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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 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.

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).

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).

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.

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

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").

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.

A new group of ureylbenzamide-based receptors (1–4) has been synthesized; its binding affinity and capacity to form supramolecular complexes in solution with different anions have been investigated. For designing these receptors, it was considered a combination of the positions of the urea and amide groups (ortho and meta), and the chromophore groups naphthyl and nitrophenyl, yielding four receptors. The position and chromophore structure affected the acidity of the urea and amide hydrogens in the order 4>3>2>1. All the spectroscopic studies showed a significant change of 1 and 2 compared with 3 and 4 in the presence of different TBAX salts in acetonitrile. The 1H-NMR spectra show a preferential interaction of the anions with the urea group in receptors 1 and 2 due to the less steric hindrance, while there is a cooperative interaction of amide group in receptors 3 and 4 due to the closeness of both groups.

α-Amino-H-phosphinic acids and derivatives are an important group of compounds of synthetic and pharmacological interest, and particular attention has been dedicated toward their stereoselective synthesis in recent years. While some of these compounds show activity by themselves, they are also valuable starting materials in the synthesis of phosphinic bioisosteres of natural peptides, where the hydrolyzable bond is substituted by a phosphinic functionality that mimics the transition state of peptide hydrolysis, thus acting as efficient enzyme­ inhibitors in which the molecular stereochemistry is demonstrated to be critical. This review summarizes the latest developments on the asymmetric synthesis of acyclic and phosphacyclic α-amino-H-phosphinic acids and derivatives following an order according to the strategy used; in addition, some implications in medicinal chemistry are disclosed., The authors gratefully acknowledge CONACYT (grant 181816, 248868) and PRODEP (project UAEMOR-PTC-379) of Mexico, Ministerio de Economía y Competitividad (grant CTQ2013-40855-R) and Gobierno de Aragón – FSE (research group E40) for their financial support.

We report here a practical and efficient synthesis of α-aminophosphonic acid incorporated into 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline heterocycles, which could be considered to be conformationally constrained analogues of pipecolic acid. The principal contribution of this synthesis is the introduction of the phosphonate group in the N-acyliminium ion intermediates, obtained from activation of the quinoline and isoquinoline heterocycles or from the appropriate δ-lactam with benzyl chloroformate. Finally, the hydrolysis of phosphonate moiety with simultaneous cleavage of the carbamate afforded the target compounds., Financial support to this work was provided by Consejo Nacional de Ciencia y Tecnología (CONACYT-Mexico, grants 181816 and 248868). Ministerio Economia y Competitividad (grant CTQ2013-40855-R), and Gobierno de Aragón-Fondo Social Europeo (research group E40). Consejo Superior de Investigaciones Científicas (grant 2008MX0044)., We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI).

This review describes the synthesis, biological interest and importance of the α-aminophosphonic acids analogs of the 20 proteinogenic α-amino acids. Special attention is devoted to those stereoselective procedures that allow the synthesis of the required compounds in enantiomerically pure form. © 2012 Bentham Science Publishers.

We describe a protocol developed for the preparation of β-enaminoketones derived from 1,3-cyclohexanediones, and their subsequent reduction by sodium in THF-isopropyl alcohol to afford cis- and trans-3-aminocyclohexanols.

A microwave assisted method for the synthesis of some typical 4-substituted oxazolidinone chiral auxiliaries used in asymmetric synthesis is reported in this work. Under these conditions, treatment of (S)-phenylalaninol, (S)-phenylglycinol, (S)-valinol and (1S, 2R)-norephedrine with ethyl carbonate or carbon disulfide under the appropriate and specific microwave reaction conditions, led to an efficient synthesis of some oxazolidin-2-ones, oxazolidine-2-thiones and thiazolidine-2-thiones. The methodology reported in this paper provides these chiral auxiliaries with improved yields and a remarkable reduction on the reaction times, particularly in the case of thiazolidine-2-thiones, as compared with the conventional methods. All the auxiliaries prepared here show spectroscopic data in full agreement with those previously reported in the literature.

The synthesis of two phosphoproline analogues possessing an octahydroisoindole structure is described for the first time. The new α-aminophosphonic acids can be viewed as the result of fusing a cyclohexane ring to the [c] face of the five-membered pyrrolidine unit. The junction of the bicyclic system is cis in both compounds, but they differ in the relative stereochemistry of the cyclohexane and phosphonate moieties. Using phthalimide as a common precursor and following stereodivergent routes, the target α-aminophosphonic acids, (1R*,3aR*,7aS*)-and (1S*,3aR*,7aS*)-octahydroisoindole-1-phosphonic acids, have been prepared with completestereocontrol and in high overall yields. The structurally related isoindoline-1-phosphonic acid, containing a benzene ring [c]-fused to pyrrolidine, has also been obtained. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim., The authors thank the Spanish Ministerio de Ciencia e Innovación (MICINN) (project CTQ2010-17436), Consejo Superior de Investigaciones Científicas (project 2008MX0044; JAE predoctoral fellowship to A. A.), Gobierno de Aragón (research group E40) and the Mexican Consejo Nacional de Ciencia y Tecnología (CONACYT) (projects 62271 and J000.400/2009) for financial support.

A series of novel naphthalimide–aminobenzamide (NAPIM-2ABZ) dyads 3 connected by different length polymethylene chains were synthesized and studied as fluorescent supramolecular receptors in metal ion binding. The photophysical properties were evaluated and compared with separated chromophores. The electronic absorption spectra of dyads 3 showed no interaction between chromophores in the ground state. The fluorescence quantum yields were lower in dyads 3 in comparison with N-propyl-2-aminobenzamide (8). The fluorescence quenching is attributed to a PET mechanism between fluorophores (from 2ABZ to NAPIM), which is dependent on the polymethylene chain length. In metal binding study was found a response towards transition metal ions such as Hg(II), Cu(II), Zn(II) and Ni(II). Dyad 3b presented selectivity towards Cu(II). The UV-vis, IR and 1H-NMR studies demonstrated the interaction with 2ABZ moiety in the ground state, and interestingly dyads with shorter polymethylene chains 3a (n = 0), 3b (n = 1) and 3c (n = 2) exhibited an OFF/ON fluorescence behaviour due to the PET inhibition and the quenching of 2ABZ fluorescence. Dyads 3d (n = 4) and 3e (n = 6) presented opposite response ON/OFF in the complex with metal ions evidencing the absence of PET in these dyads.

An efficient synthesis of enantiomerically-pure β-aryl-γ-lactams is described. The principal feature of this synthesis is the practical resolution of β-aryl-γ-lactams with (S)-Naproxen. The procedure is based on the Michael addition of nitromethane to benzylidenemalonates, which was easily obtained, followed by the reduction of the γ-nitroester in the presence of Raney nickel and the subsequent saponification/decarboxylation reaction. The utility of this methodology was highlighted by the preparation of enantiomerically-pure (R)- and (S)-Baclofen hydrochloride.

Synthesis and structural characterization of 1,4,2-oxazaphosphepines is described. The 1,4,2-oxazaphosphepines were obtained from reaction of chiral 1,3-benzoxazines with dichlorophenylphosphine or triethyl phosphite. The configuration of some of these compounds was stablished by X-ray analysis.

The reduction of (3S)-N,N-dibenzylamino-2-ketophosphonate 5 derived from L-leucine with catecholborane at -20 o C afford the (3S)-N,N-dibenzylamino-(2R)-hydroxyphosphonate syn-6, whereas the reduction of (3S)-N-benzylamino-2-ketophosphonate 9 with Zn(BH4)2 at -78 o C gave the (3S)-N-benzylamino-(2S)-hydroxyphosphonate anti-10. The reduction in both cases was in good chemical yields and high diastereoselectivity. The hydrolysis and hydrogenolysis of syn-6 and anti-10 gave phosphostatine 12 and phosphoepistatine 13, respectively.

This work was carried out with the financial support of CONACYT of Mexico (project 62271), FOSISS-10-ST-564, Ministerio de Educación y Ciencia-FEDER (project CTQ2010-17436), Gobierno de Aragón (group E40) and bilateral proyect CONACYT-CSIC (project J000.400/2009 and 2008MX0044).

A simple, mild, and efficient one-pot, three-component synthetic method has been developed for the preparation of α-aminophosphonates using phenylboronic acid as catalyst under solvent-free conditions at 50°C. The process involves the reaction of carbonyl compounds (aldehydes or ketones) with benzylamine and dimethyl phosphite. A wide range of carbonyl compounds are compatible with this reaction, producing tertiary and quaternary α-aminophosphonates in moderated to excellent yields in short time. © Georg Thieme Verlag Stuttgart · New York.

The one-pot three-component reaction of 2-formylbenzoic acid with (S)- and (R)-methylbenzylamine and dimethyl phosphite (Kabachnik-Fields reaction) proceeded in short reaction times under solvent and catalyst free-conditions to afford the corresponding (3R,1′S)- and (3S,1′R)-isoindolin-1-one-3- phosphonates 3, respectively, in good yield and with high diastereoselectivity (95:5 dr). The use of a solvent decreases the diastereoselectivity and slows the reaction rate. The reaction rate was also influenced by CO2H functionality through protonation of the imine intermediate. The absolute configuration at the new stereogenic center was determined by X-ray crystal analysis, and a mechanism was proposed to explain the high diastereoselectivity. © 2011 Elsevier Ltd. All rights reserved., The authors thank the CONACYT of Mexico, for their financial support via projects 62271 and J000.400/2009), Ministerio de Ciencia e Innovación (project CTQ2010-17436) and Consejo Superior de Investigaciones Científicas (project 2008MX0044. One of us, J.L.V.C. also thanks the CONACYT for a Graduate Scholarship.

The synthesis of two new α-aminophosphonic acids, namely (2S*,3aS*,7aS)- and (2R*,3aS*,7aS)-octahydroindole-2- phosphonic acids, is described. They are analogues of phosphoproline with a cyclohexane ring fused to the pyrrolidine moiety. The ring junction has cis stereochemistry in both cases, but the two compounds differ in the relative orientation of the cyclohexane and phosphonate moieties. The two amino acids were prepared from a common starting material following stereodivergent routes that provide the desired stereoisomer with complete stereocontrol. The relative configurations of the compounds synthesised were confirmed by X-ray diffraction analysis. Two analogues of phosphoproline with a cyclohexane ring fused to the pyrrolidine moiety have been synthesised. They differ in the stereochemistry at the α-carbon atom and have been prepared, with complete stereocontrol, following stereodivergent routes from a common precursor., The authors thank the Ministerio de Ciencia e Innovación (project CTQ2010-17436), the Consejo Superior de Investigaciones Científicas (project 2008MX0044; JAE predoctoral fellowship to A. A.), the Gobierno de Aragón (group E40) and the Consejo Nacional de Ciencia y Tecnología (CONACYT-MEXICO; projects 62271 and J000.400/2009) for financial support.

The most recent papers describing the stereoselective synthesis of cyclic quaternary alpha-amino acids are collected in this review. The diverse synthetic approaches are classified according to the size of the ring and taking into account the bond that is formed to complete the quaternary skeleton.

An overview of all methodologies published during the last few years focused to the stereoselective (diastereoselective or enantioselective) synthesis of α-aminophosphonic acids and derivatives is reported. The procedures have been classified according a retrosynthetic strategy and taking into account the formation of each one of the bonds connected to the chiral centre.

97 pages, 285 schemes, 8 figures.-- Tetrahedron: Asymmetry report number 91., γ-Amino acids have attracted considerable attention as biologically active compounds in the central nervous system (CNS) of mammals. Over the last few years, significant interest in the stereoselective synthesis and practical application of linear and cyclic chiral γ-amino acids in the synthesis and design of α,β- and β,γ-hybrid peptides with definite secondary structures and design of nanotubes has been reported, thus demonstrating the theoretical interest and the practical importance of γ-amino acids. An overview of synthetic approaches to linear and cyclic chiral γ-amino acids and derivatives is presented. Data on the practical applications of γ-amino acids are also discussed., This work was carried out with the financial support of CONACYT-MEXICO (Projects 41657-Q and 44704-Q) Ministerio de Educación y Ciencia-FEDER (project CTQ2004-5358) and Gobierno de Aragón (group E40 and project MI47/2005).

The conformational energy of the (η5-cyclopentadienyl) iron(II) dicarbonyl group was determined by variable-temperature 1H NMR spectroscopic studies on cis-4-phenyl-1-(η5-cyclopentadienyl) iron(II)...