- Catalytic Asymmetric Synthesis of Unprotected β2-Amino Acids
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We report here a scalable, catalytic one-pot approach to enantiopure and unmodified β2-amino acids. A newly developed confined imidodiphosphorimidate (IDPi) catalyzes a broadly applicable reaction of diverse bis-silyl ketene acetals with a silylated aminomethyl ether, followed by hydrolytic workup, to give free β2-amino acids in high yields, purity, and enantioselectivity. Importantly, both aromatic and aliphatic β2-amino acids can be obtained using this method. Mechanistic studies are consistent with the aminomethylation to proceed via silylium-based asymmetric counteranion-directed catalysis (Si-ACDC) and a transition state to explain the enantioselectivity is suggested on the basis of density functional theory calculation.
- Zhu, Chendan,Mandrelli, Francesca,Zhou, Hui,Maji, Rajat,List, Benjamin
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p. 3312 - 3317
(2021/04/07)
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- Direct β-Selective Hydrocarboxylation of Styrenes with CO2 Enabled by Continuous Flow Photoredox Catalysis
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The direct β-selective hydrocarboxylation of styrenes under atmospheric pressure of CO2 has been developed using photoredox catalysis in continuous flow. The scope of this methodology was demonstrated with a range of functionalized terminal styrenes, as well as α-substituted and β-substituted styrenes.
- Seo, Hyowon,Liu, Aofei,Jamison, Timothy F.
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p. 13969 - 13972
(2017/10/17)
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- Beta amino acid-modified and fluorescently labelled kisspeptin analogues with potent KISS1R activity
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Kisspeptin analogues with improved metabolic stability may represent important ligands in the study of the kisspeptin/KISS1R system and have therapeutic potential. In this paper we assess the activity of known and novel kisspeptin analogues utilising a du
- Camerino,Liu,Moriya,Kitahashi,Mahgoub,Mountford,Chalmers,Soga,Parhar,Thompson
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p. 406 - 414
(2016/08/28)
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- Aminomethylation of enals through carbene and acid cooperative catalysis: Concise access to β2-amino acids
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A convergent, organocatalytic asymmetric aminomethylation of α,β-unsaturated aldehydes by N-heterocyclic carbene (NHC) and (in situ generated) Bronsted acid cooperative catalysis is disclosed. The catalytically generated conjugated acid from the base plays dual roles in promoting the formation of azolium enolate intermediate, formaldehyde-derived iminium ion (as an electrophilic reactant), and methanol (as a nucleophilic reactant). This redox-neutral strategy is suitable for the scalable synthesis of enantiomerically enriched β2-amino acids bearing various substituents. Harmonious cooperation: An N-heterocyclic carbene (NHC) and (in situ generated) Bronsted acid cooperatively catalyze the aminomethylation of α,β-unsaturated aldehydes. This cooperative catalytic reaction provides a redox neutral strategy for quick access to β2-amino esters in an enantioselective manner.
- Xu, Jianfeng,Chen, Xingkuan,Wang, Ming,Zheng, Pengcheng,Song, Bao-An,Chi, Yonggui Robin
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supporting information
p. 5161 - 5165
(2015/04/27)
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- Organocatalysed decarboxylative protonation process from Meldrum's acid: Enantioselective synthesis of isoxazolidinones
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An asymmetric organocatalysed decarboxylative protonation reaction allowed a straightforward synthesis of α-substituted isoxazolidin-5-ones from readily available 5-substituted Meldrum's acids. This process is initiated by an anionic formal (3+2) cycloaddition-fragmentation, generated in-situ from a sulfone-amide precursor which also served as a latent source of proton.
- Tite, Tony,Sabbah, Mohamad,Levacher, Vincent,Briere, Jean-Francois
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p. 11569 - 11571
(2013/12/04)
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- Synthesis of chiral β2-amino acids by asymmetric hydrogenation
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The synthesis of chiral β2-amino acids by homogeneous asymmetric hydrogenation is discussed. Prochiral β-aryl- or β-hetaryl-α-N-benzyl/N-acetyl/N-Boc substituted α- aminomethylacrylates used as substrates were prepared by a Baylis-Hillman react
- Luehr, Susan,Holz, Jens,Zayas, Odalys,Wendisch, Volkmar,Boerner, Armin
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p. 1301 - 1319
(2012/11/07)
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- SEVEN-MEMBERED RING COMPOUND, PRODUCTION METHOD THEREOF AND PHARMACEUTICAL USE THEREOF
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A 7-membered heterocyclic compound having the formula (I), or its salt, or a solvate thereof with a chymase inhibitory action and useful for the prevention or treatment of various diseases, in which chymase is involved: a method for producing the same, and a pharmaceutical composition useful for the prevention or treatment of diseases, in which chymase is involved, including the compound of having the formula (I), or its pharmaceutically acceptable salt, or a solvate thereof are provided.
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Page/Page column 104
(2009/03/07)
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- INHIBITORS OF AKT ACTIVITY
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Invented are novel pyrazole compounds, the use of such compounds as inhibitors of protein kinase B activity and in the treatment of cancer and arthritis.
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Page/Page column 44
(2008/12/04)
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- Highly diastereoselective synthetic route to enantiopure β2-amino acids and γ-amino alcohols using a fluorinated oxazolidine (Fox) as chiral auxiliary
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(Chemical Equation Presented) The alkylation reactions of an amide enolate derived from a trifluoromethylated oxazolidine (Fox) chiral auxiliary occur with a complete diastereoselectivity and in good yields with various electrophiles. This reaction provid
- Tessier, Arnaud,Lahmar, Nour,Pytkowicz, Julien,Brigaud, Thierry
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p. 3970 - 3973
(2008/09/20)
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- Amino-substituted heterocycles, compositions thereof, and methods of treatment therewith
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Provided herein are Heterocyclic Compounds having the following structure: wherein R1, R2, X, Y and Z are as defined herein, compositions comprising an effective amount of a Heterocyclic Compound and methods for treating or preventing cancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions treatable or preventable by inhibition of a kinase pathway comprising administering an effective amount of a Heterocyclic Compound to a patient in need thereof.
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Page/Page column 56
(2008/12/07)
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- INHIBITORS OF Akt ACTIVITY
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Invented are novel thiophene compounds, the use of such compounds as inhibitors of protein kinase B activity and in the treatment of cancer and arthritis.
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Page/Page column 59-60
(2010/11/27)
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- New scalable asymmetric aminomethylation reaction for the synthesis of β2-amino acids
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β-Amino acids are useful tools in the design of peptidomimetics, and the development of new methods for their syntheses, particularly the synthesis of β2-amino acids, remains an important challenge. Here we report a new scalable route based on the aminomethylation of silyl ketene N,O-acetals by Mannich-type iminium electrophiles. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Moumne, Roba,Denise, Bernard,Guitot, Karine,Rudler, Henri,Lavielle, Solange,Karoyan, Philippe
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p. 1912 - 1920
(2008/02/06)
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- CONCISE BETA2-AMINO ACID SYNTHESIS VIA ORGANOCATALYTIC AMINOMETHYLATION
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The present invention provides a method for the synthesis of ?2-amino acids. The method also provides methods yielding a-substituted ?-amino aldehydes and ?-substituted γ-amino alcohols. The present method according to this invention allows for increased yield and easier purification using minimal chromatography or crystallization. The methods described herein are based on an aldehyde aminomethylation which involves a Mannich reaction between an aldehyde and a formaldehyde-derived N,O-acetal (iminium precursor) and a catalyst, such as, for example, L-proline or a pyrrolidine. The invention allows for large scale, commercial preparation of ?2-amino acids.
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Page/Page column 14; 32; 39; 42-43; 46
(2010/11/28)
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- Practical synthesis of enantiomerically pure β2-amino acids via proline-catalyzed diastereoselective aminomethylation of aldehydes
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Proline-catalyzed diastereoselective aminomethylation of aldehydes using a chiral iminium ion, generated from a readily prepared precursor, provides α-substituted-β-amino aldehydes with 85:15 to 90: 10 dr. The α-substituted-β-amino aldehydes can be reduce
- Chi, Yonggui,English, Emily P.,Pomerantz, William C.,Horne, W. Seth,Joyce, Leo A.,Alexander, Lane R.,Fleming, William S.,Hopkins, Elizabeth A.,Gellman, Samuel H.
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p. 6050 - 6055
(2008/02/08)
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- NOVEL COMPOUNDS
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This invention relates to novel amide derivatives and salts thereof. More particularly, it relates to novel amide derivatives and salts thereof which act as a ROCK inhibitor, to a pharmaceutical composition comprising the same and to a method of using the same therapeutically in the treatment and/or prevention of ROCK-related disease.
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Page/Page column 34
(2008/06/13)
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- 7-MEMBERED RING COMPOUND, PROCESS FOR PRODUCING THE SAME, AND MEDICINAL USE THEREOF
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A 7-membered heterocyclic compound having the formula (I), or its salt, or a solvate thereof with a chymase inhibitory action and useful for the prevention or treatment of various diseases, in which chymase is involved: a method for producing the same, and a pharmaceutical composition useful for the prevention or treatment of diseases, in which chymase is involved, including the compound of having the formula (I), or its pharmaceutically acceptable salt, or a solvate thereof are provided.
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Page/Page column 94
(2008/06/13)
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- Efficient synthesis of β2-amino acid by homologation of α-amino acids involving the reformatsky reaction and Mannich-type imminium electrophile
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Development of new methods for the synthesis of β-amino acids is important as polymers of these compounds are promising peptidomimetic candidates in medicinal chemistry. We report here our findings on a new and highly efficient general strategy for the synthesis of β2-amino acids by homologation of α-amino acids, involving the Reformatsky reaction and Mannich-type imminium electrophile.
- Moumne, Roba,Lavielle, Solange,Karoyan, Philippe
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p. 3332 - 3334
(2007/10/03)
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- Application of Oppolzer's sultam in the synthesis of cyclic α-amino acids and β-amino acids
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In this paper we describe the application of Oppolzer's sultam as a chiral auxiliary for the synthesis of cyclic α- and β2-amino acids. The key step of the synthesis is stereoselective alkylation of sultam-derived glycine and β-alanine Schiffs bases leading to diastereometrically pure products. Final compounds are obtained after mild acidic and next basic hydrolyses of auxiliary groups and can be directly converted into N-tert-butoxycarbonyl- or N-fluorenylmethoxycarbonyl derivatives useful in peptide synthesis. In the case of substrates alkylated with dihalogenoalkanes spontaneous cyclization occurring during removal of the auxiliary groups yields cyclic α-amino acids (proline homologues) with reasonable yield and stereoselectivity. Theoretical data explain the differences in tendency for cyclization between α- and β-amino acids.
- Wozniak,Szymanska,Oldziej,Lankiewicz,Grzonka
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p. 265 - 277
(2007/10/03)
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- PHARMACEUTICAL COMPOUNDS
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The invention provides novel cryptophycin compounds which can be useful for disrupting the microtubulin system, as antineoplastic agents, and for the treatment of cancer. The invention further provides a formulation for administering the novel cryptophycin compounds.
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- Expanding the utility of proteases in synthesis: Broadening the substrate acceptance in non-coded amide bond formation using chemically modified mutants of subtilisin
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The strategy of combined site directed mutagenesis and chemical modification creates chemically modified mutants (CMMs) with greatly broadened substrate specificities. We have previously reported that the CMMs of subtilisin Bacillus lentus (SBL) are efficient catalysts for the coupling of both L- and D-amino acids. We now report that these powerful catalysts also allow amide bond formation between a variety of non-coded carboxylic acids, including β-alanine and β-amino homologues of phenylalanine, with both L- and D-amino acid nucleophiles. As a guide to enzyme efficiency, a hydrolysis assay indicating pH change has been employed. CMMs selected by this screen furnished higher yields of coupling products compared to the wild-type enzyme (WT). Furthermore, both WT and CMM enzymes allow highly stereoselective aminolysis of a meso diester with an amino acid amine. These results highlight the utility of CMMs in the efficient formation of non-coded amides as potential peptide isosteres.
- Khumtaveeporn, Kanjai,Ullmann, Astrid,Matsumoto, Kazutsugu,Davis, Benjamin G.,Jones
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p. 249 - 261
(2007/10/03)
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- Diastereoselective synthesis of β2-amino acids
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As part of an ongoing project concerning the synthesis of nonnatural amino acids, we have now developed a general strategy for the preparation of β2-amino acids (or 2-aminocarboxylic acid derivatives). Our procedure involves the synthesis of the sultam β-alaninate precursor 5 whose alkylation led with high yields and excellent diastereoselectivity to the precursor of β2-homophenylalanine, β2-homoalanine, and β2-homoleucine. Subsequent deprotection and Boc-protection yielded the expected β2-amino acids. X-ray analysis of the alkylation product established that (-)-sultam yielded (R)-β2-amino acids, conversely (+)-sultam yielded the enantiomer. The topicity of this alkylation is in agreement with the alkylation of Oppolzer's precursor for the synthesis of α-amino acids and opposite to that observed for gem-dialkylation.
- Ponsinet, Rachel,Chassaing, Gérard,Vaissermann, Jacqueline,Lavielle, Solange
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- A new methodology for the synthesis of β-amino acids
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A differentially functionalized succinic acid unit 6 undergoes alkylation with excellent regio- and high stereocontrol at the carbon α to the imide to furnish the alkylated product 7 in 60-83% yield. Selective removal of the imide provides 8 in 80-90% yie
- Sibi, Mukund P.,Deshpande, Prasad K.
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p. 1461 - 1466
(2007/10/03)
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- Resolution of 4-phenyl-2-pyrrolidinone: A versatile synthetic intermediate
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A resolution of 4-phenyl-2-pyrrolidinone is described. The resulting enantiomerically pure pyrrolidinones are exploited as precursor to 3-phenylpyrrolidines and 3-phenyl-γ-amino acids (4-amino-3-phenylbutanoic acid derivatives).
- Zelle
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p. 1023 - 1026
(2007/10/02)
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