- Engineering the large pocket of an (S)-selective transaminase for asymmetric synthesis of (S)-1-amino-1-phenylpropane
-
Amine transaminases offer an environmentally benign chiral amine asymmetric synthesis route. However, their catalytic efficiency towards bulky chiral amine asymmetric synthesis is limited by the natural geometric structure of the small pocket, representing a great challenge for industrial applications. Here, we rationally engineered the large binding pocket of an (S)-selective ?-transaminase BPTA fromParaburkholderia phymatumto relieve the inherent restriction caused by the small pocket and efficiently transform the prochiral aryl alkyl ketone 1-propiophenone with a small substituent larger than the methyl group. Based on combined molecular docking and dynamic simulation analyses, we identified a non-classical substrate conformation, located in the active site with steric hindrance and undesired interactions, to be responsible for the low catalytic efficiency. By relieving the steric barrier with W82A, we improved the specific activity by 14-times compared to WT. A p-p stacking interaction was then introduced by M78F and I284F to strengthen the binding affinity with a large binding pocket to balance the undesired interactions generated by F44. T440Q further enhanced the substrate affinity by providing a more hydrophobic and flexible environment close to the active site entry. Finally, we constructed a quadruple variant M78F/W82A/I284F/T440Q to generate the most productive substrate conformation. The 1-propiophenone catalytic efficiency of the mutant was enhanced by more than 470-times in terms ofkcat/KM, and the conversion increased from 1.3 to 94.4% compared with that of WT, without any stereoselectivity loss (ee > 99.9%). Meanwhile, the obtained mutant also showed significant activity improvements towards various aryl alkyl ketones with a small substituent larger than the methyl group ranging between 104- and 230-fold, demonstrating great potential for the efficient synthesis of enantiopure aryl alkyl amines with steric hindrance in the small binding pocket.
- Liu, He,Wang, Hualei,Wei, Dongzhi,Xie, Youyu,Xu, Feng,Xu, Xiangyang,Yang, Lin
-
p. 2461 - 2470
(2021/04/22)
-
- Direct reductive amination of ketones with ammonium salt catalysed by Cp*Ir(iii) complexes bearing an amidato ligand
-
A series of half-sandwich Ir(iii) complexes1-6bearing an amidato bidentate ligand were conveniently synthesized and applied to the catalytic Leuckart-Wallach reaction to produce racemic α-chiral primary amines. With 0.1 mol% of complex1, a broad range of ketones, including aryl ketones, dialkyl ketones, cyclic ketones, α-keto acids, α-keto esters and diketones, could be transformed to their corresponding primary amines with moderate to excellent yields (40%-95%). Asymmetric transformation was also attempted with chiral Ir complexes3-6, and 16% ee of the desired primary amine was obtained. Despite the unsatisfactory enantio-control achieved so far, the current exploration might stimulate more efforts towards the discovery of better chiral catalysts for this challenging but important transformation.
- Dai, Zengjin,Pan, Ying-Min,Wang, Shou-Guo,Yin, Qin,Zhang, Xumu
-
supporting information
p. 8934 - 8939
(2021/11/04)
-
- Catalytic asymmetric oxidative carbonylation-induced kinetic resolution of sterically hindered benzylamines to chiral isoindolinones
-
A highly enantioselective kinetic resolution of sterically hindered benzylamines has been achieved for the first time through transition-metal-catalyzed oxidative carbonylation, in which the new KR strategy offered a new approach to afford chiral isoindolinones (er up to 97?:?3) and the origin of chemoselectivity and stereoselectivity was confirmed by density functional theory (DFT) calculations.
- Mu, Qiu-Qi,Nie, Yi-Xue,Li, Hang,Bai, Xing-Feng,Liu, Xue-Wei,Xu, Zheng,Xu, Li-Wen
-
supporting information
p. 1778 - 1781
(2021/02/27)
-
- General and selective synthesis of primary amines using Ni-based homogeneous catalysts
-
The development of base metal catalysts for industrially relevant amination and hydrogenation reactions by applying abundant and atom economical reagents continues to be important for the cost-effective and sustainable synthesis of amines which represent highly essential chemicals. In particular, the synthesis of primary amines is of central importance because these compounds serve as key precursors and central intermediates to produce value-added fine and bulk chemicals as well as pharmaceuticals, agrochemicals and materials. Here we report a Ni-triphos complex as the first Ni-based homogeneous catalyst for both reductive amination of carbonyl compounds with ammonia and hydrogenation of nitroarenes to prepare all kinds of primary amines. Remarkably, this Ni-complex enabled the synthesis of functionalized and structurally diverse benzylic, heterocyclic and aliphatic linear and branched primary amines as well as aromatic primary amines starting from inexpensive and easily accessible carbonyl compounds (aldehydes and ketones) and nitroarenes using ammonia and molecular hydrogen. This Ni-catalyzed reductive amination methodology has been applied for the amination of more complex pharmaceuticals and steroid derivatives. Detailed DFT computations have been performed for the Ni-triphos based reductive amination reaction, and they revealed that the overall reaction has an inner-sphere mechanism with H2metathesis as the rate-determining step.
- Beller, Matthias,Chandrashekhar, Vishwas G.,Jagadeesh, Rajenahally V.,Jiao, Haijun,Murugesan, Kathiravan,Wei, Zhihong
-
p. 4332 - 4339
(2020/05/18)
-
- Combinatorial Mutation Analysis of ω-Transaminase to Create an Engineered Variant Capable of Asymmetric Amination of Isobutyrophenone
-
ω-Transaminase (ω-TA) is an important enzyme for asymmetric synthesis of chiral amines. Rapid creation of a desirable ω-TA variant, readily available for scalable process operation, is demanded and has attracted intense research efforts. In this study, we aimed to develop a quantitative mutational analysis (i. e., R-analysis) that enables prediction of combinatorial mutation outcomes and thereby provides reliable guidance of enzyme engineering through combination of already characterized mutations. To this end, we determined three mutatable active-site residues of ω-TA from Ochrobactrum anthropi (i. e., leucine 57, tryptophan 58 and valine 154) by examining activities of nine alanine-scanning mutants for seven substrate pairs. The R-analysis of the mutatable residues is based on assessment of changes in relative activities for a series of structurally analogous substrates. Using three sets of substrates (five α-keto acids, six arylalkylamines and three arylalkyl ketones), we found that combination of two point mutations display additive effects of each mutational outcome such as steric relaxation for bulky substrates or catalytic enhancement for amination of ketones. Consistent with the R-analysis-based prediction, the ω-TA variant harboring triple alanine mutations, i. e. L57A, W58A and V154A, showed high activity improvements for bulky substrates, e. g. a 3.2×104-fold activity increase for 1-phenylbutylamine. The triple mutant even enabled asymmetric amination of isobutyrophenone, carrying a branched-chain alkyl substituent to be accepted in a small binding pocket that normally shows a steric limit up to an ethyl group, with >99% ee of a resulting (S)-amine. (Figure presented.).
- Kim, Hong-Gon,Han, Sang-Woo,Shin, Jong-Shik
-
p. 2594 - 2606
(2019/05/15)
-
- Rapid and Quantitative Profiling of Substrate Specificity of ω-Transaminases for Ketones
-
ω-Transaminases (ω-TAs) have gained growing attention owing to their capability for asymmetric synthesis of chiral amines from ketones. Reliable high-throughput activity assay of ω-TAs is essential in carrying out extensive substrate profiling and establishing a robust screening platform. Here we report spectrophotometric and colorimetric methods enabling rapid quantitation of ω-TA activities toward ketones in a 96-well microplate format. The assay methods employ benzylamine, a reactive amino donor for ω-TAs, as a cosubstrate and exploit aldehyde dehydrogenase (ALDH) as a reporter enzyme, leading to formation of benzaldehyde detectable by ALDH owing to concomitant NADH generation. Spectrophotometric substrate profiling of two wild-type ω-TAs of opposite stereoselectivity was carried out at 340 nm with 22 ketones, revealing subtle differences in substrate specificities that were consistent with docking simulation results obtained with cognate amines. Colorimetric readout for naked eye detection of the ω-TA activity was also demonstrated by supplementing the assay mixture with color-developing reagents whose color reaction could be quantified at 580 nm. The colorimetric assay was applied to substrate profiling of an engineered ω-TA for 24 ketones, leading to rapid identification of reactive ketones. The ALDH-based assay is expected to be promising for high-throughput screening of enzyme collections and mutant libraries to fish out the best ω-TA candidate as well as to tailor enzyme properties for efficient amination of a target ketone.
- Han, Sang-Woo,Shin, Jong-Shik
-
p. 3287 - 3295
(2019/06/21)
-
- Reductive amination of ketonic compounds catalyzed by Cp*Ir(III) complexes bearing a picolinamidato ligand
-
Cp*Ir complexes bearing a 2-picolinamide moiety serve as effective catalysts for the direct reductive amination of ketonic compounds to give primary amines under transfer hydrogenation conditions using ammonium formate as both the nitrogen and hydrogen source. The clean and operationally simple transformation proceeds with a substrate to catalyst molar ratio (S/C) of up to 20,000 at relatively low temperature and exhibits excellent chemoselectivity toward primary amines.
- Tanaka, Kouichi,Miki, Takashi,Murata, Kunihiko,Yamaguchi, Ayumi,Kayaki, Yoshihito,Kuwata, Shigeki,Ikariya, Takao,Watanabe, Masahito
-
p. 10962 - 10977
(2019/09/03)
-
- Axial stereocontrol in: Tropos dibenz [c, e] azepines: The individual and cooperative effects of alkyl substituents
-
6,7-Dihydro-5H-dibenz[c,e]azepines, a class of secondary amine incorporating a centre-axis chirality relay, can be prepared from N-(2-bromobenzyl)-N-(1-arylalkyl)methanesulfonamides via Pd-catalysed intramolecular direct arylation, and methylated at C(7)
- Balgobin, Sinead M. C.,Brookes, Dominic J.,Jiang, Junxiang,Pritchard, Robin G.,Wallace, Timothy W.
-
supporting information
p. 10184 - 10199
(2017/12/26)
-
- Asymmetric radical alkylation of: N -sulfinimines under visible light photocatalytic conditions
-
In this communication, a new photocatalytic strategy for the addition of alkyl-radical derivatives to N-sulfinimines with complete diastereoselectivity and moderate to good yields is presented. This is the first asymmetric photocatalytic addition to N-sulfinimines under visible light irradiation with smooth conditions and functional group tolerance.
- Garrido-Castro, Alberto F.,Choubane, Houcine,Daaou, Mortada,Maestro, M. Carmen,Alemán, José
-
p. 7764 - 7767
(2017/07/13)
-
- Methods and Intermediates Useful for the Preparation of alpha-Branched Aryl Phthalimides and alpha-Branched Aryl Amines
-
The invention provides methods and intermediates that are useful for preparing α-branched aryl phthalimides and α-branched aryl amines.
- -
-
Paragraph 0117; 0118
(2016/08/17)
-
- Microwave-Enhanced Asymmetric Transfer Hydrogenation of N-(tert-Butylsulfinyl)imines
-
Microwave irradiation has considerably enhanced the efficiency of the asymmetric transfer hydrogenation of N-(tert-butylsulfinyl)imines in isopropyl alcohol catalyzed by a ruthenium complex bearing the achiral ligand 2-amino-2-methylpropan-1-ol. In addition to shortening reaction times for the transfer hydrogenation processes to only 30 min, the amounts of ruthenium catalyst and isopropyl alcohol can be considerably reduced in comparison with our previous procedure assisted by conventional heating, which diminishes the environmental impact of this new protocol. This methodology can be applied to aromatic, heteroaromatic and aliphatic N-(tert-butylsulfinyl)ketimines, leading, after desulfinylation, to the expected primary amines in excellent yields and with enantiomeric excesses of up to 96 %. Microwave irradiation promotes the asymmetric transfer hydrogenation of N-(tert-butylsulfinyl)imines in 2-propanol catalysed by a ruthenium complex bearing an achiral β-amino alcohol as ligand. After desulfinylation, α-branched primary amines containing aromatic, heteroaromatic and aliphatic substituents are obtained in excellent yields and with enantiomeric excesses of up to 96 %.
- Pablo, Oscar,Guijarro, David,Yus, Miguel
-
p. 7034 - 7038
(2016/02/19)
-
- Structure-activity study leading to identification of a highly active thienopyrimidine based EGFR inhibitor
-
Based on the thieno[2,3-d]pyrimidine scaffold, a series of new 4-amino-6-aryl thienopyrimidines have been prepared and evaluated as EGFR tyrosine kinase inhibitors. The in vitro activity was found to depend strongly on the substitution pattern in the 6-aryl ring, the stereochemistry, and the basicity at the secondary 4-amino group. A stepwise optimization by combination of active fragments led to the discovery of three structures with EGFR IC 50 50 of 0.3 nM towards EGFR and its mutants L858R and L861Q. Studies using human cancer cell lines and an EGFR-L858R reporter cell system revealed good cellular potency, verifying the identified thienopyrimidines as promising lead structures.
- Bugge, Steffen,Kaspersen, Svein Jacob,Larsen, Synne,Nonstad, Unni,Bj?rk?y, Geir,Sundby, Eirik,Hoff, B?rd Helge
-
p. 354 - 374
(2014/03/21)
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- A versatile Ru catalyst for the asymmetric transfer hydrogenation of both aromatic and aliphatic sulfinylimines
-
A highly efficient Ru catalyst based on an achiral, very simple, and inexpensive amino alcohol ligand (2-amino-2-methylpropan-1-ol) has been developed for the asymmetric transfer hydrogenation (ATH) of chiral N-(tert-butylsulfinyl)imines. This complex is able to catalyze the ATH of both aromatic and the most challenging aliphatic sulfinylimines by using isopropyl alcohol as the hydrogen source. The diastereoselective reduction of aromatic, heteroaromatic, and aliphatic sulfinylketimines, including sterically congested cases, over short reaction times (1-4 h), followed by desulfinylation of the nitrogen atom, affords the corresponding highly enantiomerically enriched (ee up to >99%) α-branched primary amines in excellent yields. The same ligand was equally effective for the synthesis of both (R)- and (S)-amines by using the appropriate absolute configuration in the iminic substrate. DFT mechanistic studies show that the hydrogen-transfer process is stepwise. Moreover, the origin of the diastereoselectivity has been rationalized.
- Pablo, Oscar,Guijarro, David,Kovacs, Gabor,Lledos, Agusti,Ujaque, Gregori,Yus, Miguel
-
supporting information; experimental part
p. 1969 - 1983
(2012/03/26)
-
- One-pot synthesis of chiral nonracemic amines
-
One-pot five-component reactions of oxathiazolidine-S-oxides with mesitylmagnesium bromide, lithium bis(trimethylsilyl)amide, aldehydes and Grignard reagents afford chiral nonracemic amines or sulfinamides in good yields and high stereoselectivities.
- Roe, Caroline,Hobbs, Heather,Stockman, Robert A.
-
experimental part
p. 9452 - 9459
(2012/01/06)
-
- N-Substituted acetamidines and 2-methylimidazole derivatives as selective inhibitors of neuronal nitric oxide synthase
-
A series of N-substituted acetamidines and 2-methylimidazole derivatives structurally related to W1400 were synthesized and evaluated as Nitric Oxide Synthase (NOS) inhibitors. Analogs with sterically hindering isopropyl and phenyl substituents on the benzylic carbon connecting the aromatic core of W1400 to the acetamidine nitrogen, showed good inhibitory potency for nNOS (IC 50= 0.2 and 0.3 μM) and selectivity over eNOS (500 and 1166) and to a lesser extent over iNOS (50 and 100). A molecular modeling study allowed to shed light on the effects of the structural modifications on the selectivity of the designed inhibitors toward the different NOS isoforms.
- MacCallini, Cristina,Patruno, Antonia,Lannutti, Fabio,Ammazzalorso, Alessandra,De Filippis, Barbara,Fantacuzzi, Marialuigia,Franceschelli, Sara,Giampietro, Letizia,Masella, Simona,Felaco, Mario,Re, Nazzareno,Amoroso, Rosa
-
supporting information; experimental part
p. 6495 - 6499
(2011/02/16)
-
- A versatile catalyst for reductive animation by transfer hydrogenation
-
An iridium catalyst enables the reductive amination of carbonyl groups with unprecedented substrate scope, selectivity, and activity using formic acid as the hydrogen source (see scheme) The catalyst system provides significant improvement over commonly used boron hydrides.
- Wang, Chao,Pettman, Alan,Basca, John,Xiao, Jianliang
-
supporting information; experimental part
p. 7548 - 7552
(2010/12/19)
-
- BICYCLIC HETEROCYCLE DERIVATIVES AND USE THEREOF AS GPR119 MODULATORS
-
The present invention relates to Bicyclic Heterocycle Derivatives of formula (I), compositions comprising a Bicyclic Heterocycle Derivative, and methods of using the Bicyclic Heterocycle Derivatives for treating or preventing obesity, diabetes, a metabolic disorder, a cardiovascular disease or a disorder related to the activity of GPR1 19 in a patient.
- -
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Page/Page column 172
(2009/12/27)
-
- Alternative and complementary approaches to the asymmetric synthesis of C3 substituted NH free or N-substituted isoindolin-1-ones
-
Complementary synthetic approaches to enantiomerically pure C3 alkylated or arylated NH free or N-substituted isoindolinones have been developed. The key step is elaboration of diversely substituted 2-alkyl- and arylbenzylamines, which can be submitted to a bis-metallation process followed by interception with a carbonylating agent. They can be also converted into N-alkylbromobenzylcarbamates or into bromobenzyldicarbamates and the assembly of the titled compounds can be readily ensured by reliance upon the Parham cyclization process.
- Lamblin, Marc,Couture, Axel,Deniau, Eric,Grandclaudon, Pierre
-
p. 111 - 123
(2008/09/17)
-
- New C5-alkylated indolobenzazepinones acting as inhibitors of tubulin polymerization: Cytotoxic and antitumor activities
-
A series of 5-alkylindolobenzazepin-7-ones was synthesized by Suzuki coupling between 3-iodoindole-2-carboxylates and the appropriate α-alkylbenzylamino α-boronic acids followed by cyclization to the lactam. Derivatives having a linear alkyl chain at C5 were found to be highly cytotoxic to KB cells with IC50 values in the 30-80 nM range. These compounds also inhibited the polymerization of tubulin with IC50's of 1-2 μM. Compound 4f ((S)-5-ethyl) showed comparable antiproliferative activities (IC50's of 30-70 nM) in a variety of cancer cell lines, cell growth being arrested at the G2/M phase. Compound 4f induced apoptosis in a dose-dependent manner in three different cancer cell lines and was shown to affect cell morphology in a manner consistent with its inhibitory action on tubulin polymerization. Using the experimental model of glioma grafted on the chick chorio-allantoic membrane, local treatment with compound 4f markedly reduced tumor progression.
- Keller, Laurent,Beaumont, Stéphane,Liu, Jian-Miao,Thoret, Sylviane,Bignon, Jér?me S.,Wdzieczak-Bakala, Joanna,Dauban, Philippe,Dodd, Robert H.
-
supporting information; experimental part
p. 3414 - 3421
(2009/05/26)
-
- Synthesis of highly enantiomerically enriched amines by the diastereoselective addition of triorganozincates to N-(tert-butanesulfinyl)imines
-
The reaction of triorganozincates with (R)-N-(tert-butanesulfinyl) imines gives the expected α-branched sulfinamides in good to excellent yields with diastereomeric ratios of up to 98:2. The N-sulfinyl group of the products can be easily removed by acidic treatment, affording the corresponding chiral primary amines in enantiomeric excesses of up to 96%. The reactivity and the selectivity shown by the triorganozincates are different from the ones observed with the corresponding Grignard reagents, which allows, in several cases, the preparation of both enantiomers of an amine from the same imine substrate. When mixed triorganozincates are used, one can take advantage of the slow transfer rate of the methyl group to use it as a non-transferable one. Both aromatic and aliphatic aldimines, as well as activated ketimines, are good substrates for these addition reactions.
- Almansa, Raquel,Guijarro, David,Yus, Miguel
-
experimental part
p. 2484 - 2491
(2009/04/11)
-
- Triorganozincates as efficient nucleophiles for the diastereoselective addition to N-(tert-butanesulfinyl)imines
-
Triorganozincates, generated by mixing a Grignard reagent and a dialkylzinc reagent, effectively react with (R)-N-(tert-butanesulfinyl)benzaldimine to give the expected α-branched sulfinamides in good to excellent yields and with diastereomeric ratios of up to 98:2. When the R group of the organomagnesium and the R′ group of the diorganozinc are different, the selective transfer of only one of them to the imine can be achieved by the proper choice of the organometallic reagents. One can take advantage of the slow transfer rate of the methyl group to use it as a non-transferable one. The N-sulfinyl group of the products can be easily removed by acidic treatment, affording the corresponding chiral primary amines without the loss in enantiomeric purity.
- Almansa, Raquel,Guijarro, David,Yus, Miguel
-
p. 603 - 606
(2008/09/19)
-
- Highly enantioselective radical addition to N-benzoyl hydrazones using chiral ammonium salts
-
In the presence of a protonated cinchonine derivative, radical addition reactions proceeded efficiently, affording addition adducts in high yields with an extremely high enantioselectivity. The chiral ammonium salt was recyclable after a simple aqueous workup. The reaction provides environmentally benign reaction conditions. Copyright
- Doo, Ok Jang,Sang, Yoon Kim
-
supporting information; experimental part
p. 16152 - 16153
(2009/05/08)
-
- Indium - Copper-mediated barbier - Grignard-type alkylation reaction of imines in aqueous media
-
An efficient system of In/Cul/InCl3 was developed for Barbier-Grignard-type alkylation reactions of simple imines, using a one-pot condensation of various aldehydes, amines (including aliphatic and chiral version), and alkyl iodides in water or
- Shen, Zhi-Liang,Loh, Teck-Peng
-
p. 5413 - 5416
(2008/09/17)
-
- Enantioselective synthesis of protected amines by the catalytic asymmetric addition of hydrazoic acid to ketenes
-
(Chemical Equation Presented) A-mine of possibilities: An effective method for the conversion of achiral ketenes into enantioenriched protected amines was developed by tuning the structure and reactivity of a catalyst on the basis of a mechanistic hypothe
- Dai, Xing,Nakai, Takashi,Romero, Jan A. C.,Fu, Gregory C.
-
p. 4367 - 4369
(2008/03/12)
-
- Selective diethylzinc reduction of imines in the presence of ketones catalyzed by Ni(acac)2
-
(Chemical Equation Presented) A selective reduction method of an electronically deficient imine in the presence of ketone was developed by employing Et2Zn and 5 mol % of Ni(acac)2. The method was applied in the reduction of SS-tert-butanesulfinyl ketimines 1 to afford amines 2 in 23-92% yields and 73:27 to 98:2 diastereoselectivities. A plausible mechanism was proposed on the basis of an NMR study.
- Xiao, Xue,Wang, Haowei,Huang, Zhiyan,Yang, Jun,Bian, Xiaoxia,Qin, Yong
-
p. 139 - 142
(2007/10/03)
-
- SUBSTITUTED ARYLAMINE COMPOUNDS AND THEIR USE AS 5-HT6 MODULATORS
-
The invention relates to 5-HT6 receptor antagonists. Novel arylamine compounds having the formula: (see formula I) and pharmaceutically acceptable salts and/or esters thereof, wherein - n is 0, 1, 2, 3, or 4; - A, when present is a lower alkyl
- -
-
Page/Page column 50-51
(2008/06/13)
-
- 2-[3-[2-[(25)-2-cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl] -1,2,3,4-tetrahydroisoquinoline: A potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV
-
Dipeptidyl peptidase IV (DPP-IV) inhibitors are expected to become a new type of antidiabetic drugs. Most known DPP-IV inhibitors often resemble the dipeptide cleavage products, with a proline mimic at the P1 site. As off-target inhibitions of DPP8 and/or DPP9 have shown profound toxicities in the in vivo studies, it is important to develop selective DPP-IV inhibitors for clinical usage. To achieve this, a new class of 2-[3-[[2-[(2S)-2-cyano-1-pyrrolidinyl]-2- oxoethyl]amino]-1-oxopropyl]-based DPP-IV inhibitors was synthesized. SAR studies resulted in a number of DPP-IV inhibitors, having IC50 values of 50 > 100 μM) and DPP-II (IC50 > 30 μM). Compound 21a suppressed the blood glucose elevation after an oral glucose challenge in Wistar rats and also inhibited plasma DPP-IV activity for up to 4 h in BALB/c mice. The results show that compound 21a possesses in vitro and in vivo activities comparable to those of NVP-LAF237 (4), which is in clinical development. 2006 American Chemical Society.
- Tsu, Hsu,Chen, Xin,Chen, Chiung-Tong,Lee, Shiow-Ju,Chang, Chung-Nien,Kao, Kuo-His,Coumar, Mohane Selvaraj,Yeh, Yen-Ting,Chien, Chia-Hui,Wang, Hsin-Sheng,Lin, Ke-Ta,Chang, Ying-Ying,Wu, Ssu-Hui,Chen, Yuan-Shou,Lu, I.-Lin,Wu, Su-Ying,Tsai, Ting-Yueh,Chen, Wei-Cheng,Hsieh, Hsing-Pang,Chao, Yu-Sheng,Jiaang, Weir-Torn
-
p. 373 - 380
(2007/10/03)
-
- The dutch resolution variant of the classical resolution of racemates by formation of diastereomeric salts: Family behaviour in nucleation inhibition
-
The resolution of racemates through their diastereomeric salts can be positively affected by the addition of small amounts of suitable nucleation inhibitors. This discovery is a logical extension of "Dutch Resolution", in which equimolar amounts of resolving agents that are members of the same family (i.e., structurally related) are used. We conducted a systematic search for nucleation inhibitors of the resolving agent 1-phenylethylamine. A wide range of amines that bear possible family resemblances to 1-phenylethylamine was investigated. It was found that (R)-1-phenylbutylamine is a good inhibitor of (R)-1-phenylethylamine. Results of turbidity measurements showed that, for the model case of mandelic acid resolution, the chief effect of this inhibitor was to widen the metastable zone for the more soluble diastereomer. This observation is in accordance with previous experience. Further scouting for possible family members revealed a wide variation in the effectiveness of inhibitors, dependent on their structure. By far the most effective inhibitors are bifunctional 1-phenylethylamine and/or 1-phenylbutylamine analogues. The effect of racemic inhibitors was found to approach that of enantiomerically pure inhibitors of the same absolute configuration of the 1-phenylethylamine used for resolution. The most effective inhibitors were tested for the resolution of a structural variety of racemates, and were shown to be broadly applicable.
- Dalmolen, Jan,Tiemersma-Wegman, Theodora D.,Nieuwenhuijzen, Jose W.,Van Der Sluis, Marcel,Van Echten, Erik,Vries, Ton R.,Kaptein, Bernard,Broxterman, Quirinius B.,Kellogg, Richard M.
-
p. 5619 - 5624
(2007/10/03)
-
- QUINOLINE 4-CARBOXAMIDE DERIVATIVES AND THEIR USE AS NEUROKININ 3 (NK-3) RECEPTOR ANTAGONISTS
-
The invention relates to novel quinoline derivatives, processes for their preparation, pharmaceutical compositions containing them and their use as medicaments particularly in treating disorders of the central nervous system (CNS).
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-
Page/Page column 21
(2010/02/10)
-
- Kinetic resolution of amines: A highly enantioselective and chemoselective acetylating agent with a unique solvent-induced reversal of stereoselectivity
-
Solvents lend a hand: Changing the polarity of the reaction solvent from 1,3-dimethyltetrahydropyrimidin-2-one (DMPU) to toluene reverses the stereo-selectivity observed in the acetylation of amines with (1S,2S)-1 (see scheme). Optimizing the reaction conditions led to an unprecedented 90% ee (S) in DMPU at -20°C with a 33% conversion.
- Arseniyadis, Stellios,Valleix, Alain,Wagner, Alain,Mioskowski, Charles
-
p. 3314 - 3317
(2007/10/03)
-
- THIADIAZOLEDIOXIDES AND THIADIAZOLEOXIDES AS CXC- AND CC-CHEMOKINE RECEPTOR LIGANDS
-
Disclosed are novel compounds of the formula (IA) and the pharmaceutically acceptable salts and solvates thereof. Examples of groups comprising Substituent A include heteroaryl, aryl, heterocycloalkyl, cycloalkyl, aryl, alkynyl, alkenyl, aminoalkyl, alkyl or amino. Examples of groups comprising Substituent B include aryl and heteroaryl. Also disclosed is a method of treating a chemokine mediated diseases, such as, cancer, angiogenisis, angiogenic ocular diseases, pulmonary diseases, multiple sclerosis, rheumatoid arthritis, osteoarthritis, stroke and cardiac reperfusion injury, acute pain, acute and chronic inflammatory pain, and neuropathic pain using a compound of formula (IA).
- -
-
-
- 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
-
There are disclosed compounds of the formula or a pharmaceutically acceptable salt or solvate thereof which are useful for the treatment of chemokine-mediated diseases such as acute and chronic inflammatory disorders and cancer.
- -
-
Page 140; 142
(2008/06/13)
-
- 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
-
There are disclosed compounds of the formula or a pharmaceutically acceptable salt or solvate thereof which are useful for the treatment of chemokine-mediated diseases such as acute and chronic inflammatory disorders and cancer.
- -
-
-
- Asymmetric synthesis of N-protected amino acids by the addition of organolithium carboxyl synthons to ROPHy/SOPHy-derived aldoximes and ketoximes.
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A new asymmetric synthesis of alpha-amino acids is described in which the key step is the highly diastereoselective addition of organolithium carboxyl synthons (2-furyllithium, phenyllithium, vinyllithium) to (R)- and (S)-O-(1-phenylbutyl) oximes to give hydroxylamines, with vinyllithium being the most satisfactory nucleophilic reagent. Subsequent reductive cleavage of the N-O bond in hydroxylamines, followed by N-protection, and oxidative cleavage of the carboxyl precursor gave a range of N-protected amino acids and esters. The method was exemplified by the synthesis of a range of derivatives of non-proteinogenic amino acids such as 4-bromophenylalanine, tert-leucine, norvaline, cyclohexyl- and aryl-glycines, 2-amino-8-oxodecanoic acid (Aoda) and alpha-methylvaline.
- Cooper, Tracey S,Laurent, Pierre,Moody, Christopher J,Takle, Andrew K
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p. 265 - 276
(2007/10/03)
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- Synthesis and structure-activity relationships of potential anticonvulsants based on 2-piperidinecarboxylic acid and related pharmacophores
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Using N-(2,6-dimethyl)phenyl-2-piperidinecarboxamide (1) and N-(α-methylbenzyl)-2-piperidinecarboxamide (2) as structural leads, a variety of analogues were synthesised and evaluated for anticonvulsant activity in the MES test in mice. In the N-benzyl series, introduction of 3-Cl, 4-Cl, 3,4-Cl2, or 3-CF3 groups on the aromatic ring led to an increase in MES activity. Replacement of the α-methyl group by either i-Pr or benzyl groups enhanced MES activity with no increase in neurotoxicity. Substitution on the piperidine ring nitrogen led to a decrease in MES activity and neurotoxicity, while reduction of the amide carbonyl led to a complete loss of activity. Movement of the carboxamide group to either the 3- or 4-positions of the piperidine ring decreased MES activity and neurotoxicity. Incorporation of the piperidine ring into a tetrahydroisoquinoline or diazahydrinone nucleus led to increased neurotoxicity. In the N-(2,6-dimethyl)phenyl series, opening of the piperidine ring between the 1- and 6-positions gave the active norleucine derivative 75 (ED50 = 5.8 mg kg-1, TD50 = 36.4 mg kg-1, PI = 6.3). Replacement of the piperidine ring of 1 by cycloalkane (cyclohexane, cyclopentane, and cyclobutane) resulted in compounds with decreased MES activity and neurotoxicity, whereas replacement of the piperidine ring by a 4-pyridyl group led to a retention of MES activity with a comparable PI. Simplification of the 2-piperidinecarboxamide nucleus of 1 into a glycinecarboxamide nucleus led to about a six-fold decrease in MES activity. The 2,6-dimethylanilides were the most potent compounds in the MES test in each group of compounds evaluated, and compounds 50 and 75 should be useful leads in the development of agents for the treatment of tonic-clonic and partial seizures in man.
- Ho, Bin,Michael Crider,Stables, James P
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p. 265 - 286
(2007/10/03)
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- Discovery of a novel class of selective non-peptide antagonists for the human neurokinin-3 receptor. 2. Identification of (S)-N-(1-phenylpropyl)-3- hydroxy-2-phenylquinoline-4-carboxamide (SB 223412)
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Optimization of the previously reported 2-phenyl-4-quinolinecarboxamide NK-3 receptor antagonist 14, with regard to potential metabolic instability of the ester moiety and affinity and selectivity for the human neurokinin-3 (hNK-3) receptor, is described. The ester functionality could be successfully replaced by the ketone (31) or by lower alkyl groups (Et, 21, or n-Pr, 24). Investigation of the substitution pattern of the quinoline ring resulted in the identification of position 3 as a key position to enhance hNK-3 binding affinity and selectivity for the hNK-3 versus the hNK-2 receptor. All of the chemical groups introduced at this position, with the exception of halogens, increased the hNK-3 binding affinity, and compounds 53 (3-OH, SB 223412, hNK- 3-CHO binding K(i) = 1.4 nM) and 55 (3-NH2, hNK-3-CHO binding K(i) = 1.2 nM) were the most potent compounds of this series. Selectivity studies versus the other neurokinin receptors (hNK-2-CHO and hNK-1-CHO) revealed that 53 is about 100-fold selective for the hNK-3 versus hNK-2 receptor, with no affinity for the hNK-1 at concentrations up to 100 μM. In vitro studies demonstrated that 53 is a potent functional antagonist of the hNK-3 receptor (reversal of senktide-induced contractions in rabbit isolated iris sphincter muscles and reversal of NKB-induced Ca2+ mobilization in CHO cells stably expressing the hNK-3 receptor), while in vive this compound showed oral and intravenous activity in NK-3 receptor-driven models (senktide-induced behavioral responses in mice and senktide-induced miosis in rabbits). Overall, the biological data indicate that (S)-N-(1-phenylpropyl)-3-hydroxy- 2-phenylquinoline-4-carboxamide (53, SB 223412) may serve as a pharmacological tool in animal models of disease to assess the functional and pathophysiological role of the NK-3 receptor and to establish therapeutic indications for non-peptide NK-3 receptor antagonists.
- Giardina, Giuseppe A. M.,Raveglia, Luca F.,Grugni, Mario,Sarau, Henry M.,Farina, Carlo,Medhurst, Andrew D.,Graziani, Davide,Schmidt, Dulcie B.,Rigolio, Roberto,Luttmann, Mark,Cavagnera, Stefano,Foley, James J.,Vecchietti, Vittorio,Hay, Douglas W. P.
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p. 1053 - 1065
(2007/10/03)
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- Reduction of amines with isopropylidene glycerol hydrogen phthalate
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The hydrogen phthalate of isopropylidene glycerol has been recently described as an efficient resolving agent of 1-arylethylamines. In order to gain more information on its versatility and to develop a rationale which accounts for its effectiveness, further 1-arylethylamines and other racemic amines were subjected to the same resolution process. A preliminary qualitative analysis of the results reported herein allows to identify some structural features of the aminic substrates conditioning the feasibility of the resolution.
- Pallavicini, Marco,Valoti, Ermanno,Villa, Luigi,Piccolo, Oreste
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p. 1069 - 1073
(2007/10/03)
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- Asymmetric synthesis of amines using a chiral, non-racemic, benzylidene sulfinamide derived from a recoverable precursor
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The homochiral cyclic sulfinamide S(S)R-(+)-1 has been employed for the asymmetric synthesis of α-substituted benzylamines via the benzylidene sulfinamides R(S)R-(-)-4. Following diastereoselective reduction and hydrolysis S(S)R-(+)-1 can be recycled in one step from the sulfinic acid 11. The addition of zinc(II) bromide reverses the diastereoselectivity of the diisobutylaluminium hydride (DIBAL) reduction of the substrates 4. The same reversal is not observed in the reactions of analogues lacking an amide side chain. In one case the required benzylidene sulfinamide exists in the form of an enamine 15, the X-ray crystallographic structure of which is also featured. A second approach to chiral amines, via the addition of Grignard reagents to sulfinylamines derived from S(S)R-(+)-1, is also described.
- Hose, David R. J.,Mahon, Mary F.,Molloy, Kieran C.,Raynham, Tony,Wills, Martin
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p. 691 - 703
(2007/10/03)
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- Diastereoselective addition of chiral aliphatic imines and 2-alkyl-1,3-oxazolidines to organometallic reagents
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The reaction of organocerium reagents with chiral aliphatic imines derived from (R)-O-methylphenylglycinol afforded the corresponding amines with high diastereoselectivity. In contrast, the reaction of Grignard reagents with chiral 2-alkyl-1,3-oxazolidines derived from (R)-N-methylphenylglycinol afforded the amines with changeover in diastereoselectivity.
- Higashiyama,Fujikura,Takahashi
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p. 722 - 728
(2007/10/02)
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- Application of New Camphor-Derived Mercapto Chiral Auxiliaries to the Synthesis of Optically Active Primary Amines
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A series enantiomerically pure sulfinimines carrying new camphor-based mercapto chiral auxiliaries are subjected to assymetric alkylation.Such reaction offers an excellent route to the preparation of optically active primary amines.Also reported here is an unprecedented Grignard addition of a chiral sulfenimine leading to a single enantiomer of the corresponding sulfenamide and thence produced enantiopure amine after acidic aqueous workup.The chiral auxiliary can be recovered in high yield.
- Yang, Teng-Kuei,Chen, Ruey-Yuan,Lee, Dong-Sheng,Peng, Wen-Shiuan,Jiang, Yao-Zhong,et al.
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p. 914 - 921
(2007/10/02)
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- An efficient and enantioselective synthesis of a chiral primary amine
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An efficient and enantioselective method for the preparation of a chiral primary amine has been developed. Starting from N-protected L or D-amino acid the sequence involves coupling with N-methoxy-N-methylamine, acylation, olefination with potassium bis(trimethylsilyl)amide, and hydrogenation.
- Son, Youngchan,Park, Chihyo,Koh, Jong Sung,Choy, Nakyen,Lee, Chang S.,Choi, Ho-Il,Kim, Sung Chun,Yoon, Heungsik
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p. 3745 - 3746
(2007/10/02)
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- Synthesis of α,α-Disubstituted α-Amino Acid Amides by Phase-Transfer Catalyzed Alkylation
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α,α-Disubstituted α-amino acid amides were prepared in 17-88 percent chemical yield by the phase-transfer catalyzed alkylation of N-benzylidene α-H amino acid amides, followed by weak acidic hydrolysis of the Schiff bases.
- Kaptein, Bernard,Boesten, Wilhelmus H. J.,Broxterman, Quirinus B.,Schoemaker, Hans E.,Kamphuis, Johan
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p. 6007 - 6010
(2007/10/02)
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- ASYMETRIC SYNTHESIS X: THE HIGH ENANTIOSELECTIVE SYNTHESIS OF (R)-α-SUBSTITUTED BENZYLIC AMINES VIA THE MODIFIED (+)-CAMPHOR DERIVATIVE AS CHIRAL SYNTHON
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A new chiral synthon-10-substituted (+)-camphor derivative (III) is synthesized.The alkylation of the (III) with a variety of alkylating agents gives the high enantioselectivity ranging from 72-100percent e.e..And the crystal structures of the (III) and (IV) are involved in explaining the results.
- Yaozhong, Jiang,Peng, Guo,Guilan, Liu
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- BASIC STUDY OF THE AMINO ACID RESIDUE IN PROTEIN. THE ROLE OF HYDROCARBON GROUPS IN ENANTIOMER-DIFFERENTIATING ACYLATION.
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The enantiomer-differentiation acylation (kinetic resolution) of 1-phenylalkylamines and their derivatives was carried out with (S)-2-phenylbutyric anhydride and its derivatives in aqueous and nonaqueous media. On the basis of the distributions of the two diastereomeric products, the molecular interactions between hydrocarbon residues responsible for the structural recognition of the reacting molecules were studied. In nonpolar media, the (R,S)-isomer was predominantly formed over the (S,S)-isomer. Moreover, the differentiation was mainly controlled by the size of the alkyl substituents of the substrates.
- Hiraki,Tai
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p. 1570 - 1575
(2007/10/02)
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- Asymmetric Induction in the Reduction of Optically Active N-Alkylidenesulphinamides by Metal Hydrides. A New, Efficient Enantioselective Route to Chiral Amines
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A series of racemic and optically active N-alkylidenesulphinamides has been prepared and their reduction by metal hydrides studied.The extent of asymmetric synthesis mainly depends on the nature of the reducing species; the best results (up to 92percent of stereoselectivity) are obtained with alkoxy-lithium aluminium hydrides.A new, highly enantioselective synthesis of amines is described.
- Annunziata, Rita,Cinquini, Mauro,Cozzi, Franco
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p. 339 - 344
(2007/10/02)
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- OPTICALLY ACTIVE F-2-ISOPROPOXYPROPIONIC ACID: A NOVEL DERIVATIZING AGENT FOR GAS CHROMATOGRAPHIC ANALYSIS
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F-2-Isopropoxypropionic acid (PIPA) was resolved into enantiomers via its diastereomeric (+)-1-phenylethylamide. (+)-F-2-Isopropoxypropionyl derivatives of several chiral 1-arylalkylamines and α-amino acids were effectively resolved by gas chromatography at low temperature.
- Kawa, Hajimu,Yamaguchi, Fumihiko,Ishikawa, Nobuo
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p. 745 - 748
(2007/10/02)
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