. As this essential pathway is absent in mammals designing inhibitors against implied enzymes may lead to the development of antimicrobial and herbicidal agents harmless to humans. Shikimate dehydrogenase (SDH) is the fourth enzyme of the SA pathway. In this contribution, a series of SA amide derivatives were synthesised and evaluated for in vitro SDH inhibition and antibacterial activity against Escherichia coli. All tested compounds showed to be mixed type inhibitors; diamide derivatives displayed more inhibitory activity than synthesised monoamides. Among the evaluated compounds, molecules called 4a and 4b were the most active derivatives with IC50 588 and 589 µM, respectively. Molecular modelling studies suggested two different binding modes of monoamide and diamide derivatives to the SDH enzyme of E. coli.

The authors are thankful for financial support by the Mexican Consejo Nacional de Ciencia y Tecnologia (CONACYT) for financial support via project 181816, by the Spanish Ministerio de Ciencia e Innovacion (MICINN), FEDER (grant number CTQ2010- 17436) and by the Gobierno de Aragon-FSE (research group E40). J. L. V.-C. also thank CONACYT for graduate scholarships.

The amidation of unactivated ethyl esters with achiral and chiral 1,2-amino alcohols under microwave irradiation and base-free conditions is described. This procedure provides a convenient method for the synthesis of β-hydroxyacetamides bearing pyrazole, imidazole, and benzimidazole groups in high yields and without racemization. The protocol described herein is environmentally friendly and allows for the preparation of a wide variety of β-hydroxyacetamides, which are key intermediates in the synthesis of oxazolines and other derivatives of biological interest.

A simple, efficient and general method has been developed for the high diastereoselective synthesis of α-aminophosphonates through “one-pot” three-component reaction of alkyl and aryl aldehydes with (S)-α-methylbenzylamine or (S)-3,3-dimethyl-2-butylamine and dimethyl phosphite (Kabachnik-Fields reaction), which proceeds in short time using microwave irradiation under solvent and catalyst free-conditions. This method could be useful in the large-scale synthesis of α-aminophosphonates in short reaction time

A simple and practical method is reported for the synthesis of 3-(2-arylethylidene)isoindolin-1-ones and 3-(2-arylethylidene)isobenzofuran-1(3H)-ones, proceeding with good to excellent yields and (E:Z) selectivity. This methodology involves the sequential reduction-dehydration reaction of readily obtained 3-(2-oxo-2-arylethyl)isoindolin-1-ones and 3-(2-oxo-2-arylethyl)isobenzofuran-1(3H)-ones followed by a base-catalyzed double bond isomerization with K2CO3 in acetonitrile. The development of a concise synthesis of AKS-182 has been achieved using this methodology.

The most important and available references have been collected in this review to prove the versatility of stereoselective synthesis of acyclic α,α-disubstituted α-amino acids from amino acids template equivalents., The authors gratefully acknowledge financial support from CONACYT (projects 286614 and 256985), and Gobierno de Aragon-FEDER (Grupo Aminoacidos y Peptidos E19-17R; FEDER 2014–2020 ″Construyendo Europa desde Aragon").

The synthesis of new alkyl (C3 to C8) bis(naphthylureylbenzamide)-based receptors and the study of their interaction with anions by UV–Vis, molecular fluorescence and 1H NMR were performed. The results suggest both ureylbenzamide units participate in the complexion with anions due to their inherent flexibility, which promotes a cooperative binding effect. The position of the urea and amide groups, as well as, the alkyl chain length, have an important influence in the fluorescent response; meta receptors present an ON1/OFF/ON2 response, while ortho receptor have an OFF/ON response. The most significant changes were observed with dihydrogen phosphate and hydrogen pyrophosphate due to high affinity for these anions. The 1H NMR studies show differences in the interaction sites depending the relative position of the urea and amide groups, as wells as, the anion type. Finally, a theoretical analysis of complexes by DFT support the experimental results.

Phenylphosphonic acid is an efficient, friendly and reusable heterogeneous catalyst for the synthesis of α-aminophosphonates through a ‘one-pot’ three-component reaction of amines, carbonyl compounds and dialkyl phosphites under solvent-free conditions. This methodology illustrates a very simple procedure, with wide applicability, extending the scope to aliphatic and aromatic amines, aliphatic and aromatic aldehydes and aliphatic ketones. It also enabled the synthesis of α-aminophosphonates in large scale, clean conversion, easy workup and purification. Excellent results were obtained in each case obtaining the desire compounds in moderate to good yields.

A series of 3-alkylideneisoindolinones was prepared by a Horner–Wadsworth–Emmons (HWE) reaction of aromatic aldehydes with N-(ω-hydroxyalkyl)-substituted 3-phosphoisoindolin-1-ones, obtained in one-pot synthesis from 2-formylbenzoic acid. Additionally, the intramolecular HWE reaction of the N-(ω-formylalkyl)-substituted phosphoisoindolin-1-ones afforded the corresponding isoindolone derivatives.

A regioselective synthesis has been developed for the preparation of a series ofN,N′-disubstituted 4,4′-carbonylbis(carbamoylbenzoic) acids andN,N′-disubstituted bis(carbamoyl) terephthalic acids by treatment of 3,3′,4,4′-benzophenonetetracarboxylic dianhydride (1) and 1,2,4,5-benzenetetracarboxylic dianhydride (2) with arylalkyl primary amines (A-N). The carbamoylcarboxylic acid derivatives were synthesized with good yield and high purity. The specific reaction conditions were established to obtain carbamoyl and carboxylic acid functionalities over the thermodynamically most favored imide group. Products derived from both anhydrides1and2were isolated as pure regioisomeric compounds under innovative experimental conditions. The chemo- and regioselectivity of products derived from dianhydrides were determined by NMR spectroscopy and confirmed by density functional theory (DFT). All products were characterized by NMR, FTIR, and MS.

Herein we report a practical and efficient method for the synthesis of optically active 2,4-disubstituted oxazolines (S)-1a–h in good to excellent yields. The target compounds were prepared in good yield through the Horner–Wadsworth–Emmons reaction of β-phosphonoamide 3 bearing l -phenylalaninol with commercially available aryl aldehydes followed by the cyclodehydration of the corresponding N-(cinnamoyl)-(S)-phenylalaninol derivatives (S)-2a–h. Additionally, the cyclodehydration of β-phosphonoamide (S)-3 followed by the Horner–Wadsworth–Emmons reaction of β-phosphono-oxazoline (S)-4 with aryl aldehydes also gave the 2,4-disubstituted oxazolines (S)-1a–h.