- Conjugates of 1′-aminoferrocene-1-carboxylic acid and proline: Synthesis, conformational analysis and biological evaluation
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Our previous studies showed that alteration of dipeptides Y-Fca-Ala-OMe (III) into Y-Ala-Fca-OMe (IV) (Y = Ac, Boc; Fca = 1′-aminoferrocene-1- carboxylic acid) significantly influenced their conformational space. The novel bioconjugates Y-Fca-Pro-OMe (1, Y = Ac; 2, Y = Boc) and Y-Pro-Fca-OMe (3, Y = Boc; 4, Y = Ac) have been prepared in order to investigate the influence of proline, a well-known turn-inducer, on the conformational properties of small organometallic peptides with an exchanged constituent amino acid sequences. For this purpose, peptides 1-4 were subjected to detailed spectroscopic analysis (IR, NMR, CD spectroscopy) in solution. The conformation of peptide 3 in the solid state was determined. Furthermore, the ability of the prepared conjugates to inhibit the growth of estrogen receptor-responsive MCF-7 mammary carcinoma cells and HeLa cervical carcinoma cells was tested.
- Kovacevic, Monika,Molcanov, Kresimir,Radosevic, Kristina,Srcek, Visnja Gaurina,Roca, Suncica,Cace, Alan,Barisic, Lidija
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- Heteroatom-Interchanged Isomers of Lissoclinamide 5: Copper(II) Complexation, Halide Binding, and Biological Activity
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Cyclic peptides, especially those produced by marine cyanobacteria symbionts, are considered to play an important ecological role in host defence. Chemists have long compared the cyclic peptide cavitand architecture with that of macrocyclic ligands, and proposed that they mediate metal-ion transport. The study presented herein investigated the metal chelation of non-natural heteroatom-interchanged (HI) isomers of lissoclinamide 5, by using MS, EPR, and DFT calculations. The latter identified three possible structures for the CuII complex with natural lissoclinamide 5, with the most likely determined to be that with the metal ion bound through the nitrogen donors of the thiazoles and one deprotonated amide. For HI-lissoclinamide 5 the calculations suggest that the CuII ion is bound in a bidentate manner by the oxazoline nitrogen atom and one deprotonated amide nitrogen atom, with the S donor of the thiazole not involved in coordination. Along with evidence of copper binding these systems also bound halide ions. Evaluation of the anti-cancer properties demonstrated that the biological activity of HI-lissoclinamide 5 against T24 bladder cells was eleven-fold lower as compared to natural lissoclinamide 5. Addition of a CuII salt had no effect on the activity of lissoclinamide 5. Overall, this comprehensive study of the HI concept has demonstrated that small changes propagate dramatic effects in complexation, halide binding, and biological activity.
- Xie, Sida,Savchenko, Andrei I.,Kerscher, Marion,Grange, Rebecca L.,Krenske, Elizabeth H.,Harmer, Jeffrey R.,Bauer, Michelle J.,Broit, Natasa,Watters, Dianne J.,Boyle, Glen M.,Bernhardt, Paul V.,Parsons, Peter G.,Comba, Peter,Gahan, Lawrence R.,Williams, Craig M.
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- A dansyl-appended N-heterocycle for Cu2+ and S2? recognition via a displacement mode
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A novel L-proline based heterocycle 3 of C2 symmetry has been designed and synthesized for cation and anion recognition in aqueous solution. Ligand 3 shows a strong affinity to Cu2+ ion, and their interaction induces a remarkable fluorescence quenching in DMSO:H2O = 9:1 (HEPES buffer, 0.01 M, pH 7.4) among various metal ions. Both the in-situ generated and isolated 3-Cu2+ complex exhibit specific fluorescence recovery upon addition of S2?, even in the presence of S2O3 2?, L-histidine, and thiol-containing amino acids. For this dual functional switch, a combination of 1H NMR titration, ESI mass and FT-IR spectra suggest that its sensing behavior is via a displacement mode. Sequential “on-off-on” fluorescence bio-imaging of the heterocycle 3 to Cu2+ and S2? was carried out in HeLa cells.
- Wang, Xu,Xia, Peng,Huang, Xiaohuan
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- Synthesis and vibrational spectroscopic investigation of methyl l-prolinate hydrochloride: A computational insight
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In our present work, methyl L-prolinate hydrochloride has been synthesized from L-proline amino acid and characterized by Fourier transform infrared and Fourier transform Raman spectra via experimental and computational methods. Ab initio Hartree-Fock and density functional theory (B3LYP) calculations have been made for the structure, and atomic charge distributions were also predicted for the title compound by using the 6-311++G(d,p) basis set. Predicted vibrational frequencies have been assigned and compared with experimental Fourier transform infrared and Fourier transform Raman spectra. The thermodynamic properties such as heat capacity, enthalpy, entropy, and Gibbs energy have been calculated at different temperatures. The calculated highest occupied molecular orbital and lowest unoccupied molecular orbital energy show the charge transfer behavior within the molecule.
- Balachandran,Boobalan,Amaladasan,Velmathi
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- Captopril analogues as metallo-β-lactamase inhibitors
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A number of captopril analogues were synthesised and tested as inhibitors of the metallo-β-lactamase IMP-1. Structure–activity studies showed that the methyl group was unimportant for activity, and that the potencies of these inhibitors could be best improved by shortening the length of the mercaptoalkanoyl side-chain. Replacing the thiol group with a carboxylic acid led to complete loss of activity, and extending the length of the carboxylate group led to decreased potency. Good activity could be maintained by substituting the proline ring with pipecolic acid.
- Yusof, Yusralina,Tan, Daniel T.C.,Arjomandi, Omid Khalili,Schenk, Gerhard,McGeary, Ross P.
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- Exercises in pyrrolidine chemistry: Gram scale synthesis of a Pro-Pro dipeptide mimetic with a polyproline type II helix conformation
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A practical and scalable synthesis of a Fmoc-protected tricyclic dipeptide mimetic (6), that is, a 1,4-diaza-tricyclo-[8.3.03, 7]-tridec-8-ene derivative resembling a rigidified di-L-proline in a polyproline type II (PPII) helix conformation, was developed. The strategy is based on a Ru-catalyzed ring-closing metathesis of a dipeptide (4) prepared by PyBOP coupling of cis-5-vinylproline tert-butylester (2) and trans-N-Boc-3-vinylproline (rac-3) followed by chromatographic diastereomer separation. Building block 2 was prepared from L-proline in six steps via electrochemical C5-methoxylation, cyanation and conversion of the nitrile into a vinyl substituent. Building block rac-3 was prepared in five steps exploiting a Cu-catalyzed 1,4-addition of vinyl-MgBr to a 2,3-dehydroproline derivative in the key step. In the course of the investigation subtle dependencies of protecting groups on the reactivity of the 2,3- and 2,5-disubstituted pyrrolidine derivatives were observed. The configuration and conformational preference of several intermediates were determined by X-ray crystallography. The developed synthesis allows the preparation of substantial amounts of 6, which will be used in the search for new small molecules for the modulation of protein-protein interactions involving prolin-rich motifs (PRDs).
- Reuter, Cedric,Huy, Peter,Neudoerfl, Joerg-Martin,Kuehne, Ronald,Schmalz, Hans-Guenther
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- Addition of organolithium reagents to Ahc methyl ester. An approach to new α-amino ketones
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We have developed a versatile methodology to obtain α-amino ketones by acylation of methyl N-benzoyl-7-azabicyclo[2.2.1]heptane-1-carboxylate (1) with organolithium reagents. The reaction proceeds via a stable tetrahedral intermediate. When methyl ester 1 was treated under the same conditions but with a different work up procedure (careful addition of saturated NH4Cl), we observed by 1H NMR spectroscopy that a new compound had appeared in the crude reaction mixture corresponding to a hemiacetal.
- Avenoza, Alberto,Busto, Jesús H.,Peregrina, Jesús Manuel
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- Stereocontrolled Synthesis of Boranophosphate DNA by an Oxazaphospholidine Approach and Evaluation of Its Properties
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In this paper, we describe the first stereocontrolled synthesis and properties of boranophosphate DNA (PB-DNA), which contains all of the four nucleobases longer than 10mer. Synthesis was accomplished via an oxazaphospholidine approach combined with acid-labile protecting groups on nucleobases. It was demonstrated that there were significant differences between all-(Rp)- and all-(Sp)-PB-DNA in terms of the duplex-formation ability, nuclease resistance, and ribonuclease H (RNase H) activity. In particular, all-(Sp)-PB-DNA was demonstrated to show a duplex-formation ability with RNA and RNase H activity, both of which are necessary for antisense-type nucleic acid therapeutics.
- Hara, Rintaro Iwata,Saito, Tatsuya,Kogure, Tomoki,Hamamura, Yuka,Uchiyama, Naoki,Nukaga, Yohei,Iwamoto, Naoki,Wada, Takeshi
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- Ferulic acid amide derivatives with varying inhibition of amyloid-β oligomerization and fibrillization
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized, in part, by the misfolding, oligomerization and fibrillization of amyloid-β (Aβ). Evidence suggests that the mechanisms underpinning Aβ oligomerization and subsequent fibrillization are distinct, and may therefore require equally distinct therapeutic approaches. Prior studies have suggested that amide derivatives of ferulic acid, a natural polyphenol, may combat multiple AD pathologies, though its impact on Aβ aggregation is controversial. We designed and synthesized a systematic library of amide derivatives of ferulic acid and evaluated their anti-oligomeric and anti-fibrillary capacities independently. Azetidine tethered, triphenyl derivatives were the most potent anti-oligomeric agents (compound 2i: IC50 = 1.8 μM ± 0.73 μM); notably these were only modest anti-fibrillary agents (20.57% inhibition of fibrillization), and exemplify the poor correlation between anti-oligomeric/fibrillary activities. These data were subsequently codified in an in silico QSAR model, which yielded a strong predictive model of anti-Aβ oligomeric activity (κ = 0.919 for test set; κ = 0.737 for validation set).
- Kolaj, Igri,Wang, Yanfei,Ye, Kailin,Meek, Autumn,Liyanage, S. Imindu,Santos, Clarissa,Weaver, Donald F.
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supporting information
(2021/07/07)
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- Transition Metal-Free N-Arylation of Amino Acid Esters with Diaryliodonium Salts
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A transition metal-free approach for the N-arylation of amino acid derivatives has been developed. Key to this method is the use of unsymmetric diaryliodonium salts with anisyl ligands, which proved important to obtain high chemoselectivity and yields. The scope includes the transfer of both electron deficient, electron rich and sterically hindered aryl groups with a variety of different functional groups. Furthermore, a cyclic diaryliodonium salt was successfully employed in the arylation. The N-arylated products were obtained with retained enantiomeric excess.
- Kervefors, Gabriella,Kersting, Leonard,Olofsson, Berit
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supporting information
p. 5790 - 5795
(2021/03/08)
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- COMPOUNDS, COMPOSITIONS AND METHODS FOR STABILIZING TRANSTHYRETIN AND INHIBITING TRANSTHYRETIN MISFOLDING
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Provided herein are compounds having activity against TTR related conditions, and pharmaceutically accepted salts and solvates thereof. Also provided are methods of using the compounds for inhibiting and preventing TTR aggregation and/or amyloid formation in the peripheral nerves, kidney, cardiac tissue, eye and CNS, and of treating a subject with peripheral TTR amyloidosis.
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Paragraph 0854-0857
(2021/08/06)
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- Generic JAKs inhibitor and application thereof
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The invention discloses a generic JAKs inhibitor, and also discloses a composition, a preparation method and medical application of the generic JAKs inhibitor. The definition of each group in the formula is consistent with the specification.
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Paragraph 0391-0399
(2021/01/30)
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- METHODS OF TREATING PAINFUL DIABETIC PERIPHERAL NEUROPATHY
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Provided herein are methods of treating painful diabetic peripheral neuropathy, such as advanced painful DPN, in a patient by administering to the patient an effective amount of NYX-2925 or a pharmaceutically acceptable salt thereof. Also provided are crystalline forms of 3-hydroxy-2-(5-isobutyryl-1-oxo-2,5-diazaspiro[3,4]octan-2-yl)butanamide.
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Paragraph 0161-0163
(2021/05/14)
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- METHODS OF TREATING FIBROMYALGIA
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Provided herein are methods of treating fibromyalgia, in a patient by administering to the patient an effective amount of NYX-2925 or a pharmaceutically acceptable salt thereof.
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Paragraph 0267-0270
(2021/10/11)
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- Preparation method of L-prolinamide
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The invention provides a preparation method of L-prolinamide. The preparation method comprises the following steps: by using L-proline as an initial raw material, firstly forming L-proline methyl ester hydrochloride, then carrying out ammonolysis to obtain a synthetic solution containing L-prolinamide, and dissociating the residual L-prolinamide hydrochloride in the synthetic solution into L-prolinamide through inorganic alkali in a non-aqueous environment, and removing by-products through a non-aqueous solvent system. According to the preparation method, the L-prolinamide hydrochloride can befully dissociated, the by-products and the impurities can be effectively removed, the yield and purity of the target product can be remarkably improved, the preparation method is simple and convenient in process, mild in condition and easy to control, expensive reagents are not needed, the production efficiency of the L-prolinamide can be improved, and the preparation method is suitable for large-scale industrial production and has important economic and social values.
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Paragraph 0039-0040
(2021/01/28)
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- Amphiphilic immobilized diphenylprolinol alkyl ether catalyst on PS-PEG resin
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Diphenylprolinol silyl ether is a widely used organocatalyst, and its immobilization on a solid support was investigated for the easy recycling and reuse of this catalyst. Because a silyl ether bond of the catalyst is weak, its alkyl ether was attached to polymers such as a polyquinoxaline-based polymer, a polystyrene polymer (PS) resin, and a polystyrenepoly(ethylene glycol) graft copolymer (PS-PEG) resin. Although a polymer-supported organocatalyst generally decreases its reactivity compared with the monomer catalyst, diphenylprolinol anthrylmethyl ether supported on PS-PEG was found to be a reactive organocatalyst; it catalyzed the Michael reaction of an aldehyde and a nitroalkene in water without an organic solvent being present, with excellent diastereo- and enantioselectivities.
- Koshino, Seitaro,Hattori, Shusuke,Hasegawa, Shota,Haraguchi, Naoki,Yamamoto, Takeshi,Suginome, Michinori,Uozumi, Yasuhiro,Hayashi, Yujiro
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p. 790 - 797
(2021/04/14)
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- Two-Dimensional Barriers for Probing Conformational Shifts in Macrocycles
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We describe the development and use of composite two-dimensional barriers in macrocyclic backbones. These tunable constructs derive their mode of action from heterocyclic rearrangements. The Boulton-Katritzky reaction has been identified as a particularly versatile means to effect a composite barrier, allowing the examination of the influence of heterocycle translocation on conformation. Kinetic studies using 1H NMR have revealed that the in-plane atom movement is fast in 17, 18, 19-membered rings but slows down in 16-membered rings. The analysis by NMR and MD simulation experiments is consistent with the maintenance of rare cis-amide motifs during conformational interconversion. Taken together, our investigation demonstrates that heterocyclic rearrangement reactions can be used to control macrocyclic backbones and provides fundamental insights that may be applicable to the development of a wide range of other conformational control elements.
- Kobori, Shinya,Huh, Sungjoon,Appavoo, Solomon D.,Yudin, Andrei K.
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supporting information
p. 5166 - 5171
(2021/05/04)
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- Post-synthetic functionalization of tryptophan protected peptide sequences through indole (C-2) photocatalytic alkylation
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We report a selective, mild, and efficient C-H functionalization of tryptophan and tryptophan-containing peptides with activated α-bromo-carbonyl compounds under visible-light irradiation. The protocol efficiency is outlined by the wide substrate scope and excellent tolerance of sensitive functional groups present in the amino acid side chains. The method can be successfully extended to access pharmaco-peptide conjugate scaffolds.
- Ackermann, Lutz,Berlinck, Roberto G. S.,Bernardi, Darlon I.,Delgado, José A. C.,Kaplaneris, Nikolaos,Lima, Rafaely N.,Paix?o, Márcio W.
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supporting information
p. 5758 - 5761
(2021/06/16)
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- Eco-friendly synthesis of peptides using fmoc-amino acid chlorides as coupling agent under biphasic condition
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Background: Agro-waste derived solvent media act as a greener process for the peptide bond formation using Nα-Fmoc-amino acid chloride and amino acid ester salt with in situ neutralization and coupling under biphasic condition. The Fmoc-amino acid chlorides are prepared by the reported procedure of freshly distilled SOCl2 with dry CH2Cl2. The protocol found many added ad-vantages such as neutralization of amino acid ester salt and not required additional base for the neu-tralization, and directly coupling take place with Fmoc-amino acid chloride gave final product dipeptide ester in good to excellent yields. The protocol occurs with complete stereo chemical integrity of the configuration of substrates. Here, we revisited Schotten-Baumann condition, instead of using inorganic base. Objective: To develop green protocol for the synthesis of peptide bond using Fmoc-amino acid chloride with amino acid esters salt. Methods: The final product isolated is analyzed in several spectroscopic and analytical techniques such as FT-IR,1H-,13C-NMR, Mass spectrometry and RP-HPLC to check stereo integrity and puri-ty of the product. Conclusion: The present method developed greener using natural agro-waste (lemon fruit shell ash) derived solvent medium for the reaction and not required chemical entity.
- Kantharaju, Kamanna,Khatavi, Santosh Y.
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p. 699 - 707
(2021/08/23)
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- Synthesis and structure-activity relationship study of pyrrolidine-oxadiazoles as anthelmintics against Haemonchus contortus
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Parasitic roundworms (nematodes) are significant pathogens of humans and animals and cause substantive socioeconomic losses due to the diseases that they cause. The control of nematodes in livestock animals relies heavily on the use of anthelmintic drugs. However, their extensive use has led to a widespread problem of drug resistance in these worms. Thus, the discovery and development of novel chemical entities for the treatment of parasitic worms of humans and animals is needed. Herein, we describe our medicinal chemistry optimization efforts of a phenotypic hit against Haemonchus contortus based on a pyrrolidine-oxadiazole scaffold. This led to the identification of compounds with potent inhibitory activities (IC50 = 0.78–22.4 μM) on the motility and development of parasitic stages of H. contortus, and which were found to be highly selective in a mammalian cell counter-screen. These compounds could be used as suitable chemical tools for drug target identification or as lead compounds for further optimization.
- Ruan, Banfeng,Zhang, Yuezhou,Tadesse, Solomon,Preston, Sarah,Taki, Aya C.,Jabbar, Abdul,Hofmann, Andreas,Jiao, Yaqing,Garcia-Bustos, Jose,Harjani, Jitendra,Le, Thuy Giang,Varghese, Swapna,Teguh, Silvia,Xie, Yiyue,Odiba, Jephthah,Hu, Min,Gasser, Robin B.,Baell, Jonathan
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supporting information
(2020/02/04)
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- Basicities and Nucleophilicities of Pyrrolidines and Imidazolidinones Used as Organocatalysts
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The Br?nsted basicities pKaH (i.e., pKa of the conjugate acids) of 32 pyrrolidines and imidazolidinones, commonly used in organocatalytic reactions, have been determined photometrically in acetonitrile solution using CH acids as indicators. Most investigated pyrrolidines have basicities in the range 16 aH aH aH 12.6) and the 2-imidazoliummethyl-substituted pyrrolidine A21 (pKaH 11.1) are outside the typical range for pyrrolidines with basicities comparable to those of imidazolidinones. Kinetics of the reactions of these 32 organocatalysts with benzhydrylium ions (Ar2CH+) and structurally related quinone methides, common reference electrophiles for quantifying nucleophilic reactivities, have been measured photometrically. Most reactions followed second-order kinetics, first order in amine and first order in electrophile. More complex kinetics were observed for the reactions of imidazolidinones and several pyrrolidines carrying bulky 2-substituents, due to reversibility of the initial attack of the amines at the electrophiles followed by rate-determining deprotonation of the intermediate ammonium ions. In the presence of 2,4,6-collidine or 2,6-di-tert-butyl-4-methyl-pyridine, the deprotonation of the initial adducts became faster, which allowed the rate of the attack of the amines at the electrophiles to be determined. The resulting second-order rate constants k2 followed the correlation log?k2(20 °C) = sN(N + E), where electrophiles are characterized by one parameter (E) and nucleophiles are characterized by the two solvent-dependent parameters N and sN. In this way, the organocatalysts A1-A32 were integrated in our comprehensive nucleophilicity scale, which compares n-, -, and σ-nucleophiles. The nucleophilic reactivities of the title compounds correlate only poorly with their Br?nsted basicities.
- An, Feng,Maji, Biplab,Min, Elizabeth,Ofial, Armin R.,Mayr, Herbert
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supporting information
p. 1526 - 1547
(2020/02/04)
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- Design, synthesis, α-amylase inhibition and in silico docking study of novel quinoline bearing proline derivatives
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α-amylase enzyme hydrolyses carbohydrate into glucose is known to be an important molecular target for type 2 Diabetes mellitus. In the course of developing α-amylase enzyme inhibitors, we designed, synthesized seventeen novel quinoline bearing proline analogs, subsequently physico-chemical properties of designed analogs were also in silico predicted for their drug likeness evaluation. Synthesized compounds were characterized by spectral analysis such as Mass, IR, 1H NMR, 13C NMR and further screened in vitro for α-amylase inhibitory activity using acarbose as standard drug. Seven analogs, 6a, 6b, 6c, 6d, 6g, 10b and 10c showed significant α-amylase inhibitory activity. Eight analogs, 5, 6e, 6f, 6h, 6j, 10a, 10d and 10e showed good to moderate activity while other two analogs, 6i and 9 showed least activity. The molecular docking study of significantly active and weakly active compounds was performed in order to study their putative binding mode of the most and least active compounds (6c and 6i).
- Ganesan, M. S.,Kumar, Banoth Karan,Murugesan, S.,Narasimhan, K.,Raja, K. Kanmani
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- Amino acid conjugates of 2-mercaptobenzimidazole provide better anti-inflammatory pharmacology and improved toxicity profile
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Benzimidazole is an important pharmacophore for clinically active drugs against inflammation and treatment of pain, however, it is associated with gastrointestinal side effects. Here we synthesized benzimidazole based agents with significant analgesic/anti-inflammatory potential but with less gastrointestinal adverse effects. In this study, we synthesized novel, orally bioavailable 2-mercaptobenzimidazole amino acid conjugates (4a–4o) and screened them for analgesic, anti-inflammatory and gastro-protective effects. The synthesized 2-mercaptbenzimidazole derivatives were characterized for their structure using FTIR, 1H NMR and 13C NMR spectroscopic techniques. The 2-mercaptobenzimidazole amino acid conjugates have found to possess potent analgesic, anti-inflammatory and gastroprotective activities, particularly with compound 4j and 4k. Most of the compounds exhibited remarkable anti-ulcer and antisecretory effects. Molecular docking studies were carried out to study the binding affinities and interactions of the synthesized compounds with target proteins COX-2 (PDB ID: 3LN1) and H+/K+-ATPase (PDB ID: 5Y0B). Our results support the clinical promise of these newly synthesized 2-mercaptobezimidazol conjugates as a component of therapeutic strategies for inflammation and analgesia, for which the gastric side effects are always a major limitation.
- Khan, Muhammad T.,Nadeem, Humaira,Khan, Arif-ullah,Abbas, Muzaffar,Arif, Muazzam,Malik, Nadia Shamshad,Malik, Zulkifal,Javed, Ibrahim
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p. 1057 - 1072
(2020/08/13)
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- SPIRO-LACTAM NMDA RECEPTOR MODULATORS AND USES THEREOF
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Disclosed are compounds having potency in the modulation of NMDA receptor activity. Such compounds can be used in the treatment of conditions such as depression and related disorders as well as other disorders.
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Page/Page column 39
(2019/08/26)
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- Highly Diastereoselective Synthesis of Cyclic α-Aminophosphonic and α-Aminophosphinic Acids from Glycyl-l-Proline 2,5-Diketopiperazine
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This paper describes the first diastereoselective synthesis of cyclic α-aminophosphonic and α-amino phosphonic acids from glycyl-l-proline 2,5-diketopiperazine (S)-6 prepared according to the usual peptide coupling procedures. The highlights of this contribution is the chemoselective reduction of the carbamate-imide activated carbonyl group in the N-Boc 2,5-diketopiperazine (S)-11 to generate the unstable hemiaminals (1R,8aS)-12 and (1S,8aS)-13, followed by the highly diastereoselective nucleophilic addition of trimethyl phosphite or dimethyl phenylphosphonite to the chiral carbenium ion (S)-5. Acid hydrolysis of the phosphonate and phosphinate functionalities with simultaneous cleavage of the tert-butyl carbamate protecting group led to the target compounds. The high diastereoselectivity in the nucleophilic addition of trivalent phosphorus to the chiral carbenium ion (S)-5 is in agreement with our precedent reports.
- Ordó?ez, Mario,Torres-Hernández, Fernando,Viveros-Ceballos, José Luis
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p. 7378 - 7383
(2019/11/26)
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- A practical access to new pyrrolizine carboxylates via KHMDS-catalyzed carbocyclizations
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Easy and effective preparation of new 1H-pyrrolizine carboxylates was achieved with high efficiency via KHMDS-induced carbocyclization of N-alkynyl proline carboxylates under substantially mild conditions. Meanwhile, some trans-diiodoallylic N-proline carboxylates were obtained from N-propargyl proline carboxylates using molecular I2 with or without KHMDS. This method is quite feasible in terms of practical and quick access to the pyrrolizines and their derivatives over the formation of carbanions.
- Yildirim, Muhammet,Suleiman, Garba
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supporting information
p. 463 - 481
(2019/01/25)
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- PROCESS AND INTERMEDIATES FOR SYNTHESIS OF PEPTIDE COMPOUNDS
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Disclosed is a new process and intermediates for preparing dipyrrolidine peptide compounds such as, for example, rapastinel. Advantageously, the process may be industrially scalable and cost-effective and use less toxic reagents and/or solvents. Further, the process may be used to prepare peptide compounds having improved purity.
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Paragraph 0161; 0162; 0165
(2019/02/13)
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- Intramolecular [2+2] Photocycloaddition of Cyclic Enones: Selectivity Control by Lewis Acids and Mechanistic Implications
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The intramolecular [2+2] photocycloaddition of 3-alkenyl-2-cycloalkenones was performed in an enantioselective fashion (nine representative examples, 54–86 % yield, 76–96 % ee) upon irradiation at λ=366 nm in the presence of an AlBr3-activated oxazaborolidine as the Lewis acid. An extensive screening of proline-derived oxazaborolidines showed that the enantioface differentiation depends strongly on the nature of the aryl group at the 3-position of the heterocycle. DFT calculations of the Lewis acid–substrate complex indicate that attractive dispersion forces may be responsible for a change of the binding mode. The catalytic [2+2] photocycloaddition was shown to proceed on the triplet hypersurface with a quantum yield of 0.05. The positive effect of Lewis acids on the outcome of a given intramolecular [2+2] photocycloaddition was illustrated by optimizing the key step in a concise total synthesis of the sesquiterpene (±)-italicene.
- Poplata, Saner,Bauer, Andreas,Storch, Golo,Bach, Thorsten
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supporting information
p. 8135 - 8148
(2019/05/29)
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- Polymerizable Compound, Compound, and Method for Producing Boranophosphate Oligomer
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Provided a polymerizable compound represented by the following Formula A-1 or Formula A-2: In Formula A-1 or Formula A-2, R1 represents an electron-donating group; n represents an integer from 1 to 5; R2 represents a hydrogen atom, a halogen atom, or —ORO, wherein RO represents a hydrogen atom, an alkyl group, or a protecting group of a hydroxy group; R3 represents a hydrogen atom or a protecting group of a hydroxy group; and X represents a structure represented by any one of Formula B-1 to Formula B-5.
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Paragraph 0174; 0186
(2019/09/16)
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- Synthesis and evaluation of spumigin analogues library with thrombin inhibitory activity
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Spumigins are marine natural products derived from cyanobacteria Nodularia spumigena, which mimics the structure of the D-Phe-Pro-Arg sequence and is crucial for binding to the active site of serine proteases thrombin and factor Xa. Biological evaluation of spumigins showed that spumigins with a (2S,4S)-4-methylproline central core represent potential lead compounds for the development of a new structural type of direct thrombin inhibitors. Herein, we represent synthesis and thrombin inhibitory activity of a focused library of spumigins analogues with indoline ring or L-proline as a central core. Novel compounds show additional insight into the structure and biological effects of spumigins. The most active analogue was found to be a derivative containing L-proline central core with low micromolar thrombin inhibitory activity.
- ?ula, Ale?,B?dziak, Izabela,Kikelj, Danijel,Ila?, Janez
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- N-methyl-D-aspartate receptor modulators and methods of making and using same
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Disclosed are compounds having enhanced potency in the modulation of NMDA receptor activity. Such compounds are contemplated for use in the treatment of diseases and disorders, such as learning, cognitive activities, and analgesia, particularly in alleviating and/or reducing neuropathic pain. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
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Page/Page column 71; 72; 86; 87
(2018/06/25)
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- Heterocyclic pyrrolizinone and indolizinones derived from natural lactam as potential antifungal agents
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With the aim to develop highly potential active heterocyclic compounds, two series of multi-substituted pyrrolizinone and indolizinones derived from lactam were designed, synthesized and evaluated for their potential antifungal activities against six species of the plant pathogen fungi (Fusarium graminearum, Sclerotinia sclerotiorum, Phomopsis adianticola, Gloeosporium theae-sinensis, Alternaria tenuis Nees, Magnaporthe oryzae). The structure of all the newly molecules were confirmed by analytical spectroscopic data, including 1H NMR, 13C NMR and ESI-MS. According to the preliminary studies on bio-evaluation assay, some of the obtained compounds exhibited moderate and broad-spectrum activities against six fungi compared to the intermediates 6a, 6f and the hymexazol. Particularly, the inhibition rate of compounds 7l, 7m and 7t reached 69.25%, 74.76%, 65.38% against Phomopsis adianticola and Magnaporthe oryzae in vitro activity. Furthermore, compounds 7l and 7t displayed obviously inhibition activities against Phomopsis adianticola compared to the hymexazol. Consequently, compounds 7l and 7t with six-membered alkane ring could be used as new motifs for further investigation.
- Wang, Shuangshuang,Bao, Longzhu,Wang, Wenda,Song, Di,Wang, Jingjing,Cao, Xiufang
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p. 257 - 266
(2018/08/04)
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- COMPOUNDS, COMPOSITIONS AND METHODS FOR SYNTHESIS
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The present disclosure, among other things, provides technologies for synthesis, including reagents and methods for stereoselective synthesis. In some embodiments, the present disclosure provides compounds useful as chiral auxiliaries. In some embodiments, the present disclosure provides reagents and methods for oligonucleotide synthesis. In some embodiments, the present disclosure provides reagents and methods for chirally controlled preparation of oligonucleotides. In some embodiments, technologies of the present disclosure are particularly useful for constructing challenging internucleotidic linkages, providing high yields and stereoselectivity.
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Paragraph 001092; 00193; 001094; 001095
(2019/01/10)
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- Synthesis of diastereomeric pyrrolidine sulfamides via anchimerically assisted nucleophilic substitution reactions
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The Mitsunobu reaction was employed in a key step during the development of a convenient synthetic route for the enantioselective preparation of pyrrolidine-sulfamide ligands from (R)- or (S)- [(S)-1-benzylpyrrolidin-2-yl](phenyl)methanol, and employing tert-butyl pyrrolidin-1-yl-sulfonylcarbamate as a non-conventional nucleophilic source. Although it is well documented that the exposure of this type of diastereomeric amino alcohols to the above-mentioned nucleophile usually leads to the formation of piperidines via ring expansion, either through classical nucleophilic substitution or the Mitsunobu version, only the pyrrolidine derivatives were generated with retention of configuration on the exocyclic stereocenter, owing to the neighboring group participation (internal backside nucleophilic substitution, SNib). Final removal of the N-Boc protecting group from the sulfamide fragment afforded chiral compounds with significant potential as chiral ligands in asymmetric catalysis.
- Vargas-Caporali, Jorge,van der Lee, Arie,Dewynter, Georges,Juaristi, Eusebio
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supporting information
p. 352 - 358
(2018/05/22)
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- SPIRO-LACTAM NMDA RECEPTOR MODULATORS AND USES THEREOF
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Disclosed are compounds having potency in the modulation of NMDA receptor activity. Such compounds can be used in the treatment of conditions such as depression and related disorders. Orally delivered formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
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Page/Page column 41
(2018/03/28)
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- Characterization and cytotoxicity evaluation of biocompatible amino acid esters used to convert salicylic acid into ionic liquids
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The technological utility of active pharmaceutical ingredients (APIs) is greatly enhanced when they are transformed into ionic liquids (ILs). API-ILs have better solubility, thermal stability, and the efficacy in topical delivery than solid or crystalline drugs. However, toxicological issue of API-ILs is the main challenge for their application in drug delivery. To address this issue, 11 amino acid esters (AAEs) were synthesized and investigated as biocompatible counter cations for the poorly water-soluble drug salicylic acid (Sal) to form Sal-ILs. The AAEs were characterized using 1H and 13C NMR, FTIR, elemental, and thermogravimetric analyses. The cytotoxicities of the AAE cations, Sal-ILs, and free Sal were investigated using mammalian cell lines (L929 and HeLa). The toxicities of the AAE cations greatly increased with inclusion of long alkyl chains, sulfur, and aromatic rings in the side groups of the cations. Ethyl esters of alanine, aspartic acid, and proline were selected as a low cytotoxic AAE. The cytotoxicities of the Sal-ILs drastically increased compared with the AAEs on incorporation of Sal into the cations, and were comparable to that of free Sal. Interestingly, the water miscibilities of the Sal-ILs were higher than that of free Sal, and the Sal-ILs were miscible with water at any ratio. A skin permeation study showed that the Sal-ILs penetrated through skin faster than the Sal sodium salt. These results suggest that AAEs could be used in biomedical applications to eliminate the use of traditional toxic solvents for transdermal delivery of poorly water-soluble drugs.
- Moshikur, Rahman Md.,Chowdhury, Md. Raihan,Wakabayashi, Rie,Tahara, Yoshiro,Moniruzzaman, Muhammad,Goto, Masahiro
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- Design and synthesis of galactose-conjugated fluorinated and non-fluorinated proline oligomers: Towards antifreeze molecules
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Galactose-conjugated fluorinated and non-fluorinated proline oligomers that exhibit an α-helical structure with hydrophilic and lipophilic parts were designed as potential antifreeze molecules. These galactose-proline oligomers were synthesized and their physical properties were evaluated. Interestingly, the non-fluorinated galactose-proline oligomers showed in contrast to the fluorinated analogues weak antifreeze activity. The difference in antifreeze activity should be attributed to the fluorine gauche effect, which should induce a conformation in fluorinated prolines that is different from that of natural proline. The results obtained in this study thus suggest that the 3D conformation of the galactose-conjugated fluorinated and non-fluorinated proline oligomers is very important for their anti-freezing properties.
- Sumii, Yuji,Hibino, Hayata,Saidalimu, Ibrayim,Kawahara, Hidehisa,Shibata, Norio
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supporting information
p. 9749 - 9752
(2018/09/10)
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- Synthesis and evaluation of camphor and cytisine-based cyanopyrrolidines as DPP-IV inhibitors for the treatment of type 2 diabetes mellitus
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In this study, bornyl- and cytisine-based cyanopyrrolidines as potent dipeptidyl peptidase-IV (DPP-IV) inhibitors were synthesised. The in vitro inhibiting activities of bornyl- and cytisine derivatives towards DPP-IV were evaluated. Bornyl-based cyanopyrrolidines were shown to have moderate inhibitory activity with regard to DPP-IV (1.27–15.78 μM). A docking study was performed to elucidate the structure-activity relationship of the obtained compounds. The in vivo hypoglycemic activities of the same compounds were evaluated with the oral glucose tolerance test (OGTT) in mice. Bornyl-based cyanopyrrolidines were shown to have good hypoglycemic activity.
- Kuranov,Tsypysheva,Khvostov,Zainullina, Liana F.,Borisevich,Vakhitova, Yu.V.,Luzina,Salakhutdinov
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p. 4402 - 4409
(2018/07/30)
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- Synthesis method of L-prolinamide
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The invention relates to the technical field of medicines, in particular to a synthesis method of L-prolinamide. The synthesis method comprises the steps of (1) dissolving the L-prolinamide into an alcoholic solution, adding an esterification reagent for reacting, and obtaining an intermediate product II; (2) adding the product II of the step (1) into an alcoholic solution of ammonia, transferringto a high pressure reactor, and carrying out ammonia-feeding reaction; (3) decompressing and concentrating a reaction liquid in the step (2), and filtering to obtain a primary filter liquor; (4) desalinizing the primary filter liquor in the step (3), and filtering to obtain a secondary filter liquor; (5) decompressing and concentrating the secondary filter liquor of the step (4), adding a solventfor dissolving and crystalizing, cooling for suction filtration, and obtaining a product I. The synthesis method provided by the invention is simple to operate, less in waste water and waste gas, clean and environmentally-friendly. The total yield of the L-prolinamide is 78 percent, the product HPLC (High Performance Liquid Chromatography) purity is 99.6 percent, the maximum individual impurity is less than or equal to 0.3 percent, and a D type isomer is less than or equal to 0.3 percent.
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-
Paragraph 0024; 0025
(2018/03/26)
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- Preparation method of R-diphenyl prolinol
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The invention discloses a preparation method of R-diphenyl prolinol and relates to the technical field of organic synthesis. The method comprises the steps: by adopting D-prolineas a raw material, firstly preparing D-proline methyl ester hydrochloride through esterification reaction and salt-forming reaction with methanol and thionyl chloride and then preparing R-diphenyl prolinol through Grignard reaction with a Grignard reagent of bromobenzene, wherein the methanol is taken as a reaction reagent and a reaction solvent at the same time, unreacted methanol and solvent tetrahydrofuran can be recovered and reused, so that the production cost is reduced; and the mean purity of the product R-diphenyl prolinol reaches 99.2%, the mean total yield reaches 70% and the R-diphenyl prolinol is suitable for the industrial production.
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Paragraph 0017
(2017/08/29)
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- Ferrocene-modified amino acids: synthesis and in vivo bioeffects on hippocampus
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A method for the ferrocene modification of amino acids of natural and synthetic origin has been developed. In the in vivo studies, the hippocampal electrical activity under the action of ferrocenyl(phenylpyrazolyl)glycine (1) was assessed. A meaningful rise (up to 25% compared to the control) in the response amplitudes of the focal potentials of the hippocampal region СА1 after intraperitoneal administration of compound 1 at the dose of 2.0 mg kg–1 was established.
- Rodionov,Snegur,Simenel,Dobryakova, Yu. V.,Markevich
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p. 136 - 142
(2017/07/05)
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- Poly(ethylene glycol) modified Mn2+ complexes as contrast agents with a prolonged observation window in rat MRA
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A novel rigid Mn2+ complex (MnL) with pyridine and pyrrolidine rings was designed and synthesized. The complex was further modified with alkyne, and conjugated to azide-terminated PEG by click chemistry. PEGylated MnL shows considerably higher relaxivity (MnL-PEG2k-MnL: r1 = 6.38 mmol-1 s-1; MnL-PEG4.6k-MnL: r1 = 5.63 mmol-1 s-1) and much longer blood circulation time than free Mn2+ complexes (MnL: r1 = 3.73 mmol-1 s-1), providing a prolonged time window to acquire longitudinal images for rat contrast enhanced magnetic resonance angiography.
- Wu, Changqiang,Yang, Li,Chen, Zhuzhong,Zhang, Houbing,Li, Danyang,Lin, Bingbing,Zhu, Jiang,Ai, Hua,Zhang, Xiaoming
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p. 54603 - 54609
(2017/12/12)
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- The reactions of α-amino acids and α-amino acid esters with high valent transition metal halides: synthesis of coordination complexes, activation processes and stabilization of α-ammonium acylchloride cations
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Titanium tetrachloride smoothly reacted with a selection of α-amino acids (aaH) in CH2Cl2 affording yellow to orange solid coordination compounds, 1a-d, in 70-78% yields. The salts [NHEt3][TiCl4(aa)], 2a-b, were obtained from TiCl4/aaH/NEt3 (aa = l-phenylalanine, N,N-dimethylphenylalanine), in 60-65% yields. The complex , 3, was isolated from the reaction of l-proline with NbCl5/NHiPr2, performed in CH2Cl2 at room temperature. The X-ray structure of 3 features a bridging (E)-1,2-bis(3,4-dihydro-2H-pyrrol-5-yl)ethene-1,2-diolate ligand, resulting from the unprecedented C-C coupling between two proline units. Unusually stable α-ammonium acyl chlorides were prepared by the reactions of PCl5/MCln (MCln = NbCl5, WCl6) with l-proline, N,N-dimethylphenylalanine, sarcosine and l-methionine. MX5 (M = Nb, Ta; X = F, Cl) reacted with l-leucine methylester and l-proline ethylester to give ionic coordination compounds, [MX4L2][MX6] (M = Nb, L = Me2CHCH2CH(NH2)CO2Me, X = F, 9; Cl, 11a; M = Nb, X = Cl, , 11c; Ta, 11d), in moderate to good yields. [NbCl5(Me2CHCH2CHNH3CO2Me)][NbCl6], 12, was isolated as a co-product of the reaction of NbCl5 with l-leucine isopropylester, and crystallographically characterized. The reaction of NbCl5 with l-serine isopropylester afforded NbCl3(OCH2CHNHCO2iPr), 13, in 66% yield. The activation of the ester O-R bond was observed in the reactions of l-leucine methyl ester with NbF5 and l-proline ethyl ester with MBr5 (M = Nb, Ta), these reactions proceeding with the release of EtF and EtBr, respectively. All the metal products were characterized by analytical and spectroscopic methods, while DFT calculations were carried out in order to provide insight into the structural and mechanistic aspects.
- Biancalana, Lorenzo,Bortoluzzi, Marco,Ferretti, Eleonora,Hayatifar, Mohammad,Marchetti, Fabio,Pampaloni, Guido,Zacchini, Stefano
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p. 10158 - 10174
(2017/02/15)
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- Enantiomerically pure piperazines via NaBH4/I2reduction of cyclic amides
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Enantiomerically pure (3S,7R,8aS)-3-phenyloctahydropyrrolo[1,2-a]pyrazine-7-ol, (3S,7R,8aS)-3-methyl octahydropyrrolo[1,2-a]pyrazine-7-ol, (3S,7R,8aS)-3-isopropyloctahydropyrrolo[1,2-a]pyrazine-7-ol and (3S,7R,8aS)-3-isobutyloctahydropyrrolo[1,2-a]pyrazine-7-ol 16d were synthesized via preparation of the corresponding cyclic amides from enantiomerically pure L-proline and hydroxyproline derivatives followed by reduction using sodium borohydride-iodine.
- Harish, Vagala,Periasamy, Mariappan
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p. 175 - 180
(2017/01/11)
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- Carbostyril carboxylic compounds and intermediates, preparation method and application thereof
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The invention discloses carbostyril carboxylic compounds and hydrochlorides thereof and also discloses a preparation method of the compounds and the hydrochlorides thereof as well as an application of the compounds and the hydrochlorides thereof in preparing gram-positive bacterium-preventing or gram-negative bacterium-preventing drugs. Moreover, the invention discloses intermediates for preparing the compounds and a preparation method of the intermediates.
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Paragraph 0185-0186
(2017/07/12)
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- A cyclic dipeptide production method
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The invention relates to a production method for cyclic dipeptide, and belongs to a natural compound synthesis technology. Cyclic (histidine-proline) dipeptide is prepared by a cooling varying-temperature synthesis and high-pressure high-temperature water phase cyclizing technology. The production method comprises the following steps: taking hydrochloride of histidine proline dipeptide methyl ester as a raw material, and synthesizing high-quality and high-purity cyclic histidine-proline dipeptide by a high-pressure high-temperature assisted method in water containing strong basic and weak acidic salt. Compared with a conventional methanol reflux method, the production method is time-saving, efficient, high in product yield and free of racemization phenomenon.
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Paragraph 0027; 0030; 0031; 0042; 0053
(2017/08/25)
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- Quantitative Modeling of Bis(pyridine)silver(I) Permanganate Oxidation of Hydantoin Derivatives: Guidelines for Predicting the Site of Oxidation in Complex Substrates
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The bis(pyridine)silver(I) permanganate promoted hydroxylation of diketopiperazines has served as a pivotal transformation in the synthesis of complex epipolythiodiketopiperazine alkaloids. This late-stage C-H oxidation chemistry is strategically critical to access N-acyl iminium ion intermediates necessary for nucleophilic thiolation of advanced diketopiperazines en route to potent epipolythiodiketopiperazine anticancer compounds. In this study, we develop an informative mathematical model using hydantoin derivatives as a training set of substrates by relating the relative rates of oxidation to various calculated molecular descriptors. The model prioritizes Hammett values and percent buried volume as key contributing factors in the hydantoin series while correctly predicting the experimentally observed oxidation sites in various complex diketopiperazine case studies. Thus, a method is presented by which to use simplified training molecules and resulting correlations to explain and predict reaction behavior for more complex substrates.
- Bischoff, Amanda J.,Nelson, Brandon M.,Niemeyer, Zachary L.,Sigman, Matthew S.,Movassaghi, Mohammad
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supporting information
p. 15539 - 15547
(2017/11/06)
-
- PROCESSES FOR SYNTHESIS OF DIPYRROLIDINE PEPTIDE COMPOUNDS
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Disclosed is a new process for preparing dipyrrolidine peptide compounds such as, for example, GLYX-13. Advantageously, the process may be industrially scalable and cost-effective and use less toxic reagents and/or solvents. Further, the process may be used to prepare peptide compounds having improved purity.
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Paragraph 0087-0090
(2017/12/27)
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- Highly stereoselective syntheses of proline-derived vicinal amino alcohols through grignard addition onto N-tosylprolinal
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A highly diastereoselective Grignard addition to N-tosyl-l-prolinal has been developed to deliver a variety of proline-derived vicinal amino alcohols in good to excellent yields with high diastereoselectivities. A similar selectivity was also obtained by using N-tosyl-d-prolinal. The methodology has been applied to the synthesis of medicinally important 3-hydroxy-2-phenylpiperidines.
- Chaudhuri, Saikat,Parida, Amarchand,Ghosh, Santanu,Bisai, Alakesh
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supporting information
p. 215 - 220
(2016/01/20)
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- Energetic contribution to both acidity and conformational stability in peptide models
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The acidity of N-acyl amino acids is dependent upon the rotameric state of the amide bond. In this work we systematically investigated the acidity difference of the rotamers (ΔpKa) in the frames of various acetylated amino acids. Our results indicated a mutual interaction of two carbonyl groups of an attractive type. We observed conservative ΔpKas for acyclic amino acids (2.2-3.0 kJ mol-1), whereas in the case of alicyclic amino acids, the experimental values revealed a strong dependency on the structural context (1.5-4.4 kJ mol-1). In homologous amino acids (α-, β-, γ-, etc.), the strength of the attraction decays in an exponential fashion. Furthermore, the interaction can accumulate through a chain of amide bonds in a cascade fashion, as demonstrated by an Ac-Pro-Pro dipeptide. As a result, we demonstrate that ΔpKa is an experimental parameter to estimate increments in the carbonyl-carbonyl alignment, as determined by the amino acid or peptidyl context. This parameter is also important in understanding the roles of amino acids in both protein folding and translation in biological systems as well as their evolutionary appearance in the genetic code.
- Kubyshkin, Vladimir,Durkin, Patrick,Budisa, Nediljko
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supporting information
p. 5209 - 5220
(2016/07/06)
-
- Proline ester hydrochloride preparation method (by machine translation)
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The invention discloses a proline ester hydrochloride of the preparation method, comprising the following steps: 1), the initial reaction, sequentially carrying out the following steps: (1), the proline, solvent, pyridines in catalyst are put into a container, then hydrogen chloride gas, reacting at room temperature production proline hydrochloride; (2), which comprises the steps are put into a container in the after, continue to hydrogen chloride gas, the reaction is carried out at the reflux temperature, steaming and reaction solution, recrystallization cooling to separate out the solid, the solvent for washing, filtering, drying filter cake, shall be proline ester hydrochloride; filtrate and steaming and, as a next cycle of the mother liquor; 2), recycled: step (1) is changed to account for the solvent in the step (1) 0.5 - 0.7 times of the volume of the solvent, in order to step 1) the resulting mother liquor in step (1) substituted pyridines catalyst, the remaining the same steps 1), to proline ester hydrochloric acid salt, thereby realizing the recycled. (by machine translation)
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Paragraph 0031; 0032; 0033; 0034; 0035; 0036-0055; 0062
(2017/05/16)
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- Iminium Catalysis inside a Self-Assembled Supramolecular Capsule: Modulation of Enantiomeric Excess
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The noncovalent combination of a supramolecular host with iminium organocatalysis is described. Due to cation–π interactions the reactive iminium species is held inside the host and reacts in this confined environment. The products formed differ up to 92 % ee from the control experiments without added host. A model rationalizing the observed difference is presented.
- Br?uer, Thomas M.,Zhang, Qi,Tiefenbacher, Konrad
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supporting information
p. 7698 - 7701
(2016/07/07)
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- Halofluorination of N-protected α,β-dehydro-α-amino acid esters—A convenient synthesis of α-fluoro-α-amino acid derivatives
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N-protected dehydroamino acid methyl esters have been converted to α-fluoro-β-halo amino acid derivatives under halofluorination reaction conditions. The influences of the nitrogen protecting group of the substrates and of the halonium electrophile on the reaction outcome and the stability of the obtained products have been studied. Furthermore, reduction of the halogen substituent (Cl or Br) under radical conditions provided a possibility for follow-up reactions. Nucleophilic substitution reactions, however, failed.
- Ulbrich, Dirk,Daniliuc, Constantin G.,Haufe, Günter
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- A method for synthesizing allah Geleg sandbank (by machine translation)
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The invention relates to a method for preparing anti-II type diabetes drug allah Geleg sandbank method for the synthesis of bulk drug (Anagliptin). The lack of commercial synthetic allah Geleg sandbank solve the technical problems of the method. Synthetic method comprises the following steps : (1) with vinyl ether and trichloro acetyl chloride as the raw material, passes through the three-step reaction to obtain the aldehyde protected intermediates 4 ; The 3-amino-5-methyl pyrazole condensation for dehydrating and gets pyrazolo pyrimidine mother nucleus; Carboxy b ester hydrolysis to obtain 2-methyl-pyrazolo [1,5-a] pyrimidin 6-carboxylic acid 6 ; (2) to L-proline as a raw material, passes through the methyl esterification, ammoniation, acetylation, Carbonitride reaction to obtain the chiral cyano pyrrolizinone intermediate 11 ; Chiral cyano pyrrolizinone intermediate 11 And diamine fragment 12 In alkaline conditions to obtain intermediate affinity substituted 13 ; Finally, intermediate 13 Under the conditions of the hydrochloric acid removal protection Boc base namely obtain cyanopentanoyl Azolylamine intermediate 14 ; (3) 2-methyl-pyrazolo [1,5-a] pyrimidine-6-carboxylic acid 6 The cyano Azolylamine intermediate 14 The condensation conditions to obtain the bulk drug allah Geleg sandbank coupled. (by machine translation)
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Paragraph 0015
(2016/10/10)
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- Transition Metal-Free Selective Double sp3 C-H Oxidation of Cyclic Amines to 3-Alkoxyamine Lactams
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The first chemical method for selective dual sp3 C-H functionalization at the alpha-and beta positions of cyclic amines to their corresponding 3-alkoxyamine lactams is reported. Unlike traditional Cα-H oxidation of amines to amides mediated by transition metals, the present protocol, which involves the use of NaClO2/TEMPO/NaClO in either aqueous or organic solvent, not only allows the Cα-H oxidation but also the subsequent functionalization of the unreactive β-methylene group in an unprecedented tandem fashion and using environmentally friendly reactants.
- Osorio-Nieto, Urbano,Chamorro-Arenas, Delfino,Quintero, Leticia,H?pfl, Herbert,Sartillo-Piscil, Fernando
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p. 8625 - 8632
(2016/09/28)
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