- Pd-Catalysed oxidative carbonylation of α-amino amides to hydantoins under mild conditions
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The first example of palladium-catalysed oxidative carbonylation of unprotected α-amino amides to hydantoins is described here. The selective synthesis of the target compounds was achieved under mild conditions (1 atm of CO), without ligands and bases. The catalytic system overrode the common reaction pathway that usually leads instead to the formation of symmetrical ureas.
- Botla, Vinayak,Carfagna, Carla,Della Ca, Nicola,Gabriele, Bartolo,Maestri, Giovanni,Mancuso, Raffaella,Montanari, Luca,Motti, Elena,Voronov, Aleksandr
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supporting information
p. 294 - 297
(2022/01/06)
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- Divergent Stereoselectivity in Phosphothreonine (pThr)-Catalyzed Reductive Aminations of 3-Amidocyclohexanones
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Phosphothreonine (pThr)-embedded peptide catalysts are found to mediate the reductive amination of 3-amidocyclohexanones with divergent selectivity. The choice of peptide sequence can be used to alter the diastereoselectivity to favor either the cis-product or trans-product, which are obtained in up to 93:7 er. NMR studies and DFT calculations are reported and indicate that both pathways rely on secondary interactions between substrate and catalyst to achieve selectivity. Furthermore, catalysts appear to accomplish a parallel kinetic resolution of the substrates. The facility for phosphopeptides to tune reactivity and access multiple products in reductive aminations may translate to the diversification of complex substrates, such as natural products, at numerous reactive sites.
- Shugrue, Christopher R.,Featherston, Aaron L.,Lackner, Rachel M.,Lin, Angela,Miller, Scott J.
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p. 4491 - 4504
(2018/04/26)
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- Application of C-Terminal 7-Azabicyclo[2.2.1]heptane to Stabilize β-Strand-like Extended Conformation of a Neighboring α-Amino Acid
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β-Strands are formed by extended linear peptide chains that are usually paired to form β-sheet structure through interstrand hydrogen bonding. Linking a structured organic molecule with α-amino acid(s) can enforce or stabilize β-strand-like extended struc
- Zhai, Luhan,Wang, Siyuan,Nara, Masayuki,Takeuchi, Koh,Shimada, Ichio,Otani, Yuko,Ohwada, Tomohiko
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p. 13063 - 13079
(2018/10/25)
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- UNNATURAL AMINO ACIDS
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The present invention relates to a process for the preparation compounds of Formula (I): Formula (I) wherein X, Z, Q, Ar, R1, R2, R3 and R4 are each as defined herein. The present invention also relates to processes for the preparation of the compounds of quaternary amino acids and hydantions, to compound of Formula(I), to intermediate compounds of Formula (II), to quaternary amino acid compounds of Formula (III) and to hydantoin compounds of Formula (IV).
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Paragraph 00182; 00196; 00198
(2018/07/05)
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- Aromatic Interactions in Organocatalyst Design: Augmenting Selectivity Reversal in Iminium Ion Activation
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Substituting N-methylpyrrole for N-methyindole in secondary-amine-catalysed Friedel-Crafts reactions leads to a curious erosion of enantioselectivity. In extreme cases, this substrate dependence can lead to an inversion in the sense of enantioinduction. Indeed, these closely similar transformations require two structurally distinct catalysts to obtain comparable selectivities. Herein a focussed molecular editing study is disclosed to illuminate the structural features responsible for this disparity, and thus identify lead catalyst structures to further exploit this selectivity reversal. Key to effective catalyst re-engineering was delineating the non-covalent interactions that manifest themselves in conformation. Herein we disclose preliminary validation that intermolecular aromatic (CH-π and cation-π) interactions between the incipient iminium cation and the indole ring system is key to rationalising selectivity reversal. This is absent in the N-methylpyrrole alkylation, thus forming the basis of two competing enantio-induction pathways. A simple L-valine catalyst has been developed that significantly augments this interaction.
- Holland, Mareike C.,Metternich, Jan Benedikt,Daniliuc, Constantin,Schweizer, W. Bernd,Gilmour, Ryan
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supporting information
p. 10031 - 10038
(2015/07/07)
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- Readily accessible chiral at nitrogen cage structures
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The reaction of glycine-N-methyl amide with paraformaldehyde in the presence of ytterbium triflate (1 mol%) leads to a novel cage structure 6 which is chiral at nitrogen. Single crystal X-ray analysis and DFT calculations suggest this cage structure is rigid and adopts a single low energy conformation. Use of single enantiomer α-amino amides results in two diastereomeric tertiary amines that differ in their absolute configuration at nitrogen. These diastereoisomers interconvert under acidic conditions but are configurationally stable under basic conditions and can be readily separated by either crystallisation or column chromatography. By reacting racemic chiral α-amino amides a third diastereomeric cage can also be isolated through this reaction protocol. Preparation of mixed cages by reacting two different α-amino amides is also possible allowing for greater structural diversity in the products to be attained. Preliminary mechanistic studies show that all three methylene units in the cage structure are labile and can be replaced under acidic reaction conditions. The Royal Society of Chemistry 2013.
- Rowley, Julian H.,Yau, Sze Chak,Kariuki, Benson M.,Kennedy, Alan R.,Tomkinson, Nicholas C. O.
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p. 2198 - 2205
(2013/05/09)
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- Preparation of thermoresponsive polymers bearing amino acid diamide derivatives via RAFT polymerization
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We report here the synthesis of well-defined homopolymer bearing amino acid diamide, poly(N-acryloyl-L-valine N'-methylamide), via reversible addition fragmentation chain transfer (RAFT) polymerization using alkynyl-functionalized 2-dodecylsulfanylthiocarbonylsulfanyl-2-methyl-propionic acid propargyl alcohol ester as chain transfer agent (CTA) and 2, 2′azobis(isobutyronitrile) as initiator. The effects of a variety of parameters, such as temperature and solvent, on RAFT polymerization were examined to determine the optimal control of the polymerization. The controlled nature of RAFT polymerization was evidenced by the controllable molecular weight and low-molecular-weight polydispersity index [Mw/Mn) of resulting homopolymers and further demonstrated to have retained end-group functionality by the fact of the successful formation of block copolymers from further RAFT polymerization by using the resultant polymer as macro-CTA, as well as from "click" chemistry. Thermoresponsive property of the prepared polymer was evaluated in terms of the lower critical solution temperature in aqueous solution by measuring the transmittance variation at 500 nm from UV/vis spectroscopy.
- Liu, Zhilei,Hu, Jiwen,Sun, Jianping,He, Guping,Li, Yinghui,Zhang, Ganwei
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experimental part
p. 3573 - 3586
(2011/10/09)
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- A new general pathway for synthesis of reference compounds of N-terminal valine-isocyanate adducts
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Adducts to Hb could be used as biomarkers to monitor exposure to isocyanates. Particularly useful is the measurement of carbamoylation of N-terminal valines in Hb, after detachment as hydantoins. The synthesis of references from the reactive isocyanates, especially diisocyanates, has been problematic due to side reactions and polymerization of the isocyanate starting material. A simpler, safer, and more general method for the synthesis of valine adducts of isocyanates has been developed using N-[(4-nitrophenyl)-carbamate] valine methylamide (NPCVMA) as the key precursor to adducts of various mono-and diisocyanates of interest. By reacting NPCVMA with a range of isocyanate-related amines, carbamoylated valines are formed without the use of the reactive isocyanates. The carbamoylated products synthesized here were cyclized with good yields of the formed hydantoins. The carbamoylated derivative from phenyl isocyanate also showed quantitative yield in a test with cyclization under the conditions used in blood. This new pathway for the preparation of N-carbamoylated model compounds overcomes the abovementioned problems in the synthesis and is a general and simplified approach, which could make such reference compounds of adducts to N-terminal valine from isocyanates accessible for biomonitoring purposes. The synthesized hydantoins corresponding to adducts from isocyanic acid, methyl isocyanate, phenyl isocyanate, and 2,6-toluene diisocyanate were characterized by LC-MS analysis. The background level of the hydantoin from isocyanic acid in human blood was analyzed with the LC-MS conditions developed.
- Davies, Ronnie,Rydberg, Per,Westberg, Emelie,Motwani, Hitesh V.,Johnstone, Erik,Toernqvist, Margareta
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experimental part
p. 540 - 546
(2011/02/24)
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- SAR studies of non-zinc-chelating MMP-13 inhibitors: Improving selectivity and metabolic stability
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SAR studies to improve the selectivity and metabolic stability of a class of recently discovered MMP-13 inhibitors are reported. Improved selectivity was achieved by modifying interactions with the S1′ pocket. Metabolic stability was improved through reduction of inhibitor lipophilicity. This translated into lower in vivo clearance for the preferred compound.
- Gao, Donghong Amy,Xiong, Zhaoming,Heim-Riether, Alexander,Amodeo, Laura,August, E. Michael,Cao, Xianhua,Ciccarelli, Leonard,Collins, Brandon K.,Harrington, Kyle,Haverty, Kathleen,Hill-Drzewi, Melissa,Li, Xiang,Liang, Shuang,Margarit, Steluta Mariana,Moss, Neil,Nagaraja, Nelamangala,Proudfoot, John,Roman, Rene,Schlyer, Sabine,Keenan, Lana Smith,Taylor, Steven,Wellenzohn, Bernd,Wiedenmayer, Dieter,Li, Jun,Farrow, Neil A.
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scheme or table
p. 5039 - 5043
(2010/10/18)
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- AMIDE DERIVATIVES AS INHIBITORS OF ASPARTYL PROTEASES
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The invention provides compounds of the formula (I). N-oxides, addition salts, quaternary amines, metal complexes, stereochemically isomeric forms and metabolites thereof, wherein W is H, C1-C6alkyl, C3-C6cycloalkyl, aryl or heterocyclyl; Q is aryl or heterocyclyl; A is a five or six membered saturated, partially unsaturated or aromatic ring; D is formula (II) or formula (III); and the other variables are as defined in the specification. The compounds of the invention are inhibitors of aspartyl proteases such as renin and BACE and are among other things useful for the treatment and/or prophylaxis of conditions associated with activities of the RAS, such as hypertension, heart failure and renal insufficiency and for the treatment and or prophylaxis of conditions associated with BACE activity such as of Alzheimer's disease.
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Page/Page column 79
(2008/12/04)
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- N-(aryl/heteroaryl) amino acid derivatives pharmaceutical compositions comprising same and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
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Disclosed are compounds which inhibit β-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease. Also disclosed are pharmaceutical compositions comprising a compound which inhibits β-amyloid peptide release and/or its synthesis as well as methods for treating Alzheimer's disease both prophylactically and therapeutically with such pharmaceutical compositions.
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- Inhibitors of tripeptidyl peptidase II. 2. Generation of the first novel lead inhibitor of cholecystokinin-8-inactivating peptidase: A strategy for the design of peptidase inhibitors
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The cholecystokinin-8 (CCK-8)-inactivating peptidase is a serine peptidase which has been shown to be a membrane-bound isoform of tripeptidyl peptidase II (EC 3.4.14.10). It cleaves the neurotransmitter CCK-8 sulfate at the Met-Gly bond to give Asp-Tyr(SO3H)-Met-OH + Gly-Trp-Met-Asp-Phe-NH2. In seeking a reversible inhibitor of this peptidase, the enzymatic binding subsites were characterized using a fluorimetric assay based on the hydrolysis of the artificial substrate Ala-Ala-Phe-amidomethylcoumarin. A series of di- and tripeptides having various alkyl or aryl side chains was studied to determine the accessible volume for binding and to probe the potential for hydrophobic interactions. From this initial study the tripeptides Ile-Pro-Ile-OH (K(i) = 1 μM) and Ala-Pro-Ala-OH (K(i) = 3 μM) and dipeptide amide Val-Nvl-NHBu (K(i) = 3 μM) emerged as leads. Comparison of these structures led to the synthesis of Val-Pro-NHBu (K(i) = 0.57 μM) which served for later optimization in the design of butabindide, a potent reversible competitive and selective inhibitor of the CCK-8-inactivating peptidase. The strategy for this work is explicitly described since it illustrates a possible general approach for peptidase inhibitor design.
- Ganellin, C. Robin,Bishop, Paul B.,Bambal, Ramesh B.,Chan, Suzanne M. T.,Law, James K.,Marabout, Benoit,Luthra, Pratibha Mehta,Moore, Andrew N. J.,Peschard, Olivier,Bourgeat, Pierre,Rose, Christiane,Vargas, Froylan,Schwartz, Jean-Charles
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p. 664 - 674
(2007/10/03)
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- Design and synthesis of new potent C2-symmetric HIV-1 protease inhibitors. Use of L-mannaric acid as a peptidomimetic scaffold
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A study on the use of derivatized carbohydrates as C2-symmetric HIV-1 protease inhibitors has been undertaken. L-Mannaric acid (6) was bis-O- benzylated at C-2 and C-5 and subsequently coupled with amino acids and amines to give C2-s
- Alterman, Mathias,Bj?rsne, Magnus,Mühlman, Anna,Classon, Bj?rn,Kvarnstr?m, Ingemar,Danielson, Helena,Markgren, Per-Olof,Nillroth, Ulrika,Unge, Torsten,Hallberg, Anders,Samuelsson, Bertil
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p. 3782 - 3792
(2007/10/03)
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- PREPARATION, SPECTRAL AND PHYSICOCHEMICAL CHARACTERISTICS OF METHYLAMIDE Nα-PHENYLTHIOCARBAMOYL DERIVATIVES OF NATURALLY OCCURING AMINO ACIDS
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The methylamide Nα-phenylthiocarbamoyl derivatives of encoded amino acids II were prepared either by the addition of phenylisothiocyanate to amino acid methylamides or by the treatment of amino acid phenylthiohydantoins (5-alkyl-3-phenyl-2-thioxo-4-imidazolinones) I with methylamine.The derivatives were prepared of 19 amino acids and their melting points, 1H NMR, 13C NMR, mass, ultraviolet and infrared spectra were measured.
- Pavlik, Manfred,Kluh, Ivan,Pavlikova, Frantiska,Vasickova, Sona,Kostka, Vladimir
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p. 1940 - 1954
(2007/10/02)
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- Conformational Investigations of α,β-Dehydropeptides. I. Synthesis of Model Dipeptides
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Three series of model dipeptides: Ac-Pro-X-NHMe, where X = L-, D- and Δ-Ala, L-, D- and (Z)-Δ-Phe and L-, D- and Δ-Val, designed for conformational investigation of α,β-dehydroamino acid effect on peptide chain β-turn have been synthesized.
- Pietrzynski, Grzegorz,Kubica, Zbigniew,Rzeszotarska, Barbara
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p. 363 - 370
(2007/10/02)
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- Herstellung enantiomerenreiner cis- oder trans-konfigurierter 2-(tert-Butyl)-3-methylimidazolidin-4-one aus den Aminosaeuren (S)-Alanin, (S)-Phenylalanin, (R)-Phenylglycin, (S)-Methionin und (S)-Valin.
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In contrast to α-hydroxy and α-mercapto carboxylic acids, simple α-amino acids do not form acetal-type derivatives (2, X=NH) with pivalaldehyde.For the generation of amino-acid-derived chiral, nonracemic enolates (cf.3), and hence, for the α-alkylation of amino acids without racemization and without an external chiral auxiliary, the imidazolidinones 12-14 were prepared diastereoselectively.To this end, the methyl or ethyl esters of amino-acid hydrochlorides were first converted to N-methylamides of amino acids which in turn were condensed with pivalaldehyde to give (neopentylidenamino)amides (11).These Schiff bases could be cyclized either to trans- or to cis-imidazolidinones (12, 14 and 13, respectively), which were obtained in enantiomerically pure form after recrystallization.The enantiomeric purities were confirmed by HPLC with chiral stationary phases or by 1H-NMR spectroscopy in the presence of chiral shift reagents.The configurations (cis, trans) were assigned by NOE measurements on 300- or 360-MHz 1H-NMR spectrometers.
- Naef, Reto,Seebach, Dieter
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p. 135 - 143
(2007/10/02)
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