- Configurationally Stable (S)- and (R)-α-Methylproline-Derived Ligands for the Direct Chemical Resolution of Free Unprotected β3-Amino Acids
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Reported herein is a chemical method for the direct resolution of unprotected racemic β-substituted-β-amino acids (β3-AAs) that uses specially designed, stable, and recyclable α-methylproline-derived chiral ligands. The versatility of this methodology is unmatched by biocatalytic approaches. The method shows a broad synthetic generality for various aryl- or alkyl-substituted β3-AAs, and the new nonracemizable ligands can be accessed readily. Furthermore, the presented method produces an excellent stereochemical outcome and has a fully recyclable source of chirality, and the reaction conditions are operationally simple and convenient. The procedure has also been successfully applied to the scalable synthesis of the anti-HIV drug maraviroc.
- Zhou, Shengbin,Wang, Shuni,Wang, Jiang,Nian, Yong,Peng, Panfeng,Soloshonok, Vadim A.,Liu, Hong
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Read Online
- Synthetic method for novel chiral ligand, metal chelate, multiple unnatural amino acids, maraviroc and key intermediate thereof
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The invention discloses a synthetic method for a novel chiral ligand, a metal chelate, multiple unnatural amino acids, maraviroc and a key intermediate thereof. According to the synthetic method, (R)-2-methylproline is selected as a starting material, and asymmetrical resolution is induced by utilizing a nickel chelate, so that (S)-beta3-amino acid is obtained, and (S)-3-amino-3-phenylpropionic acid is taken as the key intermediate for synthesizing maraviroc, so that yield is high, and ee value reaches more than or equal to 98.2%. The method disclosed by the invention has the advantages that source of raw materials is wide, conditions of a synthetic process are mild, control is easy, and optical purity of products is high.
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Paragraph 0497-0499
(2018/04/26)
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- Ureidopeptide-based Bronsted bases: Design, synthesis and application to the catalytic enantioselective synthesis of β-amino nitriles from (arylsulfonyl)acetonitriles
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The addition of cyanoalkyl moieties to imines is a very attractive method for the preparation of β-amino nitriles. We present a highly efficient organocatalytic methodology for the stereoselective synthesis of β-amino nitriles, in which the key to success is the use of ureidopeptide-based Bronsted base catalysts in combination with (arylsulfonyl)acetonitriles as synthetic equivalents of the acetonitrile anion. The method gives access to a variety of β-amino nitriles with good yields and excellent enantioselectivities, and broadens the stereoselective Mannich-type methodologies available for their synthesis. Learning from peptides: A concise route for the catalytic enantioselective synthesis of β-amino nitriles has been achieved by using ureidopeptide-based Bronsted bases as catalysts in the Mannich reaction of N-Boc imines and (arylsulfonyl)acetonitriles (see scheme; Boc=tert-butoxycarbonyl, napht=naphthyl, TMS=trimethylsilyl).
- Diosdado, Saioa,Lopez, Rosa,Palomo, Claudio
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supporting information
p. 6526 - 6531
(2014/06/09)
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- Chemical kinetic resolution of unprotected β-substituted β-amino acids using recyclable chiral ligands
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The first chemical method for resolution of N,C-unprotected β-amino acids was developed through enantioselective formation and disassembly of nickel(II) complexes under operationally convenient conditions. The specially designed chiral ligands are inexpensive and can be quantitatively recycled along with isolation of the target β-substituted-β-amino acids in good yields and excellent enantioselectivity. The method features a broad synthetic generality including β-aryl, β-heteroaryl, and β-alkyl-derived β-amino acids. The procedure is easily scaled up, and was used for the synthetically and economically advanced preparation of the anti-diabetic drug sitagliptin. The nick of time: A chemical method for resolution of unprotected β-amino acids rac-1 was developed through enantioselective formation and disassembly of nickel(II) complexes to deliver the target β-substituted β-amino acids in good yields and excellent enantioselectivity. The chiral ligands are inexpensive and can be quantitatively recycled. The procedure was used for the preparation of anti-diabetic drug sitagliptin.
- Zhou, Shengbin,Wang, Jiang,Chen, Xia,Acena, Jose Luis,Soloshonok, Vadim A.,Liu, Hong
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supporting information
p. 7883 - 7886
(2014/08/05)
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- SONIC HEDGEHOG MODULATORS
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Sonic Hedgehog modulators and methods of use thereof are provided for.
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Paragraph 1043
(2014/04/17)
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- Asymmetric biocatalysis of S-3-amino-3-phenylpropionic acid with new isolated Methylobacterium Y1-6
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β-amino acids are widely used in drug research, and S-3-amino-3-phenylpropionic acid (S-APA) is an important pharmaceutical intermediate of S-dapoxetine, which has been approved for the treatment of premature ejaculation. Chiral catalysis is an excellent method for the preparation of enantiopure compounds. In this study, we used (±)-ethyl-3-amino-3-phenylpropanoate (EAP) as the sole carbon source. Three hundred thirty one microorganisms were isolated from 30 soil samples, and 17 strains could produce S-APA. After three rounds of cultivation and identification, the strain Y1-6 exhibiting the highest enantioselective activity of S-APA was identified as Methylobacterium oryzae. The optimal medium composition contained methanol (2.5 g/L), 1,2-propanediol (7.5 g/L), soluble starch (2.5 g/L), and peptone (10 g/L); it was shaken at 220 rpm for 4-5 days at 30 C. The optimum condition for biotransformation of EAP involved cultivation at 37 C for 48 h with 120 mg of wet cells and 0.64 mg of EAP in 1 ml of transfer solution. Under this condition, substrate ee was 92.1% and yield was 48.6%. We then attempted to use Methylobacterium Y1-6 to catalyze the hydrolytic reaction with substrates containing 3-amino-3-phenyl-propanoate ester, N-substituted-β-ethyl-3-amino-3-phenyl-propanoate, and γ-lactam. It was found that 5 compounds with ester bonds could be stereoselectively hydrolyzed to S-acid, and 2 compounds with γ-lactam bonds could be stereoselectively hydrolyzed to (-)-γ-lactam.
- Li, Yi,Wang, Wenfu,Huang, Yumian,Zou, Qianwen,Zheng, Guojun
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p. 1674 - 1678
(2013/11/19)
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- Organocatalytic asymmetric mannich reactions with JV-Boc and JV-Cbz protected α-amido sulfones (Boc: Tert-butoxycarbonyl, Cbz: Benzyloxycarbonyl)
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Different malonates and βketoesters can react with N-tert-butoxycarbonyl- (N-Boc) and N-benzyloxycarbonyl- (N-Cbz) protected α-amido sulfones in an organocatalytic asymmetric Mannich-type reaction. The reaction makes use of a simple and easily obtained ph
- Marianacci, Olindo,Micheletti, Gabriele,Bernardi, Luca,Fini, Francesco,Fochi, Mariafrancesca,Pettersen, Daniel,Sgarzani, Valentina,Ricci, Alfredo
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p. 8338 - 8351
(2008/04/01)
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- Iridium(I)-catalyzed regio- and enantioselective allylic amidation
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Ir(I)-catalyzed intermolecular allylic amidation of ethyl allyl carbonates with soft nitrogen nucleophiles under completely 'salt-free' conditions is described. A combination of [Ir(COD)Cl]2, a chiral phosphoramidite ligand L*, and DBU as a base in THF effects the reaction. The reaction appears to be quite general, accommodating a wide variety of R-groups and soft nitrogen nucleophiles, and proceeds with excellent regio- and enantioselectivities to afford the branched N-protected allylic amines. The developed reaction was conveniently utilized in the asymmetric synthesis of N-Boc protected α- and β-amino acids as well as (-)-cytoxazone.
- Singh, Om V.,Han, Hyunsoo
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p. 7094 - 7098
(2008/03/11)
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- The Mannich reaction of malonates with simple imines catalyzed by bifunctional cinchona alkaloids: Enantioselective synthesis of β-amino acids
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We describe the first efficient, direct asymmetric Mannich reactions with malonates and N-Boc aryl and alkyl imines by cooperative hydrogen-bonding catalysis with a cinchona alkaloid bearing a thiourea functionality. We have also extended the scope of thi
- Song, Jun,Wang, Yi,Deng, Li
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p. 6048 - 6049
(2007/10/03)
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- ARYLAMIDES
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The invention relates to compounds of formula (I), to a method for their production, to pharmaceutical compositions containing said compounds and to their use for the treatment and/or prophylaxis of human or animal diseases, in particular bacterial infections.
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Page/Page column 57
(2010/02/06)
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- SUBSTITUTED ALKYLAMIDES
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The invention relates to compounds, method for producing them, pharmaceutical compositions comprising them and the use thereof in the treatment and/or prophylaxis of human or animal diseases, especially bacterial infectious diseases.
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Page/Page column 42
(2010/02/10)
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- A convenient synthesis of chiral β3-amino acids
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A novel method for the synthesis of chiral β3-amino acids is developed where the acid functionality was built by oxidative cleavage of an α-allylic group that was introduced by Evans' asymmetric alkylation of an appropriate acid substrate and the amino part came from the amide of the original carboxyl group following a modified Hofmann rearrangement reaction.
- Chakraborty, Tushar K.,Ghosh, Animesh
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p. 2039 - 2040
(2007/10/03)
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- EPC-synthesis of functionalised amides via chiral β-nitrogenated organolithium compounds
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The deprotonation of chiral chloroamides or carbamates 1, 4, 7, 10, 13 and 16 with n-butyllithium followed by in situ lithiation with lithium naphthalenide, both at -78°C in THF, leads to the formation of the corresponding chiral dianionic intermediates,
- Foubelo, Francisco,Yus, Miguel
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p. 2911 - 2922
(2007/10/03)
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- A Concise Enantioselective Synthesis of Allylamines and N-Boc-β-Amino Acids
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A new and efficient enantioselective synthesis of allylamines and N-Boc-β-amino acids has been developed.Starting from enantiomerically enriched N-diphenylmethyl-3-amino-1,2-diols, allylamines are easily obtained by a Corey-Hopkins deoxygenative protocol.After a change in the nitrogen protecting group, the resulting N-Boc allylamines are converted into β-amino acids by hydroboration with 9-BBN followed by oxidation with PDC in DMF.
- Alcon, Montserrat,Canas, Marc,Poch, Marta,Moyano, Albert,Pericas, Miquel A.,Riera, Antoni
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p. 1589 - 1592
(2007/10/02)
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- Carbohydrates as Chiral Templates: Diastereoselective Synthesis of N-Glycosyl-N-homoallylamines and and β-Amino Acids from Imines
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Complexing properties and chirality of carbohydrates were utilized in diastereoselective reactions of O-pivaloylated N-galactosylimines with allylsilanes and -stannanes.With allyltrimethylsilane in the presence of SnCl4 imines 2 of aromatic and heteroaromatic aldehydes were converted to homoallylamines 3, giving ratios of diastereomers higher than 7:1.No addition products derived from α-anomeric aromatic imines were formed.Aliphatic homoallylamines 3 were synthesized by using allyltributylatannane in the presence of SnCl4.Both α- and β-anomeric aliphatic imines reacted with the allylstannane.They gave the same ratio of diastereomers and showed the same sense of asymmetric induction.
- Laschat, Sabine,Kunz, Horst
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p. 5883 - 5889
(2007/10/02)
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- ENANTIOSELECTIVE TOTAL SYNTHESIS OF (+)-(S)-DIHYDROPERIPHYLLINE
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The first enantioselective total synthesis of (+)-(S)-dihydroperiphylline was achieved from (S)-β-phenyl-β-alanine, prepared by chelation controlled phenylation of the Schiff base, by a new route involving 13-membered lactam formation via iminium cyclization.
- Kaseda, Takehiko,Kikuchi, Toyohiko,Kibayashi, Chihiro
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p. 4539 - 4542
(2007/10/02)
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- TOTAL SYNTHESIS OF (-)-DIHYDROCELACINNINE AND (+/-)-CELABENZINE
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(S)-3-amino-3-phenylpropionic acid, as an intermediate, was converted to dihydrocelacinnine and celabenzine.
- Iida, Hideo,Fukuhara, Kiyoshi,Machiba, Mitsuo,Kikuchi, Toyohiko
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p. 207 - 210
(2007/10/02)
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