- Preparation method of optically active 2-methylproline
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The invention discloses a preparation method of optically active 2-methylproline. According to the method, 5-hydroxy-2-pentanone (formula 1) is taken as a starting material to be subjected to condensation with a cyaniding reagent; hydrolysis is carried out so as to obtain 2-amino-5-hydroxy-2-methylvaleric acid (formula 2); 2-amino-5-hydroxy-2-methylvaleric acid (formula 2) and a resolving agent are subjected to salifying precipitation, followed by ph regulation and precipitation so as to obtain 2-amino-5-hydroxy-2-methylvaleric acid (formula 4) with optical activity; the compound as shown in formula 4 is protected with an amino protective agent to obtain a compound as shown in formula 5; the compound as shown in formula 5 is chlorinated with a chlorinating reagent while removing an amino protective group to obtain a compound as shown in formula 6; and one-pot cyclization is carried out to obtain the optically active 2-methylproline (formula 7). The preparation method is high in comprehensive yield, low in cost, mild in reaction condition and easy for large-scale production.
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- A Designed Approach to Enantiodivergent Enamine Catalysis
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The rational design and implementation of enantiodivergent enamine catalysis is reported. A simple secondary amine catalyst, 2-methyl-l-proline, and its tetrabutylammonium salt function as an enantiodivergent catalyst pair delivering the enantiomers of α-functionalized aldehyde products in excellent enantioselectivities. This novel concept of designed enantiodivergence is applied to the enantioselective α-amination, aldol, and α-aminoxylation/α-hydroxyamination reactions of aldehydes.
- Macharia, Juliet,Wambua, Victor,Hong, Yun,Harris, Lawrence,Hirschi, Jennifer S.,Evans, Gary B.,Vetticatt, Mathew J.
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p. 8756 - 8760
(2017/07/17)
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- Α-substd. provitamin optically active production of phosphorus
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PROBLEM TO BE SOLVED: To provide an industrial method practically suitable for producing an optically active α-substituted prolines with short process and mild conditions.SOLUTION: A method of producing an optically active α-substituted prolines (6) includes (d) a step of obtaining an optically active N, α-substituted prolines (5) by hydrolysis of an optically active N, α-substituted proline amides (4), and (e) a step of obtaining an optically active α-substituted prolines (6) by eliminating the optically active N, and a protective group Rof the α-substituted prolines (5).
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- METHOD FOR PRODUCING OPTICALLY ACTIVE ALPHA-SUBSTITUTED PROLINE
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The present invention aims to provide an industrial method practically suitable for producing optically active α-substituted prolines from an acyclic ketone compound by a small number of steps under mild conditions. The present invention relates to a production method of an optically active α-substituted proline (4) and/or an optically active α-substituted prolinamide (5), including (a) reacting an acyclic ketone compound (1) with at least one selected from ammonia, an ammonium salt, primary amine and a salt of primary amine, and a cyanating agent to give a cyclic nitrogen-containing compound (2), (b) hydrating the cyclic nitrogen-containing compound (2) to give an α-substituted prolinamide (3), and (c) resolving the α-substituted prolinamide (3) by one or more of (d) enzymatical hydrolysis, (e) resolution by diastereomeric salt formation, and (f) separation by column chromatography.
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- PROCESS FOR PRODUCING SOLID AMINO ACID
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The problem to be solved by the present invention is to ea lily and efficiently produce an amino acid having 2 to 7 carbon atoms as a high-purity solid without complicated operation, which is useful as a synthetic intermediate for medicines or agrochemicals. The present invention is characterized in comprising a step of precipitating solid amino acid with high purity. In the present invention, the by-produced salt composed of the sulfonic acid and the amine was removed to the mother liquor by reacting an amine with a sulfonic acid salt of amino acid in an aprotic polar solvent, or by reacting a sulfonic acid with an amine salt of amino acid in an aprotic polar solvent. The sulfonic acid salt of amino acid, for example, may be produced by reacting a N-(tert-butoxycarbonyl) amino acid with a sulfonic acid, or by reacting an amino acid tert-butyl ester with a sulfonic acid.
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Paragraph 0075
(2014/12/09)
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- Use of (S)-5-(2-methylpyrrolidin-2-yl)-1H-tetrazole as a novel and enantioselective organocatalyst for the aldol reaction
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The novel organocatalyst (S)-5-(2-methylpyrrolidin-2-yl)-1H-tetrazole (4) catalyzes the aldol reaction between acetone and various aldehydes with superior enantioselectivity to the existing organocatalysts (S)-proline (1) and (S)-5-(Pyrrolidin-2-yl)-1H-tetrazole (3). Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Tong, Sok-Teng,Harris, Paul W. R.,Barker, David,Brimble, Margaret A.
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p. 164 - 170
(2008/09/18)
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- Catalytic asymmetric Michael reaction under phase-transfer catalysis: Construction of chiral tetrasubstituted carbon and its application to the synthesis of a chiral pyrrolidone
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A catalytic asymmetric Michael reaction using Schiff bases promoted by D2-symmetrical ammonium salts as phase-transfer catalysts is described. The reaction of glycine Schiff base (1a) gave the Michael adduct with up to 91% ee and tetrasubstituted carbons was also constructed using alanine Schiff base (3a) with up to 63% ee.
- Arai, Shigeru,Takahashi, Fumie,Tsuji, Riichiro,Nishida, Atsushi
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p. 495 - 501
(2007/10/03)
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- Highly enantioselective synthesis of rigid, quaternary 1,4-benzodiazepine- 2,5-diones derived from proline
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(Chemical Equation Presented) Proline-derived 1,4-benzodiazepine-2,5-diones are extremely useful scaffolds in medicinal chemistry. In this paper, we describe a protocol for retentive C3 alkylation of these materials, thus accomplishing the direct synthesis of enantiopure quaternary 1,4-benzodiazepine-2,5-diones. The high enantioselectivities (up to 99.5%) are attributed to memory of chirality.
- MacQuarrie-Hunter, Stephanie,Carlier, Paul R.
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p. 5305 - 5308
(2007/10/03)
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- Chiral 3,6-dihydro-2H-1,4-oxazin-2-ones as alanine equivalents for the asymmetric synthesis of α-methyl α-amino acids (AMAAs) under mild reaction conditions
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3,6-Dihydro-2H-1,4-oxazin-2-ones 1 act as very reactive chiral cyclic alanine equivalents and can be diastereoselectively alkylated or allylated using mild reaction conditions: potassium carbonate under phase-transfer catalysis (PTC) conditions when using activated alkyl halides, organic bases such as tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2- diazaphosphorine (BEMP) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) when using unactivated alkyl halides, and neutral Pd(0)-catalysis when allylic carbonates are used. In most cases, the diastereoselectivity under all these different reaction conditions is excellent although the reactions are always carried out at room temperature. Hydrolysis of the obtained alkylated or allylated oxazinones allows the preparation of enantiomerically enriched (S)- α-methyl α-amino acids (S)-AMAAs. The PTC and organic base methodologies have also been applied to the synthesis of (R)-α-methyl α-amino acids starting from (R)-alanine. When dihalides are used as electrophiles under PTC or BEMP conditions, a spontaneous N-alkylation also takes place giving bicyclic oxazinones, which can be hydrolyzed to enantiomerically pure cyclic (S)-AMAAs.
- Chinchilla, Rafael,Galindo, Nuria,Nájera, Carmen
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p. 704 - 717
(2007/10/03)
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- Asymmetric synthesis of (S)-α-methyl α-amino acids by alkylation of chiral 3,6-dihydro-2h-1,4-oxazin-2-ones using unactivated alkyl halides and organic bases
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3,6-Dihydro-2H-1,4-oxazin-2-ones 1 have been diastereoselectively (>96% de) alkylated using unactivated alkyl halides and organic bases such as 2- tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature in the presence of LiI. Hydrolysis of the resulting alkylated systems afforded enantiomerically enriched (S)-α-methyl α-amino acids. When 1,3- diiodopropane was used, spontaneous N-alkylation also took place giving bicyclic oxazinone 6 which was hydrolyzed to (S)-α-methylproline.
- Chinchilla, Rafael,Galindo, Nuria,Najera, Carmen
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p. 2769 - 2772
(2007/10/03)
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- New synthetic method of optically active α-methylproline and α-methylpipecolinic acid using electrochemical oxidation as a key reaction
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A new method for the stereoselective α-methylation of N-protected L-proline and L-pipecolinic acid esters is presented. The method consisted of electrochemical α'-methoxylation of the α-amino acid derivatives, the replacement of the α'-methoxy group with a phenylthio group, α-methylation, and reductive removal of the α'-phenylthio group, successively. The intermediates in this method could be used for the preparation of optically active acyclic α-methylated α-amino acids.
- Matsumura, Yoshihiro,Kinoshita, Toshio,Yanagihara, Yuka,Kanemoto, Noriko,Watanabe, Mitsuaki
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p. 8395 - 8398
(2007/10/03)
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- An improved method of oxazolidinone hydrolysis in the asymmetric synthesis of α-alkylprolines
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An improvement in Seebach's method for the synthesis of α-alkylprolines is reported wherein the hydrolysis of the chiral oxazolidinone 2 is performed on a suspension of silica gel in MeOH/H2O. Following hydrolysis, the pure α-alkylproline can be obtained by filtration thereby avoiding a tedious ion exchange purification.
- Genin, Michael J.,Baures, Paul W.,Johnson, Rodney L.
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p. 4967 - 4968
(2007/10/02)
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- Preparation and Use of Chloromethyl (-)-Menthyl Ether in the Synthesis of Optically Pure α-Branched α-Amino Nitriles
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The synthesis of optically pure chloromethyl (-)-menthyl ether (2b) and its use in the synthesis of di-(-)-menthyl acetal (-)-menthyl (+)-menthyl acetals are described.The diastereomeric mixed acetals 7a,b and 8a,b are easily obtainable from the nitrones 5 and 6, KCN and 2b.The mixture of diastereomers are separated into the pure components 7a, 7b and 8a, 8b by simple silica gel column chromatography.Hydrolysis of these products (H2O2/Na2CO3, ultrasound) followed by N-O cleavage affords the heterocyclic α-methyl-α-amino amides 11a, 11b and 12a, 12b.These are subsequently hydrolyzed to give the corresponding α-methyl-α-amino acids with S and R configuration, respectively.
- Shatzmiller, Shimon,Dolithzky, Ben-Zion,Bahar, Eliezer
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p. 375 - 379
(2007/10/02)
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- Synthesis, conformational, properties, and antibody recognition of peptides containing β-turn mimetics based on α-alkylproline derivates
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Peptide recognition by monoclonal antibodies may provide a useful model for drug development, in particular to test the effects of conformational restriction on ligand binding. We have tested the influence of novel peptide mimetics upon conformation and binding affinity for the case of monoclonal antibodies raised to a peptide antigen which displays a preference for a β-turn conformation in aqueous solution. Two monoclonals were isolated that recognized the peptide Ac-Tyr-Pro-Tyr-Asp-Val-Pro-Asp-Tyr-Ala specifically at the β-turn formed by Tyr-Pro-Tyr-Asp. Peptide analogues were then synthesized containing mimetics designed to stabilize this conformation. One, analogue (3), contained a spirocyclic γ-lactam bridge between the α-position of proline-2 and the N atom of tyrosine-3, while another (2) contained (S)-α-methylproline at position 2. NMR spectroscopy and molecular modeling suggest that both analogues adopt reverse-turn conformations stablized relative to that in the native sequence. For the (S)-α-methylproline analogue binding to both monoclonal antibodies was substantially improved, compared with the native antigen, whereas the γ-lactam analogue (3) was not recognized by either antibody. Quantitative equilibrium ultrafiltration binding assays showed that the affinities of the (S)-α-methylproline analogue (2) for the two antibodies were improved over those measured with the native antigen by -2.3 and -0.65 kcal/mol. The origins of these free energy differences cannot be explained wholly on the basis of presumed extra hydrophobic contacts between the new methyl substituent and the antigen binding sites. We propose that the increased conformational stability of the analogue plays a decisive role, implying that the reverse turn detected in the native antigen, possibly a type-I turn, is important for recognition by the two antibodies.
- Hinds,Welsh,Brennand,Fisher,Glennie,Richards,Turner,Robinson
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p. 1777 - 1789
(2007/10/02)
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