cas 7146-15-8, Methyl D-valinate hydrochloride

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Convenient method for the synthesis of some novel chiral methyl 2-(2-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)propanoate derivatives and biological evaluation of their antioxidant, cytotoxic, and molecular docking properties
Ten chiral methyl 2-(2-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)propanoate derivatives 6a-6j have been synthesized from optically pure amino methyl phenol 5 and 4-nitrophenyl chloroformate. These derivatives 6a-6j are characterized by 1H NMR, 13C NMR, FT-IR, and HRMS spectral techniques. Optical purity of these derivatives was confirmed by chiral HPLC method. Ten synthesized ester derivatives 6a-6j were screened for their in vitro antioxidant activity. Among the compounds 6b-d and 6h-j have exhibited comparable antioxidant activity with ascorbic acid as a standard. Compounds 6a and 6e-g have shown moderate antioxidant activity. Further, the in vitro cytotoxicity of these compounds were studied through MTT cell proliferation assay in addition the effect on LDH leakage and NO release. Among the derivatives, 6j showed extremely best activity and the IC50 value (12.54 ± 0.71 μM) is very close to doxorubicin (7.2 ± 0.58 μM) as a standard. Compounds 6b, 6h, and 6i showed better inhibition next to compound 6j on the viability of HepG2 cells with an IC50 value (μM) of 56.02 ± 1.4, 41.76 ± 0.58, and 38.17 ± 0.34, respectively. Also, molecular docking studies have been carried out with STAT-3 (PDB ID: 1BG1) and BCL-2 (PDB ID: 4AQ3) proteins against the four active compounds 6b, 6h, 6i, and 6j. The binding energies of the tested compounds were in the range of ?7.76 to ?8.41 kcal/mol, which is very close to doxorubicin (?8.53 kcal/mol) as a standard. These molecular docking results are in good agreement with the in vitro studies.
Matam, Sivakumar,Kaliyan, Prabakaran,Selvaraj, Loganathan,Muthu, Seenivasa Perumal,Lohanathan, Bharathi Priya,Viswanadhan, Vijaya Padma,Makala, Himesh,Venkatasubramanian, Ulaganathan
supporting information
p. 569 - 579
(2020/12/11)

A Novel N-Substituted Valine Derivative with Unique Peroxisome Proliferator-Activated Receptor γbinding Properties and Biological Activities
A proprietary library of novel N-Aryl-substituted amino acid derivatives bearing a hydroxamate head group allowed the identification of compound 3a that possesses weak proadipogenic and peroxisome proliferator-Activated receptor γ(PPARI) activating properties. The systematic optimization of 3a, in order to improve its PPARγagonist activity, led to the synthesis of compound 7j (N-Aryl-substituted valine derivative) that possesses dual PPARI/PPARα agonistic activity. Structural and kinetic analyses reveal that 7j occupies the typical ligand binding domain of the PPARγagonists with, however, a unique high-Affinity binding mode. Furthermore, 7j is highly effective in preventing cyclin-dependent kinase 5-mediated phosphorylation of PPARγserine 273. Although less proadipogenic than rosiglitazone, 7j significantly increases adipocyte insulin-stimulated glucose uptake and efficiently promotes white-To-brown adipocyte conversion. In addition, 7j prevents oleic acid-induced lipid accumulation in hepatoma cells. The unique biochemical properties and biological activities of compound 7j suggest that it would be a promising candidate for the development of compounds to reduce insulin resistance, obesity, and nonalcoholic fatty liver disease.
Peiretti, Franck,Montanari, Roberta,Capelli, Davide,Bonardo, Bernadette,Colson, Cécilia,Amri, Ez-Zoubir,Grimaldi, Marina,Balaguer, Patrick,Ito, Keiichi,Roeder, Robert G.,Pochetti, Giorgio,Brunel, Jean Michel
p. 13124 - 13139
(2020/12/02)

Preparation method of valsartan intermediate
The invention belongs to the technical field of preparation of medical intermediates, and particularly relates to a preparation method of a valsartan intermediate. The method comprises the following steps: using L-valine and thionyl chloride as raw materials, in the presence of an organic solvent, carrying out esterification reaction to obtain L-valine methyl ester hydrochloride, then reacting theL-valine methyl ester hydrochloride, with 4-Bromomethyl-2-cyanobiphenyl under an alkaline condition, carrying out organic solvent extracting, crystallization, centrifugation and drying to obtain a crude product of N-[(2 '-cyano-1, 1'-biphenyl-4-yl) methyl]-L-valine methyl ester hydrochloride, and refining to obtain the product with main content of 99.5% or above and individual impurity content of0.1% or below. The method is mild in reaction condition, short in reaction time, simple and convenient to operate, simple in aftertreatment, high in yield, few in obtained product impurity, small inenvironmental pollution, low in cost and easy for industrial production.
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(2020/07/21)

Cocrystallization of Chiral N7,N16-bis (S-1-Phenylethyl)-1,4,10,13-Tetraoxo-7,16-Diazacyclooctadecane-7,16-Dicarboxamide with Hydrochlorides of Methyl Ethers of Leucine and Valine Enantiomers
An attempt to co-crystallize N7,N16-bis(S-1-phenylethyl)-1,4,10,13-tetraoxo-7,16-diazacyclooctadecane-7,16-dicarboxamide (1) with hydrochlorides of methyl ethers (HCMEs) of L- and D-valine and also L- and D-leucine results in separate crystallization of diazacrown-ether 1 (or its monohydrate 1·H2O) and HCMEs of respective α-amino acids. Crystal structures of D-leucine 1·H2O (1) and HCME (2) compounds, which were not described previously, are solved by single crystal X-ray diffraction.
Fonari,Pluzhnik-Gladyr,Kamalov,Kravtsov, V. Kh.
p. 143 - 150
(2019/04/30)

Rhodium-Catalyzed Enantioselective Synthesis of Oxazinones via an Asymmetric Ring Opening-Lactonization Cascade of Oxabicyclic Alkenes
The rhodium-catalyzed asymmetric ring opening reaction of oxabicyclic alkenes is shown to be an efficient method for synthesizing chiral heterocycles. We demonstrate that the pairwise combination of chiral catalyst with chiral amino-acid-derived pronucleophiles results in a stereodivergent synthesis of diastereomeric hydroxyesters. A favorable conformational preference induces the subsequent lactonization of one diastereomer leading to the highly enantioselective synthesis of oxazinones.
Yen, Andy,Pham, Anh Hoang,Larin, Egor M.,Lautens, Mark
supporting information
p. 7549 - 7553
(2019/10/02)

Synthesis and antiviral activity of novel glycyrrhizic acid conjugates with D-amino acid esters
Glycyrrhizic acid (GA) conjugates with methyl and ethyl esters of D-amino acids (D-Trp, D-Phe, D-Tyr, D-Val, D-Leu) have been synthesized by the activated esters method using mixtures of N-hydroxybenzotriazole or N-hydroxysuccinimide with N,N′-dicyclohexylcarbodiimide. GA conjugate with D-Trp ethyl ester exhibited antiviral activity against influenza viruses A/H3N2, A/H1N1/pdm09, A/H5N1, B (SI > 10–29), and HRSV (SI > 25). GA conjugate with D-Trp methyl ester inhibited influenza virus A/H1N1/pdm09 (SI > 30).
Fayrushina,Baltina,Baltina,Konovalova,Petrova,Eropkin, M. Yu.
p. 456 - 462
(2017/08/08)

Chemical differentiation of three DMSP lyases from the marine: Roseobacter group
Dimethylsulfoniopropionate (DMSP) catabolism of marine bacteria plays an important role in marine and global ecology. The genome of Ruegeria pomeroyi DSS-3, a model organism from the Roseobacter group, harbours no less than three genes for different DMSP lyases (DddW, DddP and DddQ) that catalyse the degradation of DMSP to dimethyl sulfide (DMS) and acrylate. Despite their apparent similar function these enzymes show no significant overall sequence identity. In this work DddQ and DddW from R. pomeroyi and the DddP homolog from Phaeobacter inhibens DSM 17395 were functionally characterised and their substrate scope was tested using several synthetic DMSP analogues. Comparative kinetic assays revealed differences in the conversion of DMSP and its analogues in terms of selectivity and overall velocity, giving additional insights into the molecular mechanisms of DMSP lyases and into their putatively different biological functions.
Burkhardt, Immo,Lauterbach, Lukas,Brock, Nelson L.,Dickschat, Jeroen S.
supporting information
p. 4432 - 4439
(2017/07/10)

Synthesis, in vitro antimicrobial, antioxidant, and antidiabetic activities of thiazolidine–quinoxaline derivatives with amino acid side chains
Abstract: A novel protocol for the rapid assembly of a hybrid framework based on amino acid, thiazolidine and quinoxaline scaffolds has been demonstrated by microwave irradiation. The quinoxalines with amino acid side chains 5a–5c were prepared in three steps from 2,4-dinitrofluorobenzene and the amino acids, valine, methionine, and tyrosine and subsequently reacted with four different aldehydes and thioglycolic acid to produce thiazolidine–quinoxaline hybrids with amino acid side chains 6a–6l. All synthesized compounds were evaluated for their in vitro antimicrobial, antioxidant, and antidiabetic activities. Compounds 6f, 6j, and 6k showed broad spectrum antimicrobial activity against Gram +ve and Gram –ve bacteria, whilst 6h, 6k, and 6l showed the best antioxidant activity in the same order of magnitude to that of ascorbic acid. Four of the compounds, 5c, 6d, 6g, and 6k showed activity against α-glucosidase and α-amylase similar to acarbose. Those compounds showing antibacterial activity possessed 4-fluorophenyl and 4-methoxyphenyl groups along with methionine and tyrosine side chains while the compounds showing antioxidant, α-glucosidase, and α-amylase activity contained 4-nitrophenyl and 4-methoxyphenyl groups on the thiazolidine moiety with mainly methionine and tyrosine side chains. The α-glucosidase and α-amylase inhibitory compound 5c did not have a thiazolidine moiety and 6d was the only active compound with a valine amino acid side chain. Compound 6k with a tyrosine side chain and a 4-methoxyphenylthiazolidine moiety on the quinoxaline scaffold showed good bioactivity in all three assays.
Shintre, Suhas A.,Ramjugernath, Deresh,Islam, Md Shahidul,Mopuri, Ramgopal,Mocktar, Chunderika,Koorbanally, Neil A.
p. 2141 - 2151
(2017/08/03)

Ferrocene-modified amino acids: synthesis and in vivo bioeffects on hippocampus
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
p. 136 - 142
(2017/07/05)

Mechanochemical Encapsulation of Fullerenes in Peptidic Containers Prepared by Dynamic Chiral Self-Sorting and Self-Assembly
Molecular capsules composed of amino acid or peptide derivatives connected to resorcin[4]arene scaffolds through acylhydrazone linkers have been synthesized using dynamic covalent chemistry (DCC) and hydrogen-bond-based self-assembly. The dynamic character of the linkers and the preference of the peptides towards self-assembly into β-barrel-type motifs lead to the spontaneous amplification of formation of homochiral capsules from mixtures of different substrates. The capsules have cavities of around 800 ?3 and exhibit good kinetic stability. Although they retain their dynamic character, which allows processes such as chiral self-sorting and chiral self-assembly to operate with high fidelity, guest complexation is hindered in solution. However, the quantitative complexation of even very large guests, such as fullerene C60 or C70, is possible through the utilization of reversible covalent bonds or the application of mechanochemical methods. The NMR spectra show the influence of the chiral environment on the symmetry of the fullerene molecules, which results in the differentiation of diastereotopic carbon atoms for C70, and the X-ray structures provide unique information on the modes of peptide-fullerene interactions.
Szymański, Marek,Wierzbicki, Micha?,Gilski, Miros?aw,J?drzejewska, Hanna,Sztylko, Marcin,Cmoch, Piotr,Shkurenko, Aleksander,Jaskólski, Mariusz,Szumna, Agnieszka
supporting information
p. 3148 - 3155
(2016/03/23)

Catalysts and temperature driven melt polycondensation reaction for helical poly(ester-urethane)s based on natural L-amino acids
Catalyst and temperature driven melt polycondensation reaction was developed for natural L-amino acid monomers to produce new classes of poly(ester-urethane)s. Wide ranges of catalysts from alkali, alkali earth metal, transition metal and lanthanides were developed for the condensation of amino acid monomers with diols to yield poly(ester-urethane)s. A-B Diblock and A-B-A triblock species were obtained by carefully choosing mono- or diols in model reactions. More than two dozens of transition metal and lanthanide catalysts were identified for the polycondensation to yield high molecular weight poly(ester-urethane)s. Theoretical studies revealed that the carbonyl carbon in ester possessed low electron density compared to the carbonyl carbon in urethane which driven the thermo-selective polymerization process. Optical purity of the L-amino acid residues in the melt polycondensation process was investigated using D- and L-isomers and the resultant products were analyzed by chiral-HPLC and CD spectroscopy. CD analysis revealed that the amino acid based polymers were self-assembled as β-sheet and polyproline type II secondary structures. Electron and atomic force microscopic analysis confirmed the formation of helical nano-fibrous morphology in poly(ester-urethane)s. The newly developed melt polycondensation process is very efficient and optimized for wide range of catalysts to produce diverse polymer structures from natural L-amino acids.
Anantharaj, Santhanaraj,Jayakannan, Manickam
p. 1065 - 1077
(2016/03/12)

Regiodivergent Enantioselective γ-Additions of Oxazolones to 2,3-Butadienoates Catalyzed by Phosphines: Synthesis of α,α-Disubstituted α-Amino Acids and N,O-Acetal Derivatives
Phosphine-catalyzed regiodivergent enantioselective C-2- and C-4-selective γ-additions of oxazolones to 2,3-butadienoates have been developed. The C-4-selective γ-addition of oxazolones occurred in a highly enantioselective manner when 2-aryl-4-alkyloxazol-5-(4H)-ones were employed as pronucleophiles. With the employment of 2-alkyl-4-aryloxazol-5-(4H)-ones as the donor, C-2-selective γ-addition of oxazolones took place in a highly enantioselective manner. The C-4-selective adducts provided rapid access to optically enriched α,α-disubstituted α-amino acid derivatives, and the C-2-selective products led to facile synthesis of chiral N,O-acetals and γ-lactols. Theoretical studies via DFT calculations suggested that the origin of the observed regioselectivity was due to the distortion energy that resulted from the interaction between the nucleophilic oxazolide and the electrophilic phosphonium intermediate.
Wang, Tianli,Yu, Zhaoyuan,Hoon, Ding Long,Phee, Claire Yan,Lan, Yu,Lu, Yixin
supporting information
p. 265 - 271
(2016/01/25)

Selective oxidation of amines to aldehydes or imines using laccase-mediated bio-oxidation
An efficient and practical chemo-enzymatic aerobic oxidation in water of benzylamines to obtain aldehydes or imines is described. Laccase from Trametes versicolor was chosen as biocatalyst, and TEMPO (radical 2,2,6,6-tetramethylpiperidine 1-oxyl) as mediator. A study on the pH dependence of the aqueous medium allowed us to realise a fine tuning on product selectivity. Under our optimized reaction conditions, the bio-oxidation of a series of primary, secondary and cyclic amines has been achieved.
Galletti, Paola,Funiciello, Federica,Soldati, Roberto,Giacomini, Daria
p. 1840 - 1848
(2015/06/02)

Highly enantioselective zirconium-catalyzed cyclization of aminoalkenes
Aminoalkenes are catalytically cyclized in the presence of cyclopentadienylbis(oxazolinyl)borato group 4 complexes {PhB(C5H 4)(OxR)2}M(NMe2)2 (M = Ti, Zr, Hf; OxR = 4,4-dimethyl-2-oxazoline, 4S-isopropyl-5,5- dimethyl-2-oxazoline, 4S-tert-butyl-2-oxazoline) at room temperature and below, affording five-, six-, and seven-membered N-heterocyclic amines with enantiomeric excesses of >90% in many cases and up to 99%. Mechanistic investigations of this highly selective system employed synthetic tests, kinetics, and stereochemistry. Secondary aminopentene cyclizations require a primary amine (1-2 equiv vs catalyst). Aminoalkenes are unchanged in the presence of a zirconium monoamido complex {PhB(C5H 4)(Ox4S-iPr,Me2)2}Zr(NMe2)Cl or a cyclopentadienylmono(oxazolinyl)borato zirconium diamide {Ph2B(C 5H4)(Ox4S-iPr,Me2)}Zr(NMe2) 2. Plots of initial rate versus [substrate] show a rate dependence that evolves from first-order at low concentration to zero-order at high concentration, and this is consistent with a reversible substrate-catalyst interaction preceding an irreversible step. Primary kinetic isotope effects from substrate conversion measurements (k′obs(H)/ k′obs(D) = 3.3 ± 0.3) and from initial rate analysis (k2(H)/k2(D) = 2.3 ± 0.4) indicate that a N-H bond is broken in the turnover-limiting and irreversible step of the catalytic cycle. Asymmetric hydroamination/cyclization of N-deutero-aminoalkenes provides products with higher optical purities than obtained with N-proteo-aminoalkenes. Transition state theory, applied to the rate constant k2 that characterizes the irreversible step, provides activation parameters consistent with a highly organized transition state (ΔS? = -43(7) cal·mol-1 K -1) and a remarkably low enthalpic barrier (ΔH ? = 6.7(2) kcal·mol-1). A six-centered, concerted transition state for C-N and C-H bond formation and N-H bond cleavage involving two amidoalkene ligands is proposed as most consistent with the current data.
Manna, Kuntal,Everett, William C.,Schoendorff, George,Ellern, Arkady,Windus, Theresa L.,Sadow, Aaron D.
supporting information
p. 7235 - 7250
(2013/06/27)

Cycloforskamide, a cytotoxic macrocyclic peptide from the sea slug Pleurobranchus forskalii
A macrocylic dodecapeptide, cycloforskamide, was isolated from the sea slug Pleurobranchus forskalii, collected off Ishigaki Island, Japan. Its planar structure was deduced by extensive NMR analyses and was further confirmed by MS/MS fragmentation analyses. Finally, the absolute configuration was determined by total hydrolysis and chiral-phase gas chromatographic analysis. This novel dodecapeptide contains three d-amino acids and three thiazoline heterocycles and exhibits cytotoxicity against murine leukemia P388 cells, with an IC 50 of 5.8 μM.
Tan, Karen Co,Wakimoto, Toshiyuki,Takada, Kentaro,Ohtsuki, Takashi,Uchiyama, Nahoko,Goda, Yukihiro,Abe, Ikuro
p. 1388 - 1391
(2013/08/23)

C-5′-substituted cinchona alkaloid derivatives catalyse the first highly enantioselective dynamic kinetic resolutions of azlactones by thiolysis
The highly enantioselective dynamic kinetic resolution (DKR) of azlactones by thiolysis has been achieved for the first time. Although both the parent alkaloid quinine and known C-5′-urea derivatives fail to promote the reaction effectively, a new class of C-5′-hydroxylated catalysts proved capable of catalysing the DKR of a range of azlactones derived from both unbranched- and, previously challenging, branched-chain amino acids in 84-92 % ee, including an example of the synthesis of an enantioenriched N-protected thioester derived from an extraterrestrial amino acid isolated from the Murchison meteorite. The highly enantioselective dynamic kinetic resolution (DKR) of azlactones by thiolysis has been achieved for the first time. Although both the parent alkaloid quinine and known C-5′-urea derivatives fail to promote the reaction effectively, a new class of C-5′-hydroxylated catalysts proved capable of catalysing the DKR of a range of azlactones in 84-92 % ee. Copyright
Palacio, Carole,Connon, Stephen J.
supporting information
p. 5398 - 5413
(2013/09/02)

NUCLEOSIDE DERIVATIVES, SYNTHESIS METHODS AND USES THEREOF FOR PREPARING ANTI-TUMOR AND ANTI-VIRUS MEDICAMENTS
The present invention relates to the field of pharmacochemistry. Disclosed are fluorinated and azido-substituted pyrimidine nucleoside derivatives, and preparation methods and uses thereof. The structural formula is as shown (I). These compounds can be used for preparing medicaments for treating diseases such as tumors and viral infections, and can be used separately or in combination with other medicaments. The compounds also have effective activity against diseases such as tumors and viral infections, while having few side effects, and thus have potential application value.
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(2013/07/25)

PYRIMIDINE NUCLEOSIDE DERIVATIVES, SYNTHESIS METHODS AND USES THEREOF FOR PREPARING ANTI-TUMOR AND ANTI-VIRUS MEDICAMENTS
The present invention relates to the field of pharmacochemistry. Disclosed are fluorinated and azido-substituted pyrimidine nucleoside derivatives, and preparation methods and uses thereof. The structural formula is as shown (I). These compounds can be used for preparing medicaments for treating diseases such as tumors and viral infections, and can be used separately or in combination with other medicaments. The compounds also have effective activity against diseases such as tumors and viral infections, while having few side effects, and thus have potential application value.
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(2013/11/19)

Design, synthesis, and applications of potential substitutes of t-Bu-phosphinooxazoline in Pd-catalyzed asymmetric transformations and their use for the improvement of the enantioselectivity in the Pd-catalyzed allylation reaction of fluorinated allyl enol carbonates
The design, synthesis, and applications of potential substitutes of t-Bu-PHOX in asymmetric catalysis is reported. The design relies on the incorporation of geminal substituents at C5 in combination with a substituent at C4 other than t-butyl (i-Pr, i-Bu, or s-Bu). Most of these new members of the PHOX ligand family behave similarly in terms of stereoinduction to t-Bu-PHOX in three palladium-catalyzed asymmetric transformations. Electronically modified ligands were also prepared and used to improve the enantioselectivity in the Pd-catalyzed allylation reaction of fluorinated allyl enol carbonates.
Belanger, Etienne,Pouliot, Marie-France,Courtemanche, Marc-Andre,Paquin, Jean-Francois
scheme or table
p. 317 - 331
(2012/02/15)

Antimicrobial toxicity studies of ionic liquids leading to a 'hit' MRSA selective antibacterial imidazolium salt
Imidazolium salts can be classed as surfactants, detergents, ionic liquids, reagents, catalysts or solvents. A study of the toxicity and ecotoxicity of these salts yields valuable information for their use as pharmaceuticals as well as impact on the environment. Our approach to screen a series of chiral imidazolium salts for toxicity to bacteria and fungi, including clinical pathogen strains, has led to the identification of a 'hit' MRSA selective antimicrobial compound. Preliminary structure-activity-relationship (SAR) information (required position of l-phenylalanine and l-valine group) is also elucidated within this first generation of compounds. Conversely, most of the imidazolium salts were nontoxic (IC95 > 2 mM) to the 12 fungi strains and 8 bacteria strains screened, and we propose that they are suitable candidates for 'green chemistry' applications. Ecotoxicity studies (Biodegradation ISO 14593 'CO2 Headspace Test') of two bromide ionic liquids containing l-phenylalanine residues indicate that these ionic liquids passed the test (>60% in 28 days) and classed as readily biodegradable.
Coleman, Deborah,Spulak, Marcel,Garcia, M. Teresa,Gathergood, Nicholas
body text
p. 1350 - 1356
(2012/06/16)

Highly tunable arylated cinchona alkaloids as bifunctional catalysts
We report the design and evaluation of a library of chiral bifunctional organocatalysts in which the distance between the catalytically active units can be systematically varied.
Quigley, Cormac,Rodriguez-Docampo, Zaida,Connon, Stephen J.
supporting information; scheme or table
p. 1443 - 1445
(2012/03/11)

Chemoselective and enantioselective oxidation of indoles employing aspartyl peptide catalysts
Catalytic enantioselective indole oxidation is a process of particular relevance to the chemistry of complex alkaloids, as it has been implicated in their biosynthesis. In the context of synthetic methodology, catalytic enantioselective indole oxidation allows a rapid and biomimetic entry into several classes of alkaloid natural products. Despite this potentially high utility in the total synthesis, reports of catalytic enantioselective indole oxidation remain sparse. Here we report a highly chemoselective catalytic system for the indole oxidation that delivers 3-hydroxy-indolenines with good chemical yields and moderate to high levels of enantio- and diastereoselectivity (up to 95:5 er and up to 92:8 dr). These results represent, to our knowledge, the most selective values yet reported in the literature for catalytic asymmetric indole oxidation. Furthermore, the utility of enantioenriched hydroxy-indolenines in stereospecific rearrangements is demonstrated.
Kolundzic, Filip,Noshi, Mohammad N.,Tjandra, Meiliana,Movassaghi, Mohammad,Miller, Scott J.
supporting information; experimental part
p. 9104 - 9111
(2011/08/04)

Chiral phosphanylferrocenecarboxamides with amino acid pendant groups as ligands for Cu-mediated asymmetric conjugate additions of diethylzinc to chalcones - Structural characterisation of precursors to the Cu catalyst
A series of chiral phosphanylferrocenecarboxamides was prepared by treatment of either l'-(diphenylphosphanyl)ferrocene-1-carboxylic acid (Hdpf) or its planar-chiral 1,2isomers with amino acid methyl esters in the presence of peptide coupling agents. The compounds were characterised by spectroscopic methods, and the crystal structure of one representative was determined by X-ray diffraction. Catalytic testing of these donors in Cu-catalysed asymmetric conjugate additions of diethylzinc to chalcones revealed that the reaction outcomes were highly sensitive to the ligand structure and the reaction conditions (copper source and solvent), whereas the chalcone substituents (Me, MeO, or Cl in positions 4 or 4') had a less pronounced influence. Compounds based on Hdpf proved to be better ligands than their planarchiral analogues. Under optimised conditions, the reaction with L-valine-Hdpf conjugate, (S)-Ph2PfcCONHCH(CHMe2)CO2Me (fc = ferrocene-1,1'-diyl) and unsubstituted chalcone gave the alkylation product with complete conversion (20 °C/ 4 h) and in 87 % ee. The catalytic behaviour of the amidophosphane ligands was correlated to the results of a model coordination study and the crystal structure of [Cu(Ph2PfcCONHCH 2CO2Me)2](CF3SO3) ·2CHCl3.
Tauchman, Jiri,Cisarova, Ivana,Stepnicka, Petr
supporting information; experimental part
p. 4276 - 4287
(2010/10/21)

Use of diphenyliodonium bromide in the synthesis of some N-phenyl-amino acids
The N-phenyl methyl esters 4 of glycine, alanine, valine, leucine, isoleucine, phenylalanine, methionine, proline, serine, threonine, tyrosine, aspartic acid, and glutamic acid have been synthesized in good to excellent yields using diphenyliodonium bromide, AgNO3, and a catalytic amount of CuBr starting from the relevant amino acid ester. The chiral integrity of the amino acids 5 was maintained during these reactions, which were confirmed by the synthesis of dipeptide for each N-phenyl amino acid. The structures of the new compounds were confirmed by the analysis of their IR, 1H, and 13C NMR spectra in addition to CHN microanalysis or high-resolution mass spectrometry for the new N-phenyl amino acids 5 and the esters 4.
McKerrow, Jason D.,Al-Rawi, Jasim M. A.,Brooks, Peter
experimental part
p. 1161 - 1179
(2010/04/28)

Use of 5,5-(dimethyl)-i-Pr-PHOX as a practical equivalent to t-Bu-PHOX in asymmetric catalysis
The use of 5,5-(dimethyl)-i-Pr-PHOX as a practical equivalent of t-Bu-PHOX in asymmetric catalysis is reported. This new member of the phosphinooxazoline (PHOX) ligand family behaves similarly in terms of stereoinduction to t-Bu-PHOX with the key advantage of being readily accessible as both enantiomers starting from either(S)- or (R)-valine.
Belanger, Etienne,Pouliot, Marie-France,Paquin, Jean-Francois
supporting information; scheme or table
p. 2201 - 2204
(2009/09/28)

Design and synthesis of N-methylmaleimide indolocarbazole bearing modified 2-acetamino acid moieties as Topoisomerase I inhibitors
A novel series of N-methylmaleimide indolocarbazole derivatives bearing modified 2-acetamino acid moieties are first reported. The cytotoxic effects of these compounds were tested in five human tumor cell lines. The potent compounds 9a, 9b, 9d, and 9e have been further evaluated for their effect on Topoisomerase I (TOPO I) and cancer cell cycle. It is concluded that the indolocarbazoles with alkyl piperazine or morpholine substituent groups instead of esters or glycosyl residues would have better activities against tumors.
Li, Zhiyu,Zhai, Fuming,Zhao, Li,Guo, Qinglong,You, Qidong
scheme or table
p. 406 - 409
(2011/02/26)

Synthesis of novel C2-symmetric chiral crown ethers and investigation of their enantiomeric recognition properties
A series of new C2-symmetric chiral aza crown ether macrocycles 1-4 have been synthesized from (S)-3-aryloxy-1,2-propanediol and (S)-1,2-propanediol for the enantiomeric recognition of amino acid ester derivatives. These new macrocycles have be
Turgut, Yilmaz,Aral, Tarik,Hosgoren, Halil
experimental part
p. 2293 - 2298
(2010/03/24)

Probing the efficiency of N-heterocyclic carbene promoted O- to C-carboxyl transfer of oxazolyl carbonates
(Chemical Equation Presented) Screening of a range of azolium salts, bases and solvents for reactivity indicates that triazolinylidenes, generated in situ with KHMDS in THF, promote the Steglich rearrangement of oxazolyl carbonates with high catalytic efficiency (typical reaction time 5 min at 1.5 mol % NHC). This protocol shows wide substrate applicability, even allowing the efficient generation of vicinal quaternary centers. An improved experimental procedure is also described that allows a simplified one-pot reaction protocol to be employed with similarly high catalytic efficiency.
Thomson, Jennifer E.,Campbell, Craig D.,Concellon, Carmen,Duguet, Nicolas,Rix, Kathryn,Slawin, Alexandra M. Z.,Smith, Andrew D.
p. 2784 - 2791
(2008/09/20)

Simple and effective preparation of amino sulfonylureas from amino acids: application to the synthesis of amino sulfonylurea-containing peptidomimetics
Several amino sulfonylureas have been synthesized, starting from amino acids. The synthetic procedure is simple affording high yields of products under mild conditions. Furthermore, it is shown that these compounds can be incorporated into a peptide sequence.
?ink, Roman,Zega, Anamarija
p. 3943 - 3945
(2008/09/21)

Synthesis and host-guest studies of chiral N-linked peptidoresorc[4]arenes
(Figure Presented) Four cone resorc[4]arene octamethyl ethers (10, 11, ent-10, and ent-11) tetrafunctionalized at the feet with valyl-leucine [LL- (6); DD- (ent-6)] and leucyl-valine [LL- (9); DD- (ent-9)] methyl esters have been synthesized. These compounds, obtained by conjugation of macrocycle tetracarboxylic acid chlorides with the appropriate terminal amino groups of the above dipeptides, are N-linked peptidoresorc[4]arenes. We found that these macrocycles (M) are capable of recognizing the homologue dipeptides as guests (G), both in solution and in the gas phase, by forming relatively stable host-guest complexes ([M·G]), resistant to chromatographic purification but not to heating. Complexation phenomena between M and G in solution were investigated by NMR methods, including NMR DOSY experiments, for the detection of translational diffusion. Heteroassociation constants of 2030 and 186 M -1 were obtained by the Foster-Fyfe method for the complexes [10·6] and [10·ent-6], respectively, the latter being comparable to the self-association constant of dipeptide itself. Conversely, the structural features of the proton-bound complexes [M·H·Gn] + (n = 1, 2), generated in the gas phase by electrospray ionization mass spectrometry (ESI-MS), were investigated by collision-induced dissociation (CID) experiments. In both cases, the four N-linked peptidoresorc[4]arenes were shown to act as synthetic receptors and to recognize the homologue dipeptide by means of hydrogen bonds.
Botta, Bruno,D'Acquarica, Ilaria,Delle Monache, Giuliano,Subissati, Deborah,Uccello-Barretta, Gloria,Mastrini, Massimo,Nazzi, Samuele,Speranza, Maurizio
p. 9283 - 9290
(2008/03/14)

Organosilicon synthesis of isocyanates: IV. Synthesis of isocyanates from aliphatic and alkylaromatic amino acid esters
Treatment of an alcoholic suspension of amino acids with trimethylchlorosilane yielded phenylglycine, valine, β-phenylalanine, and homovaline ester hydrochlorides. Their saccharin-catalyzed silylation with hexamethyldisilazane proceeds quantitatively and involves only one proton of the amino group. The best conversion of the amino acid esters to the corresponding isocyanates was achieved by phosgene treatment of their monosilyl urethanes, rather than of the silylated amino esters. Monosilyl urethanes are formed quantitatively by treatment of the amino acid ester hydrochlorides with the hexamethyldisilazane-CO2 system. The 1H NMR spectra show that monosilyl urethanes derived from α-and β-amino acid esters are characterized by intramolecular interaction of the silicon atom and the oxygen atom of the carboxy group. Nauka/Interperiodica 2007.
Lebedev,Lebedeva,Sheludyakov,Shatunov,Ovcharuk
p. 581 - 585
(2008/02/11)

Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives
We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinct SARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4A and the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potency improvements over the parent drug. In conclusion, the ProTide approach is highly successful when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinical candidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinal S9 fractions.
McGuigan, Christopher,Hassan-Abdallah, Alshaimaa,Srinivasan, Sheila,Wang, Yikang,Siddiqui, Adam,Daluge, Susan M.,Gudmundsson, Kristjan S.,Zhou, Huiqiang,McLean, Ed W.,Peckham, Jennifer P.,Burnette, Thimysta C.,Marr, Harry,Hazen, Richard,Condreay, Lynn D.,Johnson, Lance,Balzarini, Jan
p. 7215 - 7226
(2007/10/03)

Meteoritic Cα-methylated α-amino acids and the homochirality of life: Searching for a link
Catch a falling star: Peptides from chiral, Cα-methylated α-amino acids (see scheme) found in L enantiomeric excess in meteorites show diastereoselectivity when reacting with racemic proteinogenic amino acids. Accordingly, the prebiotic soup of proteinogenic amino acids may have evolved into a chirally unbalanced system, eventually seeding the homochirality of life.
Crisma, Marco,Moretto, Alessandro,Formaggio, Fernando,Kaptein, Bernard,Broxterman, Quirinus B.,Toniolo, Claudio
p. 6695 - 6699
(2007/10/03)

Synthesis and Biological Evaluation of Potential Cancer Biomarkers Radiolabelled MMP Inhibitors [11C]FMAME and [18F]FMAME
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Zheng, Q.-H.,Fei, X.,Wang, J.-Q.,Stone, K. L.,Martinez, T. D.,Gay, D. J.,Baity, W. L.,Mock, B. H.,Glick-Wilson, B. E.,Sullivan, M. L.,Miller, K. D.,et al.
p. S110 - S110
(2007/10/03)

Comparative Studies of Potential Cancer Biomarkers Carbon-11 Labelled MMP Inhibitors [11C]MSMA and [11C]CGS 25966
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Zheng, Q.-H.,Fei, X.,Liu, X.,Wang, J.-Q.,Stone, K. L.,Martinez, T. D.,Gay, D. J.,Baity, W. L.,Miller, K. D.,Sledge, G. W.,Hutchins, G. D.
p. S111 - S111
(2007/10/03)

Synthesis of MMP inhibitor radiotracers [11C]methyl-CGS 27023A and its analogs, new potential PET breast cancer imaging agents
[11C]Methyl-CGS 27023A (1a) and its analogs [11C]methyl-2-picolyl-CGS 27023A (1b), [11C]methyl-benzyl-CGS 27023A (1c), [11C]methyl-2-nitro-CGS 27023A (1d), [11C]methyl-3-nitro-CGS 27023A (1e), and [11C]methyl-4-nitro-CGS 27023A (1f), novel radiolabeled matrix metalloproteinase (MMP) inhibitors, have been synthesized for evaluation as new potential positron emission tomography (PET) breast cancer imaging agents. The appropriate precursors for radiolabeling were obtained in four to five steps from starting material amino acid D-valine with moderate to excellent chemical yields. Precursors were labeled by [11C]methyl triflate through 11C-O-methylation method at the aminohydroxyl position under basic conditions and isolated by solid-phase extraction (SPE) purification to produce pure target compounds in 40-60% radiochemical yields (decay corrected to end of bombardment), in 20-25 min synthesis time. Copyright
Fei, Xiangshu,Zheng, Qi-Huang,Hutchins, Gary D.,Liu, Xuan,Stone, K. Lee,Carlson, Kathy A.,Mock, Bruce H.,Winkle, Wendy L.,Glick-Wilson, Barbara E.,Miller, Kathy D.,Fife, Rose S.,Sledge, George W.,Sun, Hui Bin,Carr, Raymond E.
p. 449 - 470
(2007/10/03)

New 2-(2'-phenyl-9'-benzyl-8'-azapurin-6'-ylamino)-carboxylic acid methylesters as ligands for A1 adenosine receptors.
Synthesis of a series of new 2-phenyl-9-benzyl-8-azaadenines bearing on N6 an alkyl or aralkyl chain having a carbonyloxymethyl group on the carbon bound to N6 were reported. The ester group could assure to the molecule a better water-solubility than the 8-azaadenines 2, 6 and 9 substituted with lipophilic groups synthesised in the past. Compounds synthesised demonstrated only little capability of binding A1 adenosine receptors.
Biagi,Giorgi,Pacchini,Livi,Scartoni
p. 929 - 931
(2007/10/03)

Synthesis of chiral α-acetoxy-N-acetylamides from chiral pyrimidylalkanols by the oxidative cleavage of pyrimidine ring
Acetates of chiral 5-pyrimidylalkanols are transformed into chiral α- acetoxy-N-acetylamides and α-acetoxyamides without racemization in high total yields by the oxidative cleavage of pyrimidine ring using ruthenium tetroxide.
Tanji, Shigehisa,Kodaka, Yasutaka,Shibata, Takanori,Soai, Kenso
p. 151 - 158
(2007/10/03)

Asymmetric alkylations using SuperQuat auxiliaries - An investigation into the synthesis and stability of enolates derived from 5,5-disubstituted oxazolidin-2-ones
Studies on the alkylation of enolates derived from a range of N-acyl-5,5-dimethyloxazolidin-2-ones and N-acyl-5,5-diphenyloxazolidin-2-ones reveal that high yields and high diastereoselectivities are best obtained when homochiral 4-isopropyl-5,5-dimethyloxazolidin-2-one is employed as a chiral auxiliary.
Bull, Steven D.,Davies, Stephen G.,Jones, Simon,Sanganee, Hitesh J.
p. 387 - 398
(2007/10/03)

Synthesis of N-1-Adamantylcarbonylated Dipeptides
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Danilin, A. A.,Purygin, P. P.,Makarova, N. V.,Moiseev, I. K.
p. 1846 - 1847
(2007/10/03)

Synthesis of p-phosphonomethyl-L-phenylalanine using camphor sultam or D-valine as chiral auxiliaries and its incorporation into integrin sequences.
The synthesis of N-Boc-p-phosphonomethyl-L-phenylalanine with two different chiral auxiliaries, camphor sultam or D-valine is described. The preparations have essentially identical properties and have been used to incorporate the amino acid into two integrin peptides as non-hydrolyzable isosteres of phosphotyrosine.
Larsson,Luening
p. 54 - 57
(2007/10/03)

Chiral Discrimination in the Liquid Phase: Excess Volumes of Binary Mixtures of Amino Acid Derivatives
Volume changes on mixing the enantiomers of N-trifluoroacetylamino acid methyl esters (N-TFA-amino acid-OMe) were determined at 25 deg C by means of a high-precision vibrating-tube densimeter.The excess molar volume (VE) for the racemic mixtures of N-TFA-Ala-OMe 1, N-TFA-Val-OMe 2, and N-TFA-Leu-OMe 3, were found as VE = 0.0098, -0.0458, and 0.035 cm3 mol-1, respectively.For 2 and 3, these volumetric effects of discriminating interactions between enantiomers in the liquid phase are the largest ever observed.
Lepori, Luciano,Koppenhoefer, Beenhard
p. 6862 - 6864
(2007/10/02)

Enantioselective synthesis of (2S)-2-amino-3-(4-hydroxy-3- phosphonophenyl)propionic acid (= 3'-phosphono-L-tyrosine) and its incorporation into peptides
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Paladino,Guyard,Thurieau,Fauchere
p. 2465 - 2472
(2007/10/02)

Syntheses of (2S,3R)- and (2S,3R)2H>- 3-Methylaspartic acid: Slow Substrates for a syn-Elimination Reaction catalysed by Methylaspartase.
Methylaspartase catalyses the slow syn-elimination of ammonia from the (2S,3R)--diastereomer of the natural substrate, (2S,3S)-3-methylaspartic acid, to give mesaconic acid.To provide material of sufficient stereochemical purity to probe the mechanism of the reaction, two synthetic routes to (2S,3R)- and (2S,3R)2H>- 3-methylaspartic acid were devised.The use of these (2S,3R)-3-methylaspartic acids revealed that the enzymic reaction does not involve C-3 epimerisation followed by normal anti-elimination, ruling-out the possibility of a carbanion intermediate.Conversely, the substrate displayed very large primary deuterium isotope effects indicating rate-limiting C-H bond cleavage.
Archer, Catherine H.,Thomas, Neil R.,Gani, David
p. 1141 - 1152
(2007/10/02)

Preparation of an angiotensin i analog containing a p-phosphonomethyl-l-phenylalanine residue via asymmetric synthesis of t-boc-p-dimethylphosphonomethyl-l-phenylalanine
t-BOC-p-Dimethylphoshonomethyl-L-phenylalanine has been prepared and incorporated into a peptide sequence corresponding to angiotensin I. Demethylation of the dimethylphosphonomethyl moiety then yielded a peptide containing a p-phosphonomethyl-L-phenylalanine residue.
Cushman, Mark,Lee, Eung-Seok
p. 1193 - 1196
(2007/10/02)

FREE-RADICAL ADDITION TO DI- AND TRIPEPTIDES CONTAINING DEHYDROALANINE RESIDUES
Radical addition, by the alkylmercury halide/sodium borohydride method, to di- and tripeptides containing a dehydroalanine residue proceeds smoothly with good chemical yield, but low diastereoselectivity, to saturated di- and tripeptides.
Crich, David,Davies, John W.
p. 5641 - 5654
(2007/10/02)

Metal Complexes with Biologically Important Ligands, XLV. - Palladium(II) Complexes of Dehydro-α-amino and 2-Imino Acid Esters as Ligands
The preparation and spectroscopic data of the complexes trans-Cl2Pd(H2NC(CO2R)=C)2 (1) and trans-Cl2Pd(HN=C(CO2R)-CH)2 (6) and of (+)BF4(-) (2) are reported.The reactions of dehydroamino acid esters R(ROC)-C=C(CO2R)NH2 with Na2PdCl4 give 1-imino-3-ketonato chelate complexes cis- (3), of which one representative (3b) has been characterized by X-ray structure analysis.For comparison the structure of the dehydroamino acid derivative OC(Me)C(CO2Et)=C(CO2Et)NH2 (4) has also been determined.Palladium(II) binds the anion of dehydroarmentomycin via the N,O atoms (8).This coordination is also found with (η5-C5H5)(OC)2Mo and allylglycine (9).
Wanjek, Herbert,Nagel, Ulrich,Beck, Wolfgang
p. 1021 - 1026
(2007/10/02)

REGIOSELECTIVE CHLORINATION OF VALINE DERIVATIVES
Reaction of N-benzoylvaline methyl ester (5a) with sulphuryl chloride gave the β-chlorovaline derivative (6a) and lesser amounts of diastereoisomers of the γ-chlorovaline derivative (7a).A similar mixture of products was obtained throuch photolysis of the N-chloroamide (13).The reactions of the valine derivatives (5a) and (13) involve regioselective intermolecular transfer of the β-valinyl hydrogen.There is no evidence for reaction at the α-position.The β-chloroalanine derivative (23) was produced through reaction of N-benzoylalanine methyl ester (17a) with sulphuryl chloride and by photolysis of the N-chloroamide (22).Chlorination of the azetidinone (16a) gave (16b) in modest yield.These reactions establish the chemical validity of a regiospecific hydrogen-atom abstraction proposed in penicillin biosynthesis.
Bowman, Nigel J.,Hay, Michael P.,Love, Stephen G.,Easton, Christopher J.
p. 259 - 264
(2007/10/02)

REGIOSELECTIVE FORMATION OF AMIDOCARBOXY-SUBSTITUTED FREE RADICALS
Factors affecting the production of amidocarboxy-substituted free radicals have been investigated by examining reactions of derivatives of valine and sarcosine.Variations in the regioselectivity of reactions of these compounds are exemplified by the reactions of N-benzoylvaline methyl ester (4a) and N-benzoylsarcosine methyl ester (12a) with sulphuryl chloride and N-bromosuccinimide.Whereas the reaction of (4a) with sulphuryl chloride involves hydrogen-atom transfer from the β-position of (4a) with subsequent chlorine incorporation to give (4g), in direct contrast the reaction with N-bromosuccinimide proceeds via hydrogen-atom abstraction from the α-position of (4a) and yields the dibromide (4d).N-benzoylsarcosine methyl ester (12a), reacts with N-bromosuccinimide to give the α-bromosarcosine derivative (12b), whereas with sulphuryl chloride the product is the N-chloromethylglycine derivative (12c).These studies indicate that amidocarboxy-substituted radicals such as (3a) and (13) are considerably more stable than the tertiary alkyl radical (1a) and the amidosubstituted radical (14), respectively, but hydrogen-atom transfer reactions may afford the less stable products if electrophilic radicals are involved in the hydrogen-atom abstraction and if there is little development of radical character in the reaction transition state.
Easton, Christopher J.,Hay, Michael P.,Love, Stephen G.
p. 265 - 268
(2007/10/02)

Synthesis of Optically Active 1,3,2-Oxazaphospholidine 2-Sulfides and 1,3,2-Benzodioxaphosphorin 2-Sulfides
The optical isomers of ten kinds of insecticidal 1,3,2-oxazaphospholidine 2-sulfides (OS) and two kinds of 1,3,2-benzodioxaphosphorin 2-sulfides (BS), including the commercial insecticide salithion, were synthesized in high optical purity by using two optically active aryl methyl phosphorochloridothionates (AMPC) as chiral two-step phosphorylating reagents.Their configurations were assigned according to the reaction mechanism and supported by proton NMR information.
Wu, Shao-Yong,Hirashima, Akinori,Kuwano, Eiichi,Eto, Morifusa
p. 537 - 548
(2007/10/02)