- Enhancement of ibuprofen solubility and skin permeation by conjugation with l-valine alkyl esters
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New ibuprofen derivatives were made via conjugation with l-valine alkyl esters (ValOR), where R was changed from an ethyl to a hexyl group. The ionic structure was confirmed using NMR and FTIR. Specific rotation, solubility in commonly used solvents, thermal properties including phase transitions temperatures, and thermal stability were also determined. The ionic structure with a protonated amine group on an l-valine ester and melting points below 100 °C allowed inclusion of these ibuprofen derivatives into the pharmaceutically active protic ionic liquids. The ibuprofen salt solubility in deionised water and two buffer solutions at pH 5.4 and 7.4 were established and compared with the parent acid solubility. The octanol/water (buffer) partition coefficient, permeation through porcine skin, and accumulation in the skin were also measured. Ibuprofen pairing with l-valine alkyl esters [ValOR][IBU], caused higher solubility and a greater drug molecule absorption through biological membranes. log?P was lower for ibuprofen salts than for the acid and it increased with a longer l-valine ester cation alkyl chain. In vitro porcine skin tests showed that ibuprofen salts with a propyl or isopropyl ester in l-valine are particularly relevant for topical application. They provide transport for ibuprofen through the skin at much higher rate than the unmodified acid and a higher permeated ibuprofen concentration, which can improve efficacy. Thus, synthesised ibuprofen derivatives could be used as drug carriers in transdermal systems to provide better drug bioavailability, and they can be also be the source of exogenous l-valine.
- Janus, Ewa,Ossowicz, Paula,Klebeko, Joanna,Nowak, Anna,Duchnik, Wiktoria,Kucharski, ?ukasz,Klimowicz, Adam
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Read Online
- The effect of alcohols as vehicles on the percutaneous absorption and skin retention of ibuprofen modified with l-valine alkyl esters
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The effect of various alcohols as vehicles on skin permeability was compared for unmodified ibuprofen (IBU) and ion pairs of ibuprofen with l-valine alkyl esters [ValOR][IBU], in which the alkyl chain R was changed from C1 to C8. In vitro permeation experiments were conducted in a Franz cell with porcine skin. Methanol, ethanol, and isopropanol solutions of 70% (v/v) were chosen as vehicles for penetrants and a buffer solution of pH 5.4 or 7.4 as the acceptor phase. The comparisons of permeation profiles for various [ValOR][IBU] from different alcohols were determined. The cumulative mass, skin accumulation, steady-state flux, diffusion coefficient, and lag time were investigated and compared. It was observed that i-propanol was the best enhancer of skin permeation of both unmodified ibuprofen and its salts with l-valine alkyl esters for both acceptor phases. The permeability of the various carriers increases with increasing chain-length of the alcohol. In most cases, significantly higher cumulative mass was found in the acceptor buffer of pH 7.4. The conjugate of ibuprofen with l-valine propyl ester [ValOPr][IBU] permeated the skin to the highest degree in comparison to unmodified ibuprofen. The accumulation of ibuprofen was higher for all salts in relation to the parent acid applied onto the skin. The greatest amounts of ibuprofen were accumulated in the skin when ibuprofen was used as the ionic pair with l-valine butyl ester, [ValOBu][IBU] in the i-propanol solution and pH 7.4 buffer as the acceptor phase.
- Duchnik, Wiktoria,Janus, Ewa,Klebeko, Joanna,Klimowicz, Adam,Kucharski, ?ukasz,Nowak, Anna,Ossowicz, Paula
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Read Online
- Salicylic acid as ionic liquid formulation may have enhanced potency to treat some chronic skin diseases
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In recent years, numerous studies have shown that conversion of conventional drugs in ionic liquid (IL) formulation could be a successful strategy to improve their physicochemical properties or suggest a new route of administration. We report the synthesis and detailed characterization of eight salicylic acid-based ILs (SA-ILs) containing cation non-polar or aromatic amino acid esters. Using in vitro assays, we preliminary evaluated the therapeutic potency of the novel SA-ILs. We observed that conversion of the SA into ionic liquids led to a decrease in its cytotoxicity toward NIH/3T3 murine embryo fibroblasts and human HaCaT keratinocytes. It should be mentioned is that all amino acid alkyl ester salicylates [AAOR][SA] inhibit the production of the proinflammatory cytokine IL-6 in LPS-stimulated keratinocytes. Moreover, keratinocytes, pretreated with [PheOMe][SA] and [PheOPr][SA] seem to be protected from LPS-induced inflammation. Finally, the novel compounds exhibit a similar binding affinity to bovine serum albumin (BSA) as the parent SA, suggesting a similar pharmacokinetic profile. These preliminary results indicate that SA-ILs, especially those with [PheOMe], [PheOPr], and [ValOiPr] cation, have the potential to be further investigated as novel topical agents for chronic skin diseases such as psoriasis and acne vulgaris.
- ?wi?tek, Ewelina,Guncheva, Maya,Janus, Ewa,Klebeko, Joanna,Krachmarova, Elena,Ossowicz-Rupniewska, Paula,Szachnowska, Joanna,Taneva, Stefka G.
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- Stereoretentive N-Arylation of Amino Acid Esters with Cyclohexanones Utilizing a Continuous-Flow System
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The N-arylation of chiral amino acid esters with minimal racemization is a challenging transformation because of the sensitivity of the α-stereocenter. A versatile synthetic method was developed to prepare N-arylated amino acid esters using cyclohexanones as aryl sources under continuous-flow conditions. The designed flow system, which consists of a coil reactor and a packed-bed reactor containing a Pd(OH)2/C catalyst, efficiently afforded the desired N-arylated amino acids without significant racemization, accompanied by only small amounts of easily removable co-products (i. e., H2O and alkanes). The efficiency and robustness of this method allowed for the continuous synthesis of the desired product in very high yield and enantiopurity with high space-time yield (74.1 g L?1 h?1) and turnover frequency (5.9 h?1) for at least 3 days.
- Ichitsuka, Tomohiro,Komatsuzaki, Shingo,Masuda, Koichiro,Koumura, Nagatoshi,Sato, Kazuhiko,Kobayashi, Shū
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supporting information
p. 10844 - 10848
(2021/05/31)
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- Stereospecific Synthesis of 3,4-Dihydro-2 H-naphtho-1,4-oxazin-2-ones by Unification of Benzoxepine-4-carboxylates with Chiral Amino Acid Ethyl Esters
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A novel and efficient stereocontrolled method has been developed for the preparation of chiral 3,4-dihydro-2H-naphtho[1,2-b][1,4]oxazin-2-ones by the reaction of benzoxepine-4-carboxylates with chiral amino acid ethyl esters for the first time. The chiral 3,4-dihydro-2H-naphtho-1,4-oxazinones have been achieved in one step by the formation of C-N, C-C, and C-O bonds.
- Bhimapaka, China Raju,Kasagani, Veera Prasad,Kurma, Siva Hariprasad
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supporting information
p. 2976 - 2983
(2020/03/23)
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- Ketoprofen-based ionic liquids: Synthesis and interactions with bovine serum albumin
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The development of ionic liquids based on active pharmaceutical ingredients (API-ILs) is a possible solution to some of the problems of solid and/or hydrophobic drugs such as low solubility and bioavailability, polymorphism and an alternative route of administration could be suggested as compared to the classical drug. Here, we report for the first time the synthesis and detailed characterization of a series of ILs containing a cation amino acid esters and anion ketoprofen (KETO-ILs). The affinity and the binding mode of the KETO-ILs to bovine serum albumin (BSA) were assessed using fluorescence spectroscopy. All compounds bind in a distance not longer than 6.14 nm to the BSA fluorophores. The estimated binding constants (KA) are in order of 105 L mol-1, which is indicative of strong drug or IL-BSA interactions. With respect to the ketoprofen-BSA system, a stronger affinity of the ILs containing l-LeuOEt, l-ValOBu, and l-ValOEt cation towards BSA is clearly seen. Fourier transformed infrared spectroscopy experiments have shown that all studied compounds induced a rearrangement of the protein molecule upon binding, which is consistent with the suggested static mechanism of BSA fluorescence quenching and formation of complexes between BSA and the drugs. All tested compounds were safe for macrophages.
- ?wi?tek, Ewelina,Angelov, Ivan,Guncheva, Maya,Janus, Ewa,Kardaleva, Proletina,Klebeko, Joanna,Ossowicz, Paula,Yancheva, Denitsa
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- Accessing d-Valine Synthesis by Improved Variants of Bacterial Cyclohexylamine Oxidase
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Chemoenzymatic deracemization was applied to prepare d-valine from racemic valine ethyl ester or l-valine ethyl ester in high yield (up to 95 %) with excellent optical purity (>99 % ee) by employing a newly evolved cyclohexylamine oxidase (CHAO) variant Y321I/M226T exhibiting catalytic efficiency that was 30 times higher than that of the wildtype CHAO. Interestingly, CHAO and its variants showed opposite enantioselectivity for valine ethyl ester and phenylalanine ethyl ester.
- Gong, Rui,Yao, Peiyuan,Chen, Xi,Feng, Jinhui,Wu, Qiaqing,Lau, Peter C. K.,Zhu, Dunming
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p. 387 - 390
(2017/12/26)
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- Carbon Dioxide-Mediated C(sp3)-H Arylation of Amine Substrates
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Elaborating amines via C-H functionalization has been an important area of research over the past decade but has generally relied on an added directing group or sterically hindered amine approach. Since free-amine-directed C(sp3)-H activation is still primarily limited to cyclization reactions and to improve the sustainability and reaction scope of amine-based C-H activation, we present a strategy using CO2 in the form of dry ice that facilitates intermolecular C-H arylation. This methodology has been used to enable an operationally simple procedure whereby 1° and 2° aliphatic amines can be arylated selectively at their γ-C-H positions. In addition to potentially serving as a directing group, CO2 has also been demonstrated to curtail the oxidation of sensitive amine substrates.
- Kapoor, Mohit,Liu, Daniel,Young, Michael C.
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p. 6818 - 6822
(2018/05/31)
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- Temperature-triggered switchable helix-helix inversion of poly(phenylacetylene) bearing L-valine ethyl ester pendants and its chiral recognition ability
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A phenylacetylene containing the L-valine ethyl ester pendant (PAA-Val) was synthesized and polymerized by an organorhodium catalyst (Rh(nbd)BPh4) to produce the corresponding one-handed helical cis-poly(phenylacetylene) (PPAA-Val). PPAA-Val showed a unique temperature-triggered switchable helix-sense in chloroform, while it was not observed in highly polar solvents, such as N,N′-dimethylformamide (DMF). By heating the solution of PPAA-Val in chloroform, the sign of the CD absorption became reversed, but recovered after cooling the solution to room temperature. Even after six cycles of the heating-cooling treatment, the helix sense of the PPAA-Val's backbone was still switchable without loss of the CD intensity. The PPAA-Val was then coated on silica gel particles to produce novel chiral stationary phases (CSPs) for high-performance liquid chromatography (HPLC). These novel PPAA-Val based CSPs showed a high chiral recognition ability for racemic mandelonitrile (α = 2.18) and racemic trans-N,N′-diphenylcyclohexane-1,2-dicarboxamide (α = 2.60). Additionally, the one-handed helical cis-polyene backbone of PPAA-Val was irreversibly destroyed to afford PPAA-Val-H by heating in dimethyl sulfoxide (DMSO) accompanied by the complete disappearance of the Cotton effect. Although PPAA-Val-H had the same L-valine ethyl ester pendants as its cis-isomer PPAA-Val, it showed no chiral recognition. It was concluded that the one-handed helical cis-polyene backbone of PPAA-Val plays an important role in the chiral recognition ability.
- Zhou, Yanli,Zhang, Chunhong,Qiu, Yuan,Liu, Lijia,Yang, Taotao,Dong, Hongxing,Satoh, Toshifumi,Okamoto, Yoshio
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- Orthogonally Protected Sch?llkopf's Bis-lactim Ethers for the Asymmetric Synthesis of α-Amino Acid Derivatives and Dipeptide Esters
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Alkylation of the aza-enolates of orthogonally protected chiral bis-lactim ethers with electrophiles proceeds with good levels of diastereocontrol to afford trans-alkylated adducts that can be efficiently deprotected via hydrolysis/hydrogenation procedures to afford non-proteinogenic α-amino acid or dipeptide ester derivatives.
- Hutchby, Marc,Sedgwick, Adam C.,Bull, Steven D.
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p. 2036 - 2049
(2016/07/06)
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- Design and synthesis of a s-triazene based asymmetric organocatalyst and its application in enantioselective alkylation
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A very efficient chiral organocatalyst was prepared from the readily available cyanuric chloride. The asymmetric catalyst exhibited a highly enantioselective catalytic performance for the alkylation of a glycinate Schiff base, which provides a useful procedure for the enantioselective synthesis of structurally diverse natural and unnatural α-alkyl-α-amino acids.
- Mangawa, Shrawan K.,Singh, Ashawani K.,Awasthi, Satish K.
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p. 61144 - 61147
(2015/08/03)
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- Synthesis and cytotoxic evaluation of N2-benzylated quaternary β-carboline amino acid ester conjugates
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The β-carboline alkaloids have been characterized as a class of potential antitumor agents. To further enhance the cytotoxic potency and improve water solubility of β-carboline, a series of new β-carboline amino acid ester, β-carboline amino acid and N2-benzylated quaternary β-carboline amino acid ester conjugates were designed and synthesized, and the cytotoxic activities of these compounds were evaluated using a panel of human tumor cell lines. The N2-benzylated quaternary β-carboline amino acid ester conjugates represented the most interesting cytotoxic activities. Particularly, compounds 8b and 8g were found to be the most potent compounds with IC50 values lower than 20?μM against all human tumor cell lines investigated. These results confirmed that the N2-benzyl substituent on the β-carboline ring played an important role in the modulation of the cytotoxic potencies.
- Ma, Chunming,Cao, Rihui,Shi, Buxi,Li, Shaoxue,Chen, Zhiyong,Yi, Wei,Peng, Wenlie,Ren, Zhenhua,Song, Huacan
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experimental part
p. 1515 - 1523
(2010/06/16)
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- General approach to the total synthesis of 9-methoxy-substituted indole alkaloids: Synthesis of mitragynine, as well as 9-methoxygeissoschizol and 9-methoxy-Nb-methylgeissoschizol
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(Chemical Equation Presented) Herein, the full details of the synthesis of the 9-methoxy-substituted Corynanthe indole alkaloids mitragynine (1), 9-methoxygeissoschizol (3), and 9-methoxy-Nb-methylgeissoschizol (4) are described. Initially, an efficient synthetic route to the optically active 4-methoxytryptophan ethyl ester 20 on a multigram scale was developed via a Mori-Ban-Hegedus indole synthesis. The ethyl ester of D-4-methoxytryptophan 20 was obtained with a radical-mediated regioselective bromination of indoline 12 serving as a key step. Alternatively, the key 4-methoxytryptophan intermediate 22 could be synthesized by the Larock heteroannulation of aryl iodide 10b with the internal alkyne 21a. The use of the Boc-protected aniline 10b was crucial to the success of this heteroannulation. The α,β-unsaturated ester 6 was synthesized via the Pictet-Spengler reaction as the pivotal step. This was followed by a Ni(COD)2-mediated cyclization to set up the stereocenter at C-15. The benzyloxy group in 31 was removed to provide the intermediate ester 5. This chiral tetracyclic ester 5 was employed to accomplish the first total synthesis of 9-methoxygeissoschizol (3) and 9-methoxy-N b-methylgeissoschizol (4) as well as the opioid agonistic indole alkaloid mitragynine (1).
- Ma, Jun,Yin, Wenyuan,Zhou, Hao,Liao, Xuebin,Cook, James M.
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supporting information; experimental part
p. 264 - 273
(2009/04/10)
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- Mechanism study on the oligomerization of amino acids into peptides by phosphorus trichloride
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As treated by phosphorus trichloride, amino acids could oligomerize into polypeptides. Based on the results obtained by 31P-NMR and ESI-MS/MS, a possible reaction mechanism was proposed. The mechanism might undergo a penta-coordinated phosphorus intermediat. The activated amino acid was a five-membered cyclic penta-coordinated phosphorus intermediate. The nucleophilic attack of the amino group from an amino acid or peptide on the carbonyl group of intermediate led to the formation of peptide and released one equivalent dichloride phosphoric acid. The repetition of the reaction sequence generated a series of oligopeptides. Copyright Taylor & Francis Group, LLC.
- Zhao, Wenjie,Zhao, Dongxin,Lu, Kui
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scheme or table
p. 691 - 698
(2009/05/07)
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- Total synthesis of the opioid agonistic indole alkaloid mitragynine and the first total syntheses of 9-methoxygeissoschizol and 9-methoxy-N b-methylgeissoschizol
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An enantiospecific method for the synthesis of 4-methoxytryptophan has been developed via a regiospecific Larock heteroannulation and employed for the first total syntheses of 9-methoxygeissoschizol and 9-methoxy-N b-methylgeissoschizol, as well as the total synthesis of the opioid agonistic alkaloid mitragynine. The asymmetric Pictet-Spengler reaction and a Ni(COD)2-mediated cyclization served as key steps.
- Ma, Jun,Yin, Wenyuan,Zhou, Hao,Cook, James M.
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p. 3491 - 3494
(2008/02/12)
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- Analogs of 4-hydroxyisoleucine and uses thereof
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The invention relates to analogs of 4-hydroxyisoleucine, and to lactones, pharmaceutically acceptable salts, and prodrugs thereof, to processes for their preparation, and to pharmaceutical compositions comprising the same. The analogs of the invention stimulate both glucose uptake and insulin secretion, and may thus be useful for the prevention and treatment of disorders of carbohydrate or lipid metabolism, including diabetes mellitus (type 1 and type 2 diabetes), pre-diabetes, and Metabolic Syndrome.
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Page/Page column 46-47
(2008/06/13)
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- Compounds and compositions for use in the prevention and treatment of obesity and related syndromes
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The invention relates to 4-hydroxyisoleucine, isomers, analogs, lactones, salts, and prodrugs thereof, to processes for their preparation, and to pharmaceutical compositions comprising the same. More particularly, the invention relates to the use of those compounds in the prevention and treatment of obesity and related syndromes.
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Page/Page column 59
(2010/11/24)
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- Efficient asymmetric synthesis of biologically important tryptophan analogues via a palladium-mediated heteroannulation reaction
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A novel and concise synthesis of optically active tryptophan derivatives was developed via a palladium-catalyzed heteroannulation reaction of substituted o-iodoanilines with an internal alkyne. The required internal alkyne 14a or 25 was prepared in greater than 96% de via alkylation of the Schoellkopf chiral auxiliary 19 employing diphenyl phosphate as the leaving group. The Schoellkopf chiral auxiliary was chosen here for the preparation of L-tryptophans would be available from D-valine while the D-isomers required for natural product total synthesis would originate from the inexpensive L-valine (300-g scale). Applications of the palladium-catalyzed heteroannulation reaction were extended to the first asymmetric synthesis of L-isotryptophan 38 and L-benz[f]tryptophan 39. More importantly, the optically pure 6-methoxy-D-tryptophan 62 was prepared by this protocol on a large scale (>300 g). This should permit entry into many ring-A oxygenated indole alkaloids when coupled with the asymmetric Pictet-Spengler reaction. In addition, an improved total synthesis of tryprostatin A (9a) was accomplished in 43% overall yield employing this palladium-mediated process.
- Ma,Liu,Li,Flippen-Anderson,Yu,Cook
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p. 4525 - 4542
(2007/10/03)
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- A Strategy Towards the Stereoselective Synthesis of 5-Hydroxylysine
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A stereoselective synthesis of 5-hydroxylysine is described in which the α-stereogenic centre is generated by a Schoellkopf amino acid synthesis, and the ethanolamine structure is obtained via Sharpless aminohydroxylation from an olefin moiety. The reactions and their selectivities are studied.
- Loehr, Birgit,Orlich, Simone,Kunz, Horst
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p. 1139 - 1141
(2007/10/03)
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- A mild and convenient procedure for the esterification of amino acids
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Chiral amino acids are esterified in high yield and purity at room temperature by stirring with amberlyst-15 in alcohols.
- Anand, Ramesh C.,Vimal
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p. 1963 - 1965
(2007/10/03)
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- A Concise Synthesis of Optically Active 2- Bromotryptophan Amino Acids Present in Konbamide and Jaspamide Via A Regiospecific Bromination Procedure
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A highly stereoselective synthesis of optically active 2-bromo-5-hydroxytryptophan 1a and important derivatives 1b and 1c as well as their 2-bromotryptophan analogs was achieved in three steps from 2-bromo-3-bromomethylindoles 3a and 3b, respectively.
- Zhang, Puwen,Liu, Ruiyan,Cook, James M.
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p. 9133 - 9136
(2007/10/02)
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- 68. Stereoselective Synthesis of (2S,6S)-2,6-Diaminoheptanedioic Acid and of Unsymmetrical Derivatives of meso-2,6-Diaminoheptanedioic Acid
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Specific inhibition of enzymes of the diaminopimelate pathway (L-lysine biosynthesis) should, in principle, lead to selective antibacterial agents or herbicides.For this purpose, enantioselective syntheses were devised for (2S,6S)-2,6-diaminoheptanedioic acid (L,L-diaminopimelate, 1), (2R,6S)-2,6-diamino-2-methylhept-3-enedioic acid (10), (2R,6S)-2,6-diaminohept-3-enedioic acid (9),(2R,6S)-2,6-diamino-4-fluorohept-3-enedioic (42),and (2S,6S)-2,6-diamino-3-chloroheptanedioic acid (5).The Schoellkopf bislactim-ether methodology was applied to control the configuration of C(2) and C(6) of 1, C(2) of 10, as well as C(6) of 9 and 42.Semialdehyde derivatives of L-glutamate afforded C(6) of 10 and 5, while the (R)-configurated C(2) of 9 and 42 were derived from L-serine.For this purpose, the synthesis of the Garner aldehyde 32 has been improved.As chromatographic purifications and the low temperatures for the reduction of the carboxylic acid are eliminated, this valuable intermediate can now be prepared in bulk quantities.An enantio- and diastereoselective aldol addition of a glycine titanium-enolate was applied for the construction of 5(C(2) and C(3)).As all chiral building blocks and reagents used are available in both enantiomeric forms, these routes should also be suitable for the selective synthesis of the other stereoisomers of these bis(α-amino acids).
- Bold, Guido,Allmendinger, Thomas,Herold, Peter,Moesch, Luzia,Schaer, Hans-Peter,et al.
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p. 865 - 882
(2007/10/02)
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- A New Chiral Glycine Synthon. Synthesis, X-Ray Structure of (-)-(2S,4R)-2-Ethoxycarbonyl-4-phenyl-1,3-oxazolidine and Diastereoselective Nucleophilic Ring Opening to (R)-Ethyl α-Amino Carboxylates.
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Condensation of (R)-N-benzyl-2-phenylglycinol 1 with the methyl hemiacetal of ethyl glyoxylate leads to (2S,4R)-2-ethoxycarbonyl-4-phenyl-1,3-oxazolidine 2 as the major product, obtained as a pure enantiomer after column chromatography.Compound 2 is stereoselectively cleaved by dialkylzinc reagents, prepared from alkylmagnesium iodides and ZnCl2, with moderate to good d.e. (72-94 percent).These compounds, after separation by column chromatography and debenzylation by hydrogenolysis in the presence of 10percent Pd on carbon, lead to enantiomerically pure ethyl α-amino carboxylates with good chemical yields. Key words: Chiral Oxazolidines, alpha-amino Esters, Chiral Glycine Synthon, Ring Opening, Asymmetric Synthesis
- Andres, Celia,Gonzalez, Alfonso,Pedrosa, Rafael,Perez-Encabo,Garcia-Granda, Santiago,et al.
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p. 4743 - 4746
(2007/10/02)
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- ENANTIOSELECTIVE SYNTHESES OF α-AMINO ACIDS FROM 10-SULFONAMIDO-ISOBORNYL ESTERS AND DI-t-BUTYL AZODICARBOXYLATE
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Successive treatment of chiral esters 7 with LDA/Me3SiCl and di-t-butyl azodicarboxylate/TiCl4 and Ti(OiPr)4 gave N,N-di-t-butoxycarbonylhydrazinoesters 11 which on deacylation, hydrogenolysis, transesterification and acidic hydrolysis furnished (2S)-α-amino acid hydrochlorides 13 in good overall yields, high enantiomeric purity and with efficient recovery of the alcohol auxiliary 4.Experimental evidence for the configuration and conformation of the intermediate O-silyl ketene acetals 1 is provided.
- Oppolzer, Wolfgang,Moretti, Robert
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p. 5541 - 5552
(2007/10/02)
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