- TPN10456, preparation method thereof and application of TPN10456 in medicine for treating multiple sclerosis
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The invention relates to a compound, a pharmaceutical application thereof, specifically relates to TPN10456, a preparation method of the TPN10456 and an application of the TPN10456 in a medicine for treating multiple sclerosis. The characteristics of the small molecular compound TPN10456 are disclosed in the invention. The invention relates to TPN10456 and application thereof in preparation of a medicine for treating multiple sclerosis.
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- Caffeic acid phenethyl ester (CAPE)-derivatives act as selective inhibitors of acetylcholinesterase
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Unexpected inhibitory effects against eeAChE could be found for a newly synthesized class of caffeic acid phenethyl ester (CAPE)derivatives. Thus, phenethyl-(E)-3-(3,5-dimethoxy-4-phenethoxyphenyl)-acrylate (Ki = 1.97 ± 0.38 μM, Ki′ = 2.44 ± 0.07 μM)and 4-(2-(((E)-3-(3,4-bis(benzyloxy)phenyl)acryloyl)oxy)ethyl)-1,2-phenylene (2E,2′E)-bis(3-(3,4-bis(benzyloxy)phenyl)acrylate)(Ki = 0.72 ± 0.31 μM, Ki′ = 1.80 ± 0.21 μM)showed very good inhibition of eeAChE, while being non cytotoxic for malignant human cancer cells and non-malignant mouse fibroblasts. Also, they are weak inhibitors for BChE (from equine serum).
- Gie?el, Josephine M.,Loesche, Anne,Csuk, René
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p. 259 - 268
(2019/06/05)
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- Synthesis of cinnamic amide derivatives and their anti-melanogenic effect in α-MSH-stimulated B16F10 melanoma cells
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Of the three enzymes that regulate the biosynthesis of melanin, tyrosinase and its related proteins TYRP-1 and TYRP-2, tyrosinase is the most important because of its ability to limit the rate of melanin production in melanocytes. For treating skin pigmentation disorders caused by an excess of melanin, the inhibition of tyrosinase enzyme is by far the most established strategy. Cinnamic acid is a safe natural product with an (E)-β-phenyl-α,β-unsaturated carbonyl motif that we have previously shown to play an important role in high tyrosinase inhibition. Since cinnamic acid is relatively hydrophilic, which hinders its absorption on the skin, fifteen less hydrophilic cinnamic amide derivatives (1–15) were designed as safe and more potent tyrosinase inhibitors and were synthesized through a Horner-Wadsworth-Emmons reaction. The use of conc-HCl and acetic acid for debenzylation of the O-benzyl-protected cinnamic amides 40–54 produced the following three results. 1) Cinnamic amides 43, 48, and 53 with a 2,4-dibenzyloxyphenyl group, irrespective of the amine type of the amides, produced complex compounds with high polarity. 2) Cinnamic amides 40–42, 44, 50–52, and 54 with a benzylamino, or diethylamino group produced the desired debenzylated cinnamic amides 1–3, 5, 10–13, and 15. 3) Cinnamic amides 45–47, and 49 with an anilino moiety provided 3,4-dihydroquinolinones 16–19 through intramolecular Michael addition of the anilide group. Notably, the use of BBr3 as an alternative debenzylating agent for debenzylation of cinnamic amides 45–49 with the anilino moiety provided our desired cinnamic amides 6–10 without inducing the intramolecular Michael addition. Debenzylation of cinnamic amides 43, 48, and 53 with a 2,4-dibenzyloxyphenyl group was also successfully accomplished using BBr3 to give 4, 9, and 14. Among the nine compounds that inhibited mushroom tyrosinase more potently at 25 μM than kojic acid, four cinnamic amides 4, 5, 9, and 14 showed 3-fold greater tyrosinase inhibitory activity than kojic acid. The docking simulation using tyrosinase indicated that these four cinnamic amides (?6.2 to ?7.9 kcal/mol) bind to the active site of tyrosinase with stronger binding affinity than kojic acid (?5.7 kcal/mol). All four cinnamic amides inhibited melanogenesis and tyrosinase activity more potently than kojic acid in α-MSH-stimulated B16F10 melanoma cells in a dose-dependent manner without cytotoxicity. The strong correlation between tyrosinase activity and melanin content suggests that the anti-melanogenic effect of cinnamic amides is due to tyrosinase inhibitory activity. Considering that the cinnamic amides 4, 9, and 14, which exhibited strong inhibition on mushroom tyrosinase and potent anti-melanogenic effect in B16F10 cells, commonly have a 2,4-dihydroxyphenyl substituent, the 2,4-dihydroxyphenyl substituent appears to be essential for high anti-melanogenesis. These results support the potential of these four cinnamic amides as novel and potent tyrosinase inhibitors for use as therapeutic agents with safe skin-lightening efficiency.
- Ullah, Sultan,Kang, Dongwan,Lee, Sanggwon,Ikram, Muhammad,Park, Chaeun,Park, Yujin,Yoon, Sik,Chun, Pusoon,Moon, Hyung Ryong
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- Tyrosinase inhibition and anti-melanin generation effect of cinnamamide analogues
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Abnormal melanogenesis results in excessive production of melanin, leading to pigmentation disorders. As a key and rate-limiting enzyme for melanogenesis, tyrosinase has been considered an important target for developing therapeutic agents of pigment disorders. Despite having an (E)-β-phenyl-α,β-unsaturated carbonyl scaffold, which plays an important role in the potent inhibition of tyrosinase activity, cinnamic acids have not attracted attention as potential tyrosinase inhibitors, due to their low tyrosinase inhibitory activity and relatively high hydrophilicity. Given that cinnamic acids’ structure intrinsically features this (E)-scaffold and following our experience that minute changes in the chemical structure can powerfully affect tyrosinase activity, twenty less hydrophilic cinnamamide derivatives were designed as potential tyrosinase inhibitors and synthesised using a Horner-Wadsworth-Emmons reaction. Four of these cinnmamides (4, 9, 14, and 19) exhibited much stronger mushroom tyrosinase inhibition (over 90% inhibition) at 25 μM compared to kojic acid (20.57% inhibition); crucially, all four have a 2,4-dihydroxy group on the β-phenyl ring of the scaffold. A docking simulation using tyrosinase indicated that the four cinnamamides exceeded the binding affinity of kojic acid, and bound more strongly to the active site of tyrosinase. Based on the strength of their tyrosinase inhibition, these four cinnamamides were further evaluated in B16F10 melanoma cells. All four cinnamamides, without cytotoxicity, exhibited higher tyrosinase inhibitory activity (67.33 – 79.67% inhibition) at 25 μM than kojic acid (38.11% inhibition), with the following increasing inhibitory order: morpholino (9) = cyclopentylamino (14) cyclohexylamino (19) N-methylpiperazino (4) cinnamamides. Analysis of tyrosinase activity and melanin content in B16F10 cells showed that the four cinnamamides dose-dependently inhibited both cellular tyrosinase activity and melanin content and that their inhibitory activity at 25 μM was much better than that of kojic acid. The results of melanin content analysis well matched those of the cellular tyrosinase activity analysis, indicating that tyrosinase inhibition by the four cinnamamides is a major factor in the reduction of melanin production. These results imply that these four cinnamamides with a 2,4-dihydroxyphenyl group can act as excellent anti-melanogenic agents in the treatment of pigmentation disorders.
- Ullah, Sultan,Park, Chaeun,Ikram, Muhammad,Kang, Dongwan,Lee, Sanggwon,Yang, Jungho,Park, Yujin,Yoon, Sik,Chun, Pusoon,Moon, Hyung Ryong
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- Efficient synthesis and physicochemical characterization of natural danshensu, its S isomer and intermediates thereof
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The synthesis and molecular structure details of R- 3,4-dihydroxyphenyl lactic acid (danshensu) and related compounds, i.e. S isomer and the key intermediates have been described. Danshensu is an important water soluble phenolic acid of Salvia miltiorrhiza herb (danshen or red sag) with numerous applications in traditional Chinese medicine (TCM). Our synthetic approach was based on the Knoevenagel condensation of the protected 3,4-dihydroxybenzaldehyd and Meldrum acid derivative, followed by asymmetric Sharples dihydroxylation, reductive mono dehydroxylation and final deprotection. All compounds were characterized by various spectroscopic techniques: 1H-, 13C- magnetic resonance (NMR); Fourier-transformed infrared (FTIR); Raman, HR mass spectroscopy. For the determination of compound optical purities original HPLC methods were developed which allowed for the efficient resolution of danshensu R and S enantiomers as well as its intermediate enantiomers, using commercially available chiral stationary phases. Furthermore, in order to better understand danshensu specificity as a potential API in drug formulation, the physicochemical properties of the compounds were studied by thermal analysis, including differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA).
- Sidoryk, Katarzyna,Filip, Katarzyna,Cmoch, Piotr,?aszcz, Marta,Cybulski, Marcin
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p. 135 - 148
(2017/10/13)
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- Design, synthesis and anti-melanogenic effect of cinnamamide derivatives
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Pigmentation disorders are attributed to excessive melanin which can be produced by tyrosinase. Therefore, tyrosinase is supposed to be a vital target for the treatment of disorders associated with overpigmentation. Based on our previous findings that an (E)-β-phenyl-α,β-unsaturated carbonyl scaffold can play a key role in the inhibition of tyrosinase activity, and the fact that cinnamic acid is a safe natural substance with a scaffolded structure, it was speculated that appropriate cinnamic acid derivatives may exhibit potent tyrosinase inhibitory activity. Thus, ten cinnamamides were designed, and synthesized by using a Horner-Emmons olefination as the key step. Cinnamamides 4 (93.72% inhibition), 9 (78.97% inhibition), and 10 (59.09% inhibition) with either a 2,4-dihydroxyphenyl, or 4-hydroxy-3-methoxyphenyl substituent showed much higher mushroom tyrosinase inhibition at 25 μM than kojic acid (18.81% inhibition), used as a positive control. Especially, the two cinnamamides 4 and 9 having a 2,4-dihydroxyphenyl group showed the strongest inhibition. Docking simulation with tyrosinase revealed that these three cinnamamides, 4, 9, and 10, bind to the active site of tyrosinase more strongly than kojic acid. Cell-based experiments carried out using B16F10 murine skin melanoma cells demonstrated that all three cinnamamides effectively inhibited cellular tyrosinase activity and melanin production in the cells without cytotoxicity. There was a close correlation between cellular tyrosinase activity and melanin content, indicating that the inhibitory effect of the three cinnamamides on melanin production is mainly attributed to their capability for cellular tyrosinase inhibition. These results imply that cinnamamides having the (E)-β-phenyl-α,β-unsaturated carbonyl scaffolds are promising candidates for skin-lighting agents.
- Ullah, Sultan,Park, Yujin,Ikram, Muhammad,Lee, Sanggwon,Park, Chaeun,Kang, Dongwan,Yang, Jungho,Akter, Jinia,Yoon, Sik,Chun, Pusoon,Moon, Hyung Ryong
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p. 5672 - 5681
(2018/10/24)
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- Synthesis method of procyanidine compound Catechin
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The invention relates to a synthesis method of a procyanidine compound Catechin and belongs to the field of chemical synthesis. The method is as below: conducting benzyl protection reaction on trans-caffeic acid to produce O-Bz caffeic acid; subjecting O-Bz caffeic acid to an ester reduction reaction for synthesis of allyl alcohol; subjecting allyl alcohol to a Sharpless dihydroxylation reaction to synthesize a trihydroxy compound; subjecting the trihydroxy compound to a selective sulfonylation reaction to synthesize sulfonate; subjecting the sulfonate to an O-Ts leaving reaction to synthesize ternary epoxy; conducting a hydroxy mitsunobu reaction to synthesiz O-Ph epoxy; subjecting O-Ph epoxy to a ring-forming reaction to synthesize O-Bz Catechi; subjecting O-Bz Catechin to a palladium carbon deprotection reaction to synthesize the procyanidine compound Catechin (shown in figure). The invention has the characteristics of few reaction steps, high total yield, good product selectivity, and suitability for industrial production.
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Paragraph 0015; 0017
(2017/02/09)
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- Method for synthesizing kukoamine A and analogue thereof
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The invention relates to the technical field of medicines, and relates to a method for synthesizing a natural product kukoamine A and analogue thereof. The method comprises the following steps: (1) performing a nucleophilic reaction on hydroxyl, halogen or C1-C10 alkoxy or C1-C10 alkyl substituted or unsubstituted benzaldehyde and malonic acid to obtain a compound 1; (2) reacting the compound 1 in the step (1) with N-hydroxy succinimide to obtain a compound 2; (3) reacting the compound 2 with spermine to obtain a compound 3; and (4) reacting the compound 3 with hydrogen to reduce carbon-carbon double bond, and purifying. The preparation method is simple, and provides a compound base to pharmacological activity research of compounds with similar structures.
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- Synthesis of derivatives of methyl rosmarinate and their inhibitory activities against matrix metalloproteinase-1 (MMP-1)
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A series of MMP-1 inhibitors have been identified based upon a methyl rosmarinate scaffold using structure-based drug design methods. The best compound in the series showed an IC50 value of 0.4 μM. A docking study was conducted for compound (S)
- Yuan, Hu,Lu, Weiqiang,Wang, Liyan,Shan, Lei,Li, Honglin,Huang, Jin,Sun, Qingyan,Zhang, Weidong
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supporting information
p. 148 - 157
(2013/05/09)
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- Radical scavenging activity and performance of novel phenolic antioxidants in oils during storage and frying
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Novel phenolic antioxidants: 2a (6′-hydroxy-2′,5′, 7′,8′-tetramethylchroman-2′-yl)methyl 3-methoxy-4- hydroxycinnamate, 2b (6′-hydroxy-2′,5′,7′,8′- tetramethylchroman-2′-yl)methyl 3,5-dimethoxy-4-hydroxycinnamate, 2c (6′-hydroxy-2′,5′,7′,8′-tetramethylchr
- Catel, Yohann,Aladedunye, Felix,Przybylski, Roman
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- Efficient and practical asymmetric synthesis of isopropyl (R)-3-(3′,4′-dihydroxyphenyl)-2-hydroxypropanoate and its enantiomer
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The highly enantioselective synthesis of (R)-isopropyl 3-(3′, 4′-dihydroxyphenyl)-2-hydroxypropanoate and its enantiomer has been achieved starting from 3,4-dihydroxybenzaldehyde. The stereogenic centers were established through asymmetric dihydroxylation of (E)-isopropyl 3,4-bis(benzyloxy) cinnamate. A convenient manipulation in selective catalytic hydrogenation and deprotection was also accomplished in HCl-iPrOH employing 10% Pd/C catalyst.
- Chen, Ming,Chen, Hui,Wang, Yuzhen,Wang, Haibo,Nan, Yefei,Zheng, Xiaohui,Jiang, Ru
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experimental part
p. 4 - 7
(2011/04/17)
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- Chemical synthesis of hydroxycinnamic acid glucosides and evaluation of their ability to stabilize natural colors via anthocyanin copigmentation
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This work describes the chemical synthesis of O-aryl-β-D-glucosides and 1-O-β-D-glucosyl esters of hydroxycinnamic acids. In particular, O-aryl-β-D-glucosides were efficiently prepared via a simple diastereoselective glycosylation procedure using phase transfer conditions. Despite the lability of its ester linkage, 1-O-β-D-caffeoylglucose could also be obtained using a Lewis acid catalyzed glycosylation step and a set of protective groups that can be removed under neutral conditions. Hydroxycinnamic acid O-aryl-β-D-glucosides were then quantitatively investigated for their affinity for the naturally occurring anthocyanin malvin (pigment). Formation of the π-stacking molecular complexes (copigmentation) was characterized in terms of binding constants and enthalpy and entropy changes. The glucosyl moiety did not significantly alter these thermodynamic parameters, in line with a binding process solely involving the polyphenolic nuclei.
- Galland, Stephanie,Mora, Nathalie,Abert-Vian, Maryline,Rakotomanomana, Njara,Dangles, Olivier
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p. 7573 - 7579
(2008/09/18)
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- Synthesis and retrostructural analysis of libraries of AB3 and constitutional isomeric AB2 phenylpropyl ether-based supramolecular dendrimers
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We report the synthesis of methyl esters of 3-(4-hydroxyphenyl)propionic, 3-(3,4-dihydroxyphenyl)propionic, 3-(3,5-dihydroxyphenyl)propionic, and 3-(3,4,5-trihydroxyphenyl)propionic acids and their use in a convergent iterative strategy to prepare up to four generations of three libraries, one of 3,4,5- and two of constitutional isomeric 3,4- and 3,5-substituted 3-phenylpropyl dendrons. Each library contains 3-[3,4,5-tris(dodecyl-1-oxy) phenyl]propyl-, 3-[3,4-bis(dodecyl-1-oxy)phenyl]propyl-, 3-{3,4-bis[3-(4- dodecyl-1-oxyphenyl)propyl-1-oxy]phenyl}propyl-, and 3-{3,4,5-tris[3-(4-dodecyl- 1-oxyphenyl)propyl-1-oxy]phenyl}propyl ether first-generation dendrons on their periphery and -CO2CH3, -COOH, and -CH2OH groups at their apex. Regardless of their generation number and their periphery, internal, and apex structures, these dendrons self-assemble into supramolecular dendrimers that self-organize into all periodic and quasi-periodic assemblies encountered previously and in several unencountered with architecturally related benzyl ether-based supramolecular dendrimers. A variety of porous columnar lattices that were previously obtained only from dendritic dipeptides and hollow supramolecular spheres were also discovered from these building blocks. The more flexible and less compact 3-phenylpropyl ether repeat units are stable under acidic conditions, facilitate a simpler synthetic strategy, provide faster dynamics of self-assembly into higher-order supramolecular structures of larger dimensions, exhibit lower transition temperatures than the corresponding benzyl ether homologues, and demonstrate the generality of the self-assembly concept based on amphiphilic dendrons.
- Percec, Virgil,Peterca, Mihai,Sienkowska, Monika J.,Ilies, Marc A.,Aqad, Emad,Smidrkal, Jan,Heiney, Paul A.
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p. 3324 - 3334
(2007/10/03)
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- Antioxidant and antimicrobial activity evaluation of polyhydroxycinnamic acid ester derivatives
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Polyhydroxycinnamic acid esters 5a-p have been synthesized starting from the appropriately substituted benzaldehydes. The antioxidant activity of these esters has been determined by superoxide free radical scavenging activity and DPPH free radical scavenging activity. The SAR studies reveal that pyrogallol, catechol moieties are essential for good antioxidant activity and an increase in the length of alkyl chain of the ester decreases the activity. Butyl hydroxycinnamates exhibit higher antibacterial activity among the synthesized hydroxycinnamates 5a-p, but, none of these show significant antifungal activity.
- Venkateswarlu, Somepalli,Ramachandra, Mareullapudi S.,Krishnaraju, Alluri V.,Trimurtulu, Golakoti,Subbaraju, Gottumukkala V.
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p. 252 - 257
(2007/10/03)
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- Very short and efficient syntheses of the spermine alkaloid kukoamine A and analogs using isolable succinimidyl cinnamates
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Direct selective acylation of the primary amino functions of spermine and spermidine with a variety of isolable succinimidyl cinnamates, followed by catalytic hydrogenation, gave high yields of the spermine alkaloid kukoamine A and analogs suitable for structure-activity relationship studies. Suitable succinimidyl cinnamates were readily obtained through Wittig reaction of aromatic aldehydes with the ylides Ph3P=CRCO2Me, followed by saponification and activation with N-hydroxysuccinimide in the presence of N,N'-dicyclohexylcarbodiimide. Copyright
- Garnelis, Thomas,Athanassopoulos, Constantinos M.,Papaioannou, Dionissios,Eggleston, Ian M.,Fairlamb, Alan H.
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p. 264 - 265
(2007/10/03)
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- A convenient synthesis of the Echinacea-derived immunostimulator and HIV-1 integrase inhibitor (-)-(2R,3R)-chicoric acid
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The Echinacea-derived immunostimulator and HIV-1 integrase inhibitor (-)-chicoric acid (=2,3-bis{[3- (3,4-dihydroxyphenyl)-1-oxoprop-2-enyl]oxy}butanedioic acid; 1a) was conveniently prepared via a silane-promoted Pd-mediated chemoselective hydrogenolysis of its perbenzylated derivative 12a, which was generated from an efficient and reliable carbodiimide-mediated coupling reaction between the caffeic acid dibenzyl ether derivative 7 and commercially available (+)-dibenzyl L-tartrate (9a). The other naturally occurring dextrorotatory chicoric acid (1b) can be similarly prepared.
- Lamidey, Anne-Marie,Fernon, Lionel,Pouysegu, Laurent,Delattre, Charlotte,Quideau, Stephane,Pardon, Patrick
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p. 2328 - 2334
(2007/10/03)
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- A one-pot synthesis of 3-amino-3-arylpropionic acids
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3-Aminopropionic acids (β-amino acids) are biologically active compounds of interest in medicinal and pharmaceutical chemistry. Twenty-one 3-amino-3-arylpropionic acids were synthesized via a facile one-pot synthesis. In addition, a series of mechanistic studies have been performed to optimize the production of these β-amino acids. The reaction mechanism of this one-pot synthesis of β-amino acids, as well as the electronic effect of para-substitution and the influence of solvent polarity on the proposed reaction mechanism are discussed.
- Tan,Weaver
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p. 7449 - 7461
(2007/10/03)
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- Synthesis of vinyl caffeate, an antioxidant from Perilla frutescens Britton var. crispa (Thunb.)
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Mercuric acetate mediated trans vinylation has been used as a key step in the synthesis of vinyl caffeate 1. The title compound has been obtained from 3,4-dihydroxybenzaldehyde in four steps with an overall yield of 20%.
- Kavitha, Jakka,Rajasekhar,Subbaraju,Ramesh
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p. 1280 - 1281
(2007/10/03)
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- Synthesis of (±)-Rosmarinic Acid Methylester
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Regioselective cleavage of the glycidic ester 3 by BF3/ether to pyruvic acid ester 4 followed by NaBH4 reduction affords the lactic acid derivative 5a which in turn can be acylated by caffeoyl chloride 8c to yield the O-protected rosmarinic acid ester 9a. Alternatively, 9a can be prepared by acylation of 5a with diethylphosphono acetyl chloride (6c) thus generating the Wadsworth-Emmons reagent 7a which is subsequently reacted with the aldehyde 1a. The analogous reaction using the silyl protected educts 7d and 1b failed to give 9d. Finally, 9a is debenzylated by BCl3 furnishing the title compound 10a in fair total yield.
- Reimann,Maas,Pflug
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p. 995 - 1008
(2007/10/03)
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