cas 16273-37-3, 3-Chlorophenylglycolic acid

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Resolution of halogenated mandelic acids through enantiospecific co-crystallization with levetiracetam
The resolution of halogenated mandelic acids using levetiracetam (LEV) as a resolving agent via forming enantiospecific co-crystal was presented. Five halogenated mandelic acids, 2-chloromandelic acid (2-ClMA), 3-chloromandelic acid (3-ClMA), 4-chloromandelic acid (4-ClMA), 4-bromomandelic acid (4-BrMA), and 4-fluoromandelic acid (4-FMA), were selected as racemic compounds. The effects of the equilibrium time, molar ratio of the resolving agent to racemate, amount of solvent, and crystallization temperature on resolution performance were investigated. Under the optimal conditions, the resolution efficiency reached up to 94% and the enantiomeric excess (%e.e.) of (R)-3-chloromandelic acid was 63%e.e. All five halogenated mandelic acids of interest in this study can be successfully separated by LEV via forming enantiospecific co-crystal, but the resolution performance is significantly different. The results showed that LEV selectively co-crystallized with S enantiomers of 2-ClMA, 3-ClMA, 4-ClMA, and 4-BrMA, while it co-crystallized with R enantiomers of 4-FMA. This indicates that the position and type of substituents of racemic compounds not only affect the co-crystal configuration, but also greatly affect the efficiency of co-crystal resolution.
Peng, Yangfeng,Wang, Jie
(2021/09/18)

Diastereomeric resolution of 3-chloromandelic acid with threo-(1S,2S)-2-amino-l-p-nitrophenyl-1,3-propanediol
An optical resolution of 3-chloromandelic acid (3-ClMA) using threo-(1S,2S)-2-amino-l-p-nitrophenyl-1,3-propanediol ([S,S]-SA) as a resolving agent was presented. The effects of the type of solvents, the amount of solvent, molar ratio of the resolving agent to racemate and filtration temperature on resolution were investigated. Under the optimal resolution conditions, the content of less soluble salt reached 98%, and the resolution efficiency was as high as 94%. The weak intermolecular interactions (such as hydrogen bond, halogen bond, CH/π and van der Waals interactions) and molecular packing mode in crystal structure of the less soluble salt (R)-3-ClMA(S,S)-SA were investigated. A wall-like 2-D hydrogen-bonding network and hydrophobic structure between hydrogen-bonding walls were revealed. (S,S)-SA was also used to resolve 2-ClMA and 4-ClMA respectively and the corresponding less soluble salts (R)-2-ClMA·(R,R)-SA and (R)-4-ClMA·(R,R)-SA were obtained using threo-(1R,2R)-2-amino-l-p-nitrophenyl-1,3-propanediol ((R,R)-SA) as a resolving agent. In addition, two other resolving agents, (R)-ɑ-phenethylamine ((R)-PEA) and (R)-N-benzyl phenethylamine ((R)-BPA) reported in the literature for the resolution of 3-ClMA were examined along with the newly proposed resolving agent, (S,S)-SA. The crystal structures of the resulting less soluble salts (R)-3-ClMA·(S,S)-SA, (R)-3-ClMA·(R)-PEA and (R)-3-ClMA·(R)-BPA were compared and examined.
Wang, Jie,Ao, Qiong,Peng, Yangfeng,Feng, Cai
p. 824 - 839
(2021/09/13)

Oxalyl-CoA Decarboxylase Enables Nucleophilic One-Carbon Extension of Aldehydes to Chiral α-Hydroxy Acids
The synthesis of complex molecules from simple, renewable carbon units is the goal of a sustainable economy. Here we explored the biocatalytic potential of the thiamine-diphosphate-dependent (ThDP) oxalyl-CoA decarboxylase (OXC)/2-hydroxyacyl-CoA lyase (HACL) superfamily that naturally catalyzes the shortening of acyl-CoA thioester substrates through the release of the C1-unit formyl-CoA. We show that the OXC/HACL superfamily contains promiscuous members that can be reversed to perform nucleophilic C1-extensions of various aldehydes to yield the corresponding 2-hydroxyacyl-CoA thioesters. We improved the catalytic properties of Methylorubrum extorquens OXC by rational enzyme engineering and combined it with two newly described enzymes—a specific oxalyl-CoA synthetase and a 2-hydroxyacyl-CoA thioesterase. This enzymatic cascade enabled continuous conversion of oxalate and aromatic aldehydes into valuable (S)-α-hydroxy acids with enantiomeric excess up to 99 %.
Burgener, Simon,Cortina, Ni?a Socorro,Erb, Tobias J.
supporting information
p. 5526 - 5530
(2020/02/20)

Kinetic Resolution of Allylic Alcohol with Chiral BINOL-Based Alkoxides: A Combination of Experimental and Theoretical Studies
The development and characterization of enantioselective catalytic kinetic resolution of allylic alcohols through asymmetric isomerization with chiral BINOL derivatives-based alkoxides as bifunctional Br?nsted base catalysts were described in the study. A number of chiral BINOL derivatives-based alkoxides were synthesized, and their structure-enantioselectivity correlation study in asymmetric isomerization identified a promising chiral Br?nsted base catalyst, which afforded various chiral secondary allylic alcohols (ee up to 99%, S factor up to >200). In the mechanistic study, alkoxide species were identified as active species and the phenol group of BINOL largely affected the high reactivity and enantioselectivity via hydrogen bonding between the chiral Br?nsted base catalyst and substrates. The strategy is the first successful synthesis strategy of various chiral secondary allylic alcohols through enantioselective transition-metal-free base-catalyzed isomerization. The applicability of the strategy had been demonstrated by the synthesis of the bioactive natural product (+)-veraguensin.
Liu, Yidong,Liu, Song,Li, Dongmei,Zhang, Nan,Peng, Lei,Ao, Jun,Song, Choong Eui,Lan, Yu,Yan, Hailong
supporting information
p. 1150 - 1159
(2019/01/11)

Enantioseparation of chiral mandelic acid derivatives by supercritical fluid chromatography
Mandelic acid and its derivatives are important chiral analogs which are widely used in the pharmaceutical synthetic industry. The present study investigated the enantiomeric separation of six mandelic acids (mandelic acid, 2-chloromandelic acid, 3-chloromandelic acid, 4-chloromandelic acid, 4-bromomandelic acid, 4-methoxymandelic acid) on the Chiralpak AD-3 column by supercritical fluid chromatography. The influences of volume fraction of trifluoroacetic acid, type and percentage of modifier, column temperature, and backpressure on the separation efficiency were investigated. And the enantiomer elution order was determined. The results show that, for a given modifier, the retention factor, the separation factor, and the separation resolution decreased gradually with increasing the volume ratio of the modifier. At the same volume ratio of modifier, the retention factor of the mandelic acid and its derivatives increased in the order of methanol, ethanol, and isopropanol, except 3-chloromandelic acid. The separation factor and the separation resolution decreased with the increase of column temperature (below the temperature limit). The backpressure affected the enantioseparation process: As the backpressure increased, a corresponding decrease in retention factor was observed. Under the same chiral column conditions, the SFC method exhibited faster and more efficient separation with better enantioselectivity than the HPLC method.
Ding, Jiawei,Zhang, Ming,Dai, Huixue,Lin, Chunmian
p. 1245 - 1256
(2018/09/25)

Highly Efficient Deracemization of Racemic 2-Hydroxy Acids in a Three-Enzyme Co-Expression System Using a Novel Ketoacid Reductase
Enantiopure 2-hydroxy acids (2-HAs) are important intermediates for the synthesis of pharmaceuticals and fine chemicals. Deracemization of racemic 2-HAs into the corresponding single enantiomers represents an economical and highly efficient approach for synthesizing chiral 2-HAs in industry. In this work, a novel ketoacid reductase from Leuconostoc lactis (LlKAR) with higher activity and substrate tolerance towards aromatic α-ketoacids was discovered by genome mining, and then its enzymatic properties were characterized. Accordingly, an engineered Escherichia coli (HADH-LlKAR-GDH) co-expressing 2-hydroxyacid dehydrogenase, LlKAR, and glucose dehydrogenase was constructed for efficient deracemization of racemic 2-HAs. Most of the racemic 2-HAs were deracemized to their (R)-isomers at high yields and enantiomeric purity. In the case of racemic 2-chloromandelic acid, as much as 300 mM of substrate was completely transformed into the optically pure (R)-2-chloromandelic acid (> 99% enantiomeric excess) with a high productivity of 83.8 g L?1 day?1 without addition of exogenous cofactor, which make this novel whole-cell biocatalyst more promising and competitive in practical application.
Xue, Ya-Ping,Wang, Chuang,Wang, Di-Chen,Liu, Zhi-Qiang,Zheng, Yu-Guo
p. 1 - 13
(2018/04/26)

The Synthesis of Chiral α-Aryl α-Hydroxy Carboxylic Acids via RuPHOX-Ru Catalyzed Asymmetric Hydrogenation
A ruthenocenyl phosphino-oxazoline-ruthenium complex (RuPHOX?Ru) catalyzed asymmetric hydrogenation of α-aryl keto acids has been successfully developed, affording the corresponding chiral α-aryl α-hydroxy carboxylic acids in high yields and with up to 97% ee. The reaction could be performed on a gram scale with a relatively low catalyst loading (up to 5000 S/C) and the resulting products can be transformed to several chiral building blocks, biologically active compounds and chiral drugs. (Figure presented.).
Guo, Huan,Li, Jing,Liu, Delong,Zhang, Wanbin
p. 3665 - 3673
(2017/09/11)

Asymmetric hydrogenation reaction of alpha-ketoacids compound
The invention relates to the technical field of organic chemistry, especially to an asymmetric hydrogenation reaction of an alpha-ketoacids compound. The asymmetric hydrogenation reaction comprises a scheme shown in the description. In the scheme, R1 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, C1-C6 alkyl, or aralkyl; a substituent group is C1-C6 alkyl, C1-C6 alkoxy, or halogen; and the number of the substituent group is 1-3. In the scheme, M is a chiral spiro-pyridylamino phosphine ligand iridium complex having a structure shown in the description. In the structure, R is hydrogen, 3-methyl, 4-tBu, or 6-methyl.
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Paragraph 0031; 0032; 0033; 0037; 0043

(2016/10/10)

Production Of Enantiopure alpha-Hydroxy Carboxylic Acids From Alkenes By Cascade Biocatalysis
The invention provides compositions comprising an alkene epoxidase and a selective epoxide hydrolase, such as a recombinant microorganism comprising a first heterologous nucleic acid encoding an alkene epoxidase and a second heterologous nucleic acid encoding a selective epoxide hydrolase. Exemplary alkene epoxidases include StyAB, while exemplary selective epoxide hydrolases include epoxide hydrolases from Sphingomonas, Solanum tuberosum, or Aspergillus. The invention also provides non-toxic methods of making enantiomerically pure vicinal diols or enantiomerically pure alpha-hydroxy carboxylic acids using these compositions and microorganisms.
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Paragraph 0089; 0090

(2016/05/02)

Solid phase behavior in the chiral systems of various 2-hydroxy-2-phenylacetic acid (mandelic acid) derivatives
The solid phase behavior of a series of monosubstituted F-, Cl-, Br-, I-, and CH3- and two 2,4-halogen-disubstituted 2-hydroxy-2-phenylacetic acid (mandelic acid) derivatives was investigated. The study includes detailed information about melting temperature, melting enthalpy, X-ray diffraction data, as well as selected binary phase diagrams of the respective chiral systems. Aside from the known metastable conglomerate 2-chloromandelic acid, evidence for two more metastable conglomerates was found.
Von Langermann, Jan,Temmel, Erik,Seidel-Morgenstern, Andreas,Lorenz, Heike
p. 721 - 728
(2015/03/30)

Design of nitrilases with superior activity and enantioselectivity towards sterically hindered nitrile by protein engineering
Abstract The enantioselective hydrolysis of ortho-chloromandelonitrile with nitrilase is one of the most attractive approaches to prepare (R)-ortho-chloromandelic acid. To date, efforts to develop this nitrilase-mediated process were plagued by either insufficient eep (enantiomeric excess of product) or low activity due to the steric hindrance from the ortho-substituted substrate. To improve the nitrilase potential for producing (R)-ortho-chloromandelic acid, an enhancement of both activity and enantioselectivity towards sterically hindered nitriles would be highly desirable. Molecular docking of the (R)-ortho-chloromandelonitrile into the active site of wild-type 2A6 nitrilase (nitA) allowed the identification of proximal nitA active site residues. Several residues (52, 132, 189 and 190) were selected as targets for single and double point mutation to improve nitA activity and enantioselectivity towards ortho-chloromandelonitrile. Targeted mutagenesis yielded several nitA variants with superior activity and enantioselectivity. The best mutant T132A/F189T exhibited a 4.37-fold higher specific activity (7.39 U/mg) towards ortho-chloromandelonitrile than the wild-type nitA. More importantly, the enantioselectivity (E) was improved from 17.34 to >200, resulting in a highly enantiopure product. Molecular docking experiments further support the enhanced activity and enantioselectivity shown experimentally and the structural effects of this amino acid substitution on the active site of nitA are provided. The amino acids at sites 189 and 132 determine the activity and enantioselectivity towards ortho-chloromandelonitrile. With mutant T132A/F189T as a catalyst, a maximum of 450 mM of (R)-ortho-chloromandelic acid was produced with a 90% conversion and >99% eep within 3 h. This is the first time that a high productivity of (R)-ortho-chloromandelic acid of up to 671.76 g L-1d-1 using a nitrilase-mediated approach is reported. The engineered T132A/F189T variant represents a promising and competitive biocatalyst for practical application in synthesizing (R)-ortho-chloromandelic acid.
Xue, Ya-Ping,Shi, Cheng-Ci,Xu, Zhe,Jiao, Biao,Liu, Zhi-Qiang,Huang, Jian-Feng,Zheng, Yu-Guo,Shen, Yin-Chu
p. 1741 - 1750
(2015/06/02)

Nitrilases
The invention relates to nitrilases and to nucleic acids encoding the nitrilases. In addition, methods of designing new nitrilases and methods of use thereof are also provided. The nitrilases have increased activity and stability at increased pH and temperature.
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Paragraph 0351; 0355

(2015/09/22)

Increased catalyst productivity in α-hydroxy acids resolution by esterase mutation and substrate modification
Optically pure α-hydroxy acids and their derivatives are versatile chiral building blocks in the pharmaceutical industry. In this study, the potential of a recombinant Pseudomonas putida esterase (rPPE01) for the enzymatic resolution of α-acetoxy acids was significantly improved by combinatorial engineering of both the biocatalyst and substrate. Semirational design based on homologous modeling and molecular docking provided a single-point variant, W187H, whose kcat/KM for sodium 2-acetoxy-2-(2′-chlorophenyl)acetate (Ac-CPA-Na) was increased 100-fold, from 0.0611 to 6.20 mM-1 s-1, while retaining its excellent enantioselectivity and broad substrate spectrum. Biocatalyst deactivation under the operating conditions was decreased by using the potassium salt of Ac-CPA instead of Ac-CPA-Na. With 0.5 g L-1 of lyophilized cells containing rPPE01-W187H, 500 mM (R,S)-Ac-CPA-K was selectively deacylated with 49.9% conversion within 15 h, giving satisfactory enantiomeric excesses (ee) for both the S product (>99% ee) and the remaining R substrate (98.7% ee). Consequently, the amount of (S)-2-hydroxy-2-(2′-chlorophenyl)acetate prepared per unit weight of lyophilized cells was improved by a factor of 18.9 compared with the original productivity of the wild-type esterase. Further enzymatic resolution of other important hydroxy acids at the 100 mL scale demonstrated that the rPPE01-W187H-based bioprocess is versatile and practical for the large-scale preparation of chiral α-hydroxy acids.
Ma, Bao-Di,Kong, Xu-Dong,Yu, Hui-Lei,Zhang, Zhi-Jun,Dou, Shuai,Xu, Yan-Peng,Ni, Yan,Xu, Jian-He
p. 1026 - 1031
(2014/04/03)

Kinetic resolution of mandelate esters via stereoselective acylation catalyzed by lipase PS-30
By using lipase PS-30 as catalyst, the kinetic resolution of a series of racemic mandelate esters has been achieved via stereoselective acylation. The value of kinetic enantiomeric ratio (E) reached up to 197.5. Substituent effect is briefly discussed.
Chen, Peiran,Yang, Wenhong
supporting information
p. 2290 - 2294
(2014/04/17)

Relationships between the racemic structures of substituted mandelic acids containing 8- and 10-membered hydrogen bonded dimer rings
The structures of 27 monosubstituted mandelic acids, including several of their polymorphs, plus unsubstituted mandelic acid itself (two polymorphs) are investigated for structural similarity. The results, presented pictorially as a structural relationship plot, show that rather more structures are built up from the carboxyl-chain hydroxyl hydrogen bonded dimer than from the conventional carboxylic acid dimer. The results show how all the structures are related and, based on the two types of dimer, the degree of similarity that they possess. Some structures with Z′ > 1 contain both sorts of dimers and there are many examples of isostructural sets within the structures so far determined. We also present an example where analysing similarity in related families of structures highlights a structure that should be present and which has indeed then proceeded to be synthesised and determined.
Coles,Ellis,Leung,Sarson,Threlfall,Tizzard
p. 10816 - 10823
(2015/02/19)

Direct asymmetric hydrogenation of α-keto acids by using the highly efficient chiral spiro iridium catalysts
A new efficient and highly enantioselective direct asymmetric hydrogenation of α-keto acids employing the Ir/SpiroPAP catalyst under mild reaction conditions has been developed. This method might be feasible for the preparation of a series of chiral α-hydroxy acids on a large scale.
Yan, Pu-Cha,Xie, Jian-Hua,Zhang, Xiang-Dong,Chen, Kang,Li, Yuan-Qiang,Zhou, Qi-Lin,Che, Da-Qing
p. 15987 - 15990
(2015/02/19)

One-pot, single-step deracemization of 2-hydroxyacids by tandem biocatalytic oxidation and reduction
A facile and efficient one-pot, single-step method for deracemizing a broad range of 2-hydroxyacids to (R)-2-hydroxyacids was established by combination of resting cells of an (S)-hydroxyacid dehydrogenase-producing microorganism and an (R)-ketoacid reductase-producing microorganism.
Xue, Ya-Ping,Zheng, Yu-Guo,Zhang, Ya-Qin,Sun, Jing-Lei,Liu, Zhi-Qiang,Shen, Yin-Chu
supporting information
p. 10706 - 10708
(2013/11/06)

Amberlyst A-26: An efficient and reusable heterogeneous catalyst for a one-pot oxidation-Cannizarro reaction
Amberlyst A-26 catalyses the efficient synthesis of α-hydroxy- arylacetic acids from aryl methyl ketones in the presence of SeO2. After simple separation, the catalyst does not lose its activity and can be reused without significant loss in activity for at least four cycles.
Shen, Ming-Gui,Shang, Shi-Bin,Song, Zhan-Qian,Wang, Dan,Rao, Xiao-Ping,Gao, Hong,Liu, He
p. 51 - 52
(2013/03/29)

Asymmetric synthesis and evaluation of a hydroxyphenylamide voltage-gated sodium channel blocker in human prostate cancer xenografts
Voltage-gated sodium channels are known to be expressed in neurons and other excitable cells. Recently, voltage-gated sodium channels have been found to be expressed in human prostate cancer cells. α-Hydroxy-α- phenylamides are a new class of small molecules that have demonstrated potent inhibition of voltage-gated sodium channels. The hydroxyamide motif, an isostere of a hydantoin ring, provides an active scaffold from which several potent racemic sodium channel blockers have been derived. With little known about chiral preferences, the development of chiral syntheses to obtain each pure enantiomer for evaluation as sodium channel blockers is important. Using Seebach and Frater's chiral template, cyclocondensation of (R)-3-chloromandelic acid with pivaldehyde furnished both the cis- and trans-2,5-disubsituted dioxolanones. Using this chiral template, we synthesized both enantiomers of 2-(3-chlorophenyl)-2-hydroxynonanamide, and evaluated their ability to functionally inhibit hNav isoforms, human prostate cancer cells and xenograft. Enantiomers of lead demonstrated significant ability to reduce prostate cancer in vivo.
Davis, Gary C.,Kong, Yali,Paige, Mikell,Li, Zhang,Merrick, Ellen C.,Hansen, Todd,Suy, Simeng,Wang, Kan,Dakshanamurthy, Sivanesan,Cordova, Antoinette,McManus, Owen B.,Williams, Brande S.,Chruszcz, Maksymilian,Minor, Wladek,Patel, Manoj K.,Brown, Milton L.
experimental part
p. 2180 - 2188
(2012/05/05)

Robust enzymatic resolution of 3-fluoromandelic acid with lipase PS supported on celite
The resolution of different mandelic acids using the lipase PS Amano SD enzyme is described. By supporting the lyophilized enzyme over Celite, both the activity and the stability of lipase PS in organic media were significantly improved, enabling the robust resolution scale-up of 3-fluoromandelic acid. The methodology was extended to produce a range of optically pure (R)-mandelic acids, avoiding tedious extractions or chromatography.
Mendiola, Javier,Garcia-Cerrada, Susana,De Frutos, Oscar,De La Puente, Maria Luz
experimental part
p. 1312 - 1316
(2012/10/18)

Highly enantioselective hydrolysis of phenyl-1,2-ethanediol cyclic carbonates by newly isolated Bacillus sp. ECU0015
A bacterial strain (No. ECU0015), which catalyzes the hydrolysis of phenyl-1,2-ethanediol cyclic carbonates (4-phenyl-1,3-dioxolan-2-one, 1) to (S)-1-phenyl-1,2-ethanediol (2) with high enantioselectivity, was newly isolated from soil samples utilizing the cyclic carbonate as sole carbon and energy source. The bacterium was later identified as Bacillus species by its 16S rDNA sequence and phylogenetic analysis. The optimal reaction temperature and pH for the asymmetric hydrolysis of 1 using whole cells were 35 °C and pH 7.3, respectively. Partial bio-oxidation of the produced (R)-diol was observed, resulting in an increase in the eep (enantiomeric excess of product) of the main product (S)-diol. Under the improved reaction condition, the target product (S)-diol was prepared in gram scale, affording an excellent ee p (>99%) with a moderate yield (27.8%) as compared to the maximum theoretical yield of 50% for kinetic resolution. This strain of Bacillus sp. also displayed fairly good activity and enantioselectivity towards some other compounds tested, such as 2-acetoxy-2-phenylacetic acid (3) and its derivatives.
Chang, Lei,Ouyang, Li-Ming,Xu, Yi,Pan, Jiang,Xu, Jian-He
experimental part
p. 95 - 100
(2011/01/03)

Hydrogen-bonding sheets in crystals for chirality recognition: synthesis and application of (2S,3S)-2,3-dihydroxy- and (2S,3S)-2,3-dibenzyloxy-1,4-bis(hydroxyamino)butanes
Two enantiopure bis(hydroxyamino) compounds were successfully prepared from dialkyl tartrate by a chiral-pool method and applied as basic resolving agents in the enantioseparation of 2-arylpropanoic acids and arylglycolic acids. (2S,3S)-2,3-Dihydroxy-1,4-bis(hydroxyamino)butane (2S,3S)-1a could moderately recognize the chirality of the 2-arylpropanoic acids, while (2S,3S)-2,3-dibenzyloxy-1,4-bis(hydroxyamino)butane (2S,3S)-1b could not due to the low crystallinity of both the corresponding diastereomeric salts. On the other hand, (2S,3S)-1b showed a similar chirality-recognition ability for the arylglycolic acids. The ability of (2S,3S)-1b was different from those generally observed for widely used primary amine-type resolving agents with regard to the relationship between the resolution efficiency and the similarity in the relative molecular length of a resolving agent and a target racemate. The X-ray crystallographic analyses of the less-soluble diastereomeric salts revealed that in the salts (2S,3S)-1a formed a supramolecular sheet, of which the distance was variable to make the resultant dissymmetric space fit to the shape of the target acids, and that (2S,3S)-1b was constructed from a robust supramolecular sheet, consisting of hydrogen-bonding 21 columns, with the participation of the hydroxy group of the arylglycolic acids. These X-ray crystallographic analyses also suggested that for the formation of a supramolecular sheet, the coexistence of two hydroxyamino groups is essential.
Kobayashi, Yuka,Kokubo, Yasushi,Aisaka, Takamitsu,Saigo, Kazuhiko
scheme or table
p. 2536 - 2541
(2009/04/11)

CeCl3·7H2O: An effective additive in ru-catalyzed enantioselective hydrogenation of aromatic α-ketoesters
(Chemical Equation Presented) In the presence of catalytic amounts of CeCl3·7H2O, [RuCl(benzene)(S)-SunPhos]Cl is a highly effective catalyst for the asymmetric hydrogenation of aromatic α-ketoesters. A variety of ethyl α-hydroxy-α-arylacetates have been prepared in up to 98.3% ee with a TON up to 10 000. Challenging aromatic α-ketoesters with ortho substituents are also hydrogenated with high enantioselectivities. The addition of CeCl3·7H2O not only improves the enantioselectivity but also enhances the stability of the catalyst. The ratio of CeCl3·7H2O to [RuCl(benzene)(S)-SunPhos]Cl plays an important role in the hydrogenation reaction with a large substrate/catalyst ratio.
Meng, Qinghua,Sun, Yanhui,Ratovelomanana-Vidal, Virginie,Genet, Jean Pierre,Zhang, Zhaoguo
p. 3842 - 3847
(2008/09/21)

Acylaminothiazole derivatives, preparation and therapeutic use thereof
This invention discloses and claims a compound conforming to the general formula (I): Wherein R1, R2, R′2, R3, R4 and R5 are as described herein. The compounds of the present invention exhibit an inhibitory effect on the production of β-amyloid peptide (β-A4) by inhibition of gamma protease. Therefore, the compounds of the present invention are useful in the treatment of pathologies such as senile dementia, Alzheimer's disease, Down's syndrome, Parkinson's disease, amyloid angiopathy and/or cerebrovascular disorders.
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Page/Page column 12

(2008/06/13)

Preparation of (S)-mandelic acids by enantioselective degradation of racemates with a new isolate Pseudomonas putida ECU1009
An enantioselective (R)-mandelate degrading bacterium, Pseudomonas putida ECU1009, was newly isolated from soil. The degradation activity of the bacterial cells was significantly enhanced by supplementing an optimal amount of racemic mandelic acid (0.4%), benzoylformic acid (0.4%), or benzoic acid (0.2%) to the culture medium as the enzyme inducer. Using the resting cells as a biocatalyst, three kinds of (S)-mandelic acids 1-3 were prepared with high isolated yields and enantiomeric excesses. Moreover, in a one-pot fermentation-transformation process using 1.25% (RS)-mandelic acid as the sole carbon/energy source for cultivation of the bacterium, (S)-mandelic acid 1 was accumulated after 48 h of bioconversion with 46.5% yield and >99% ee.
Huang, Han-Rong,Xu, Jian-He,Xu, Yi,Pan, Jiang,Liu, Xiang
p. 2113 - 2117
(2007/10/03)

Method for producing optically active mandelic acid derivatives
The present invention provides a method for enzymatically producing optically active mandelic acid derivatives. An optically active mandelic acid derivative (shown as Formula II) is produced by reacting a culture or cell body of a microorganism, or processed products thereof, with a phenylglyoxylic acid derivative, and then recovering the obtained optically active mandelic acid derivative, wherein the microorganism has the ability to stereo-selectively reduce the phenylglyoxylic acid derivative. An optically active mandelic acid obtained according to the present invention is useful as an intermediate for the synthesis of pharmaceuticals and agricultural chemicals.
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Page column 18,19

(2008/06/13)

AMINO ACID DERIVATIVES
There is provided amino acid derivatives of formula I, wherein p, q, R 1, R 2, R 3, R 4, Y, n and B have meanings given in the description which are useful as competitive inhibitors of trypsin-like proteases, such as thrombin, and in particular in the treatment of conditions where inhibition of thrombin is required (e.g. thrombosis) or as anticoagulants.
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Page column 46

(2010/01/30)

An enzyme library approach to biocatalysis: Development of nitrilases for enantioselective production of carboxylic acid derivatives
The discovery, from Nature, of a large and diverse set of nitrilases is reported. The utility of this nitrilase library for identifying enzymes that catalyze efficient production of valuable hydroxy carboxylic acid derivatives is demonstrated. Unprecedented enantioselectivity and substrate scope are highlighted for three newly discovered and distinct nitrilases. For example, a wide array of (R)-mandelic acid derivatives and analogues were produced with high rates, yields, and enantiomeric excesses (95-99% ee). We also have found nitrilases that provide direct access to (S)-phenyllactic acid and other aryllactic acid derivatives, again with high yields and enantioselectivities. Finally, different nitrilases have been discovered that catalyze enantiotopic hydrolysis of 3-hydroxyglutaronitrile to afford either enantiomer of 4-cyano-3-hydroxybutyric acid with high enantiomeric excesses (>95% ee). The first enzymes are reported that effect this transformation to furnish the (R)-4-cyano-3-hydroxybutyric acid which is a precursor to the blockbuster drug Lipitor. Copyright
DeSantis, Grace,Zhu, Zuolin,Greenberg, William A.,Wong, Kelvin,Chaplin, Jenny,Hanson, Sarah R.,Farwell, Bob,Nicholson, Lawrence W.,Rand, Cynthia L.,Weiner, David P.,Robertson, Dan E.,Burk, Mark J.
p. 9024 - 9025
(2007/10/03)

Selective ET(A) antagonists. 5. Discovery and structure-activity relationships of phenoxyphenylacetic acid derivatives
The fifth paper in this series describes the culmination of our investigations into the development of a potent and selective ETA receptor antagonist for the treatment of diseases mediated by ET-1. Receptor site mapping of several ETA antagonists prepared previously identified a common cationic binding site which prompted synthesis of phenoxyphenylacetic acid derivative 13a, which showed good in vitro activity (IC50 59 nM, rat aortic ET(A)). Optimization of 13a led to the identification of 27b, which exhibited an IC50 of 4 nM. Although this did not translate into the expected in vivo potency, a compound of comparable in vitro activity, 27a (RPR118031A), showed a far better pharmacokinetic profile and in vivo potency (75 μmol/kg) and was duly proposed and accepted as a development candidate.
Astles, Peter C.,Brown, Thomas J.,Halley, Frank,Handscombe, Caroline M.,Harris, Neil V.,Majid, Tahir N.,McCarthy, Clive,McLay, Lain M.,Morley, Andrew,Porter, Barry,Roach, Alan G.,Sargent, Carol,Smith, Christopher,Walsh, Roger J. A.
p. 900 - 910
(2007/10/03)

Thrombin inhibitors, their preparation and use
PCT No. PCT/SE96/00878 Sec. 371 Date Aug. 7, 1996 Sec. 102(e) Date Aug. 7, 1996 PCT Filed Jul. 2, 1996 PCT Pub. No. WO97/02284 PCT Pub. Date Jan. 23, 1997There is provided amino acid derivative formula I, wherein p, q, R1, R2, R3, R4, Y, n and B have meanings given in the description which are useful as competitive inhibitors of trypsin-like proteases, such as thrombin, and in particular in the treatment of conditions where inhibition of thrombin is required (e.g. thrombosis) or as anticoagulants.
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(2008/06/13)

Process for preparing [R-(R*,R*)]-5-(3-chlorophenyl)-3-[2-(3,4-dimethoxylphenyl)-1-methyl-ethyl]-oxazolidin-2-one
The present invention relates to a process for preparing [R-(R*,R*)]-5-(3-chlorophenyl)-3-[2-(3,4-dimethoxyphenyl)-1-methyl-ethyl]-oxazolidin-2-one of Formula (1), characterized in that said process comprises the step of reacting (R)-3, 4-methoxy-amphetamine of Formula (3), with (R)-3-chloro-mandelic acid, of Formula (9): STR1
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(2008/06/13)

Aromatic amino-alcohol derivatives having anti-diabetic and anti-obesity properties, their preparation and their therapeutic uses
Compounds of formula (I): STR1 (wherein: R0 is hydrogen, methyl or hydroxymethyl; R1 is substituted alkyl; R2 and R3 are each hydrogen, halogen, hydroxy, alkoxy, carboxy, alkoxycarbonyl, alkyl, nitro, haloalkyl, or substituted alkyl; X is oxygen or sulfur; and Ar optionally substituted phenyl or naphthyl); and pharmaceutically acceptable salts thereof have a variety of valuable pharmaceutical activities, including anti-diabetic and anti-obesity activities; in addition, they are capable of treating or preventing hyperlipemia and hyperglycemia and, by inhibiting the action of aldose reductase, they can also be effective in the treatment and prevention of complications of diabetes.
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(2008/06/13)

Oxazolidine derivatives having anti-diabetic and anti-obesity properties, their preparation and their therapeutic uses
Compounds of formula (I): STR1 wherein: R is an alkyl group; X is oxygen or sulfur; Y is hydrogen atom or --A--COOH, in which A is an alkylene group; Ar is aryl or substituted aryl group; and pharmaceutically acceptable salts and esters thereof, have use in the treatment or prophylaxis of diabetes, obesity, hyperlipemia, hyperglycemia, complications of diabetes, obesity-related hypertension and osteoporosis.
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(2008/06/13)

THIAZOLE AND OXAZOLE-BASED BETA3 ADRENERGIC RECEPTOR AGONISTS
Compounds having the formula STR1 and pharmaceutically acceptable salts thereof where A is STR2 R 3 is--(CH 2) n--or in the case where R 2 is STR3 R 3 in addition to the above may be STR4 R 4 is hydroxy, alkoxy, amino, alkylamino or dialkylamino; R 5 is hydrogen, fluorine, chlorine, bromine, iodine,--CN, CF 3, lower alkyl, lower alkoxy, cycloalkyl or aryl;R 6 is lower alkyl, cycloalkyl or aryl;R 7, R 7 ', R 8 and R. sub.8 ' are independently hydrogen or a lower alkyl or R. sub.7 and R 8 may together be CH 2 CH 2 ; Z is hydrogen or STR5 m is an integer of 1 or 2; n is zero or an integer of 1 to 6; andp is an integer of 1 to 5. These compounds are beta 3 adrenergic receptor agonists and are useful, therefore for example, in the treatment of diabetes, obesity and gastrointestinal diseases.
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(2008/06/13)

Reduction of manganate(VI) by mandelic acid and its significance to development of a general mechanism for oxidation of organic compounds by high-valent transition metal oxides
Results obtained from a study of the oxidation of mandelic acid and cyclobutanol by manganate(VI) indicate that reaction mechanisms traditionally applied to oxidations of this type (i.e., hydrogen atom or hydride ion transfers) may not be correct. Instead it appears that the reaction may be initiated by a 2 + 2 addition of the α-C-H bond to a manganese oxo double bond. This interpretation may be useful in the development of a general mechanism for the oxidation of organic compounds by high-valent transition metal oxides including more common oxidants such as permanganate, ruthenium tetroxide, and chromic acid.
Lee, Donald G.,Chen, Tao
p. 11231 - 11236
(2007/10/02)

The Oxidation of Alcohols by Permanganate. A Comparison with Other High-Valent Transition-Metal Oxidants
The results obtained from a study of the oxidation of mandelic acid and cyclobutanol by permanganate in 1.0 M KOH are best accomodated by a mechanism in which the initial reaction is the addition of a manganese-oxo bond to the α-C-H bond of the alcohol, followed by homolytic cleavage of the resulting Mn-C bond to give free-radical intermediates.A comparison with other high-valent transition-metal oxidants suggests that it is possible to systematically classify the way in which these reagents react with alcohols on the basis of the initial reaction (C-H or O-H addition) and the cleavage mode of the metal-oxygen or metal-carbon bond (homolytic or heterolytic).The approach provides a framework for understanding these reactions that is less chaotic than the current situation where distinctive mechanisms have been proposed for each individual oxidant.
Lee, Donald G.,Chen, Tao
p. 5341 - 5345
(2007/10/02)

ENZYME-CATALYZED SYNTHESIS OF (S)-CYANOHYDRINS AND SUBSEQUENT HYDROLYSIS TO (S)-α-HYDROXY-CARBOXYLIC ACIDS
(S)-Cyanohydrins 2 are obtained with high enantioselectivity from aromatic aldehydes and HCN in the presence of (S)-oxynitrilase (E.C.4.1.2.11).Acid-catalyzed hydrolysis of the cyanohydrins 2 affords the corresponding (S)-α-hydroxy carboxylic acids 3 without racemization.
Effenberger, Franz,Hoersch, Brigitte,Foerster, Siegfried,Ziegler, Thomas
p. 1249 - 1252
(2007/10/02)

Process for the O-alkylation of N-(hydroxy)aralkylphenylethanolamines
A process for the preparation of a compound of formula STR1 wherein X represents hydrogen, halogen, trifluoromethyl or lower alkyl group; W represents methyl, Q represents hydrogen or W and Q, together, form an ethylene group and R' represents a lower alkyl group which comprises protecting the amino group of the phenol corresponding to the compound of formula I, submitting the compound thus obtained to an alkylation (with a compound of formula Hal--CH2 --COOR', wherein R' is as defined hereinabove for the formula I and Hal is chlorine, bromine or iodine) and then releasing the amino group of the product thus obtained.
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(2008/06/13)

3-Chlorophenyl anti-obesity agents
Compounds of formula (III): STR1 and esters, amides and pharmaceutically acceptable salts thereof, wherein A1 is hydrogen or methyl; A2 is hydrogen or methyl; and n is 1, 2 or 3 have anti-obesity activity. Methods for their preparation pharmaceutical formulations of the compounds and their use in medicine are described.
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(2008/06/13)

7-α-Amino-substituted acylamino-3-(1-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acids
Certain 7-acylamido-3-(1-carboxy-loweralkyl-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acids and their salts and easily hydrolyzed esters of the 4-carboxyl group were synthesized and found to be potent antibacterial agents which exhibited good aqueous solubility. In a preferred embodiment the 7-substituent was 2'-aminomethylphenylacetamido.
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(2008/06/13)

7-(D-α-Hydroxy-2-arylacetamido)-3-(2-carboxyalkyl-2,3-dihydro-s-triazolo-[4,3-b]pyridazin-3-on-6-ylthiomethyl)-3-cephem-4-carboxylic acids and derivatives
7-(D-α-Hydroxy-2-arylacetamido)-3-(2-carboxyalkyl-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-on-6-ylthiomethyl)-3-cephem-4-carboxylic acids and derivatives containing blocking groups on the α-hydroxy group and their nontoxic, pharmaceutically acceptable salts are valuable as antibacterial agents and are particularly valuable as therapeutic agents in poultry and in animals, including man, in the treatment of infectious diseases caused by many Gram-positive and Gram-negative bacteria. A preferred compound is 7-(D-mandelamido)-3-(2-carboxyalkyl-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-on-6-ylthiomethyl)-3-cephem-4-carboxylic acid.
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(2008/06/13)

7-(D-α-Hydroxy-2-arylacetamido)-3-(tetrazolo-[4,5-b]pyridazin-6-ylthiomethyl)-3-cephem-4-carboxylic acids
7-(D-α-Hydroxy-2-arylacetamido)-3-(tetrazolo-[4,5-b]pyridazin-6-ylthiomethyl)-3-cephem-4-carboxylic acids and their nontoxic, pharmaceutically acceptable salts are valuable as antibacterial agents and are particularly valuable as therapeutic agents in poultry and animals, including man, in the treatment of infectious diseases caused by many Gram-positive and Gram-negative bacteria.
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(2008/06/13)