- Regiodivergent Enantioselective γ-Additions of Oxazolones to 2,3-Butadienoates Catalyzed by Phosphines: Synthesis of α,α-Disubstituted α-Amino Acids and N,O-Acetal Derivatives
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Phosphine-catalyzed regiodivergent enantioselective C-2- and C-4-selective γ-additions of oxazolones to 2,3-butadienoates have been developed. The C-4-selective γ-addition of oxazolones occurred in a highly enantioselective manner when 2-aryl-4-alkyloxazol-5-(4H)-ones were employed as pronucleophiles. With the employment of 2-alkyl-4-aryloxazol-5-(4H)-ones as the donor, C-2-selective γ-addition of oxazolones took place in a highly enantioselective manner. The C-4-selective adducts provided rapid access to optically enriched α,α-disubstituted α-amino acid derivatives, and the C-2-selective products led to facile synthesis of chiral N,O-acetals and γ-lactols. Theoretical studies via DFT calculations suggested that the origin of the observed regioselectivity was due to the distortion energy that resulted from the interaction between the nucleophilic oxazolide and the electrophilic phosphonium intermediate.
- Wang, Tianli,Yu, Zhaoyuan,Hoon, Ding Long,Phee, Claire Yan,Lan, Yu,Lu, Yixin
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supporting information
p. 265 - 271
(2016/01/25)
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- Rapid asymmetric synthesis of amino acids via NiII complexes based on new fluorine containing chiral auxiliaries
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New fluorine-containing chiral auxiliaries (S)-N-(2-benzoylphenyl)-1-(2- fluorobenzyl)-, (S)-N-(2-benzoylphenyl)-1-(3-fluorobenzyl)-, and (S)-N-(2-benzoylphenyl)-1-(4-fluorobenzyl)-pyrrolidine-2-carboxamide and their NiII complexes of Schiff bases with glycine and alanine have been synthesized. The greater efficiency of the complexes in terms of faster reaction rates and stereoselectivities in the asymmetric synthesis of (S)-α-amino acids has also been demonstrated.
- Saghyan, Ashot S.,Dadayan, Ani S.,Dadayan, Slavik A.,Mkrtchyan, Anna F.,Geolchanyan, Arpine V.,Manasyan, Luiza L.,Ajvazyan, Hrant R.,Khrustalev, Victor N.,Hambardzumyan, Hasmik H.,Maleev, Victor I.
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experimental part
p. 2956 - 2965
(2011/03/19)
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- Stereoselective functionalisation of cis- and trans-2-ferrocenyl-3- pivaloyl-4-alkyl-1,3-oxazolidin-5-ones: Asymmetric synthesis of (R)- and (S)-2-alkyl-2-aminopent-4-enoic acids and (2R,3S)-2-amino-2-methyl-3-hydroxy-3- phenylpropanoic acid
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Treatment of a range of cis- and trans-2-ferrocenyl-3-pivaloyl-4-alkyl-1,3- oxazolidin-5-ones with LDA followed by the addition of allyl bromide promotes highly stereoselective allylation (>98% de) at the 4-position of the oxazolidinone ring anti to the s
- Alonso, Francisco,Davies, Stephen G.,Elend, Almut S.,Leech, Michael A.,Roberts, Paul M.,Smith, Andrew D.,Thomson, James E.
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experimental part
p. 527 - 536
(2009/07/18)
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- The influence of imine structure, catalyst structure and reaction conditions on the enantioselectivity of the alkylation of alanine methyl ester imines catalyzed by Cu(ch-salen)
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Systematic variation of the substrate structure has shown that the most effective substrates for Cu(ch-salen)-catalyzed asymmetric enolate alkylation reactions carried out under phase-transfer conditions are the para-chlorophenyl imines of amino esters. T
- Belokon', Yuri N.,Davies,Fuentes, Jose A.,North, Michael,Parsons, Teresa
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p. 8093 - 8096
(2007/10/03)
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- Chiral salen-metal complexes as novel catalysts for the asymmetric synthesis of α-amino acids under phase transfer catalysis conditions
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Chiral salen-metal complexes have been tested as catalysts for the C-alkylation of Schiff's bases of alanine and glycine esters with alkyl bromides under phase-transfer conditions (solid sodium hydroxide, toluene, ambient temperature, 1-10 mol% of the catalyst). The best catalyst, which was derived from a Cu(II) complex of (1R, 2R or 1S,2S)-[N,N′-bis(2′-hydroxybenzylidene)]-1,2-diaminocyclohexane, gave α-amino and α-methyl-α-amino acids with enantiomeric excesses of 70-96%.
- Belokon, Yuri N,North, Michael,Churkina, Tatiana D,Ikonnikov, Nikolai S,Maleev, Victor I
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p. 2491 - 2498
(2007/10/03)
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- Mag: A Cα-methylated, side-chain unsaturated α-amino acid. Introduction into model peptides and conformational preference
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By a chemo-enzymatic approach we synthesized the chiral, C(α)- methylated α-amino acid Mag, characterized by a side-chain C(γ)=C(δ) bond. We also prepared a series of model peptides containing Mag in combination with Aib and Ala. All of the peptides were fully characterized and their conformational preference was determined in solution by FT-IR absorption and 1H NMR investigations. X-Ray diffraction analyses of L-Mag, a derivative and three peptides are also presented. We find that this C(α)-methylated α- amino acid is an excellent β-turn and 310-helix former. A peptide with two Mag residues one on top of the other after one complete turn of the 310- helix has been synthesized and characterized. 2000 Elsevier Science Ltd.
- Peggion, Cristina,Flammengo, Roberto,Mossel, Eric,Broxterman, Quirinus B.,Kaptein, Bernard,Kamphuis, Johan,Formaggio, Fernando,Crisma, Marco,Toniolo, Claudio
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p. 3589 - 3601
(2007/10/03)
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- Asymmetric PTC C-Alkylation Catalyzed by Chiral Derivatives of Tartaric Acid and Aminophenols. Synthesis of (R)- and (S)-α-Methyl Amino Acids
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A new type of efficient chiral catalyst has been elaborated for asymmetric C-alkylation of CH acids under PTC conditions. Sodium alkoxides formed from chiral derivatives of tartaric acid and aminophenols (TADDOL's 2a-e and NOBIN's 3a-h) can be used as chiral catalysts in the enantioselective alkylation, as exemplified by the reaction of Schiffs bases la-e derived from alanine esters and benzaldehydes with active alkyl halides. Acid-catalyzed hydrolysis of the products formed in the reaction afforded (R)-α-methylphenylalanine, (R)-α-naphthylmethylalanine, and (R)-α-allylalanine in 61-93% yields and with ee 69-93%. The procedure could be successfully scaled up to 6 g of substrate 1b. When (S,S)-TADDOL or (R)-NOBIN are used, the (S)-amino acids are formed. A mechanism rationalizing the observed features of the reaction has been suggested.
- Belokon, Yuri N.,Kochetkov, Konstantin A.,Churkina, Tatiana D.,Ikonnikov, Nikolai S.,Chesnokov, Alexey A.,Larionov, Oleg V.,Singh, Ishwar,Parmar, Virinder S.,Vyskocil, Stepan,Kagan, Henri B.
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p. 7041 - 7048
(2007/10/03)
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- Enantioselective syntheses of 2-amino-4-fluoropent-4-enoic acids. Isosteres of asparagine
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Diastereoselective alkylation of (R)-(+)-camphor-based glycine or alanine esterimines with 3-bromo-2-fluoropropene after hydrolytic deprotection gave (R)-(+)-2-amino-4-fluoropent-4-enoic acid with 38% overall yield and 90% ee, or (R)-(+)-2-amino-4-fluoro-2-methylpent-4-enoic acid (19% overall yield, 59% ee), respectively. Deprotection under drastic conditions was accompanied by hydrolysis of the fluorovinyl moiety to give (R)-(-)-2- amino-4-oxopentanoic acid hydrochloride with 28% overall yield and >95% ee. Ab initio calculations of acetamide and 2-fluoropropene as models for a primary amide or a fluorovinyl group despite of their different electronic structure show a similar electrostatic potential on the van der Waals surface suggesting their isosteric behavior.
- Laue, Klaus W.,Mueck-Lichtenfeld, Christian,Haufe, Guenter
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p. 10413 - 10424
(2007/10/03)
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- Asymmetric alkylation catalyzed by chiral alkali metal alkoxides of TADDOL. Synthesis of α-methyl amino acids
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It is shown that sodium alkoxides formed from (4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-bis(diphenylmethanol) ((R,R)-TADDOL) and some of its derivatives can be used as chiral catalysts for enantioselective alkylation of Schiff's bases derived from alanine with reactive alkyl halides. Acid hydrolysis of the reaction products affords (R)-α-methytphenyl-alanine, (R)-α-allylalanine, and (R)-α-methylnaphthylalanine in 61-93% yields and with ee 69-94%. When (S,S)-TADDOL is used, the (3)-amino acid is formed. A mechanism explaining the observed features of the reaction is proposed.
- Belokon',Kochetkov,Churkina,Ikonnikov,Chesnokov,Larionov,Kagan
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p. 917 - 923
(2007/10/03)
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- Chiral salen-metal complexes as novel catalysts for asymmetric phase transfer alkylations
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Chiral, salen-metal complexes have been tested as catalysts for the C- alkylation of aldimine Schiff's bases of alanine esters with alkyl bromides under phase-transfer conditions (solid sodium hydroxide, toluene, ambient temperature, 1-10% of the catalyst
- Belokon, Yuri N.,North, Michael,Kublitski, Vadim S.,Ikonnikov, Nikolai S.,Krasik, Pavel E.,Maleev, Viktor I.
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p. 6105 - 6108
(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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- Enantiospecific alkylations of alanine
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Reaction of ferrocenecarbaldehyde 3 with sodium (S)-alaninate followed by pivaloyl chloride generates (2S,4S)-2-ferrocenyl-3-pivaloyl-4-methyl-1,3-oxazolidin-5-one 5 (>98% de). Compound 5 undergoes stereospecific 4-alkylation with complete retention of configuration on treatment sequentially with lithium diisopropylamide and an appropriate alkyl bromide {benzyl bromide, allyl bromide, crotyl [(E)-2-enyl] bromide, α-bromo-o-xylene, cinnamyl bromide, 2-(bromomethyl)naphthalene, 1-(tert-butoxycarbonyl)-3-(bromomethyl)indole and bromoacetonitrile} to generate the corresponding (2S,4R)-2-ferrocenyl-3-pivaloyl-4-alkyl-4-methyl-1,3-oxazolidin-5-ones 7a-h. Hydrolysis of (2S,4R)-7a-h on Amberlyst-15 generates the free (R)-α-methyl-α-amino acids (R)-8a-h.
- Alonso, Francisco,Davies, Stephen G.,Elend, Almut S.,Haggitt, Jane L.
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p. 257 - 264
(2007/10/03)
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- Asymmetric synthesis of α-methyl α-amino acids by diastereoselective alkylation of optically active 6-isopropyl-3-methyl-2,3-dihydro-6H-1,4-oxazin-2-ones
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At room temperature already highly diastereoselective alkylation of the new, cyclic, chiral alanine ester derivatives (6R)-1 can be achieved with either K2CO3 as base under solid liquid phase-transfer catalysis or Pd catalysis under neutral conditions. The products (3S,6R)-2 can be easily hydrolyzed to form (S)-α-methyl α-amino acids.
- Chinchilla,Falvello,Galindo,Najera
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p. 995 - 997
(2007/10/03)
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- Enzymatic resolution of α,α-disubstituted α-amino acid esters and amides
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The scope and limitations of the enzymatic resolution of α,α-disubstituted α-amino acid amides by an amino acid amidase from Mycobacterium neoaurum and of the corresponding ethyl esters with Pig liver esterase (PLE) have been studied. Moderate enantiomeric excesses were obtained with PLE, with only a narrow substrate specificity. Mycobacterium neoaurum on the contrary yields a broad range of S-α,α-disubstituted α-amino acids 1 and the corresponding R-amides 2.
- Kaptein,Boesten,Broxterman,Peters,Schoemaker,Kamphuis
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p. 1113 - 1116
(2007/10/02)
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- Process for the preparation of alpha-alkylated alpha-amino acids and alpha-halogenated alpha-amino acids
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A novel process for the preparation of α-alkylated α-amino acids and α-halogenated α-amino acids is disclosed. These α-alkylated α-amino acids and α-halogenated α-amino acids are useful as intermediates for the preparation of enzyme inhibitors (for example, renin inhibitors) and other peptides or amino acid derivatives or analogs.
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- Synthesis of (Optically Active) Sulfur-Containing Trifunctional Amino Acids by Radical Addition to (Optically Active) Unsaturated Amino Acids
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Sulfur-based radicals, generated from R-S-H-type precursors (R = alkyl, acyl) with AIBN, smoothly add to α-allylglycines protected at none, one, or both of the amino acid functions (NH2 and/or CO2H).Sulfur-containing trifunctional amino acids were obtained in good to excellent yields (64-100 percent).The solvent used for the reaction is critical.Optimal results were obtained when both the unsaturated amino acid and RSH dissolve completely in the medium (dioxane/water or methanol/water are good solvent systems).The scope of the reaction includes α-substituted α-allylglycine derivative and derivatives as well as β-substituted β-allyl-β-amino alcohols.In the case of optically active α-allylglycine derivatives, radical addition is accompanied by a small amount of racemization, the amount depending on the type of protection and R-S-H.The products are easily optically enriched by crystallization.Addition of sulfur-based radicals to α-allylglycine is believed to be an example of a general method for synthesizing optically active trifunctional amino acids from unsaturated amino acids.
- Broxterman, Quirinus B.,Kaptein, Bernard,Kamphuis, Johan,Schoemaker, Hans E.
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p. 6286 - 6294
(2007/10/02)
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- GENERAL METHOD FOR THE ASYMMETRIC SYNTHESIS OF α-AMINO ACIDS VIA ALKYLATION OF THE CHIRAL NICKEL(II) SCHIFF BASE COMPLEXES OF GLYCINE AND ALANINE
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Nickel(II) complexes of Schiff bases derived from (S)-o-benzaldehyde and alanine (3), or (S)-O-benzophenone and alanine (4), or glycine (5) have been used for the asymmetric synthesis of α-amino acids under a variety of conditions.The method of choice consists of the reaction of the corresponding complex with the appropriate alkyl halide in DMF at 25 deg C using solid NaOH as a catalyst.Low diastereoselective excess (d.e.) is observed for the alkylation of complex (3) with benzyl bromide and allyl bromide.Large selectivity (80 percent) is observed for the alkylation of complex (4).Optically pure(R)- and (S)-O-benzyl-α-methyl-α-amino acids were obtained (70-90 percent) after the alkylated diastereoisomeric complexes had been seperated on SiO2 and hydrolysed with aqueous HCl.The initial chiral reagents were recovered (80-92 percent).The alkylation of complex (5) gave (S)-alanine, (S)-valine, (S)-phenylalanine, (S)-tryptophan, (S)-isoleucine, (S)-2-aminohexanoic acid, and 3,4-dimethoxyphenylalanine with optical yields of 70-92 percent.The optically pure α-amino acids were obtained after the separation of the alkylated diastereoisomeric complexes on SiO2.The stereochemical mechanism of the alkylation reaction is discussed.
- Belokon, Yuri N.,Bakhmutov, Vladimir I.,Chernoglazova, Nina I.,Kochetkov, Konstantin A.,Vitt, Sergei V.,et al.
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p. 305 - 312
(2007/10/02)
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- Preparation of Optically Pure α-Methyl-α-amino Acids via Alkylation of the Nickel(II) Schiff Base of (R,S)-Alanine with (S)-2-N-(N'-Benzylprolyl)aminobenzaldehyde
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Chiral nickel(II) complexes of Ala with (S)-2-N-(N'-benzylprolyl)aminobenzaldehyde were alkylated with alkyl halides and the diastereoisomeric complexes formed were separated on SiO2; their decomposition led to the isolation of enantiomerically pure (R)- and (S)-α-alkyl-α-amino acids with recovery of the initial (S)-bba.
- Belokon', Yuri N.,Chernoglazova, Nina I.,Kochetkov, Constantin A.,Garbalinskaya, Natalia S.,Belikov, Vasili M.
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p. 171 - 172
(2007/10/02)
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