- Improved procedures for the synthesis of (S)-2-[N-(N'-benzyl- prolyl)amino]benzophenone (BPB) and Ni(II) complexes of Schiff's bases derived from BPB and amino acids
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(S)-N-Benzylproline (BP) was obtained by the reaction of (S)-proline and benzylchloride in high chemical yield (89%). (S)-2-[N-(N'- Benzylprolyl)amino]benzophenone (BPB) was synthesized in amounts greater than 100 g by the SOCl2 promoted condensation of BP with 2-aminobenzophenone (yield 82%). Ni(II) complexes of Schiff's bases derived from BPB and amino acids were prepared by an improved procedure involving the use of KOH as a base and MeOH as solvent (yield 90-91%).
- Belokon', Yuri N.,Tararov, Vitali I.,Maleev, Viktor I.,Savel'eva, Tatiana F.,Ryzhov, Michael G.
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- Self-Masked Aldehyde Inhibitors: A Novel Strategy for Inhibiting Cysteine Proteases
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Cysteine proteases comprise an important class of drug targets, especially for infectious diseases such as Chagas disease (cruzain) and COVID-19 (3CL protease, cathepsin L). Peptide aldehydes have proven to be potent inhibitors for all of these proteases. However, the intrinsic, high electrophilicity of the aldehyde group is associated with safety concerns and metabolic instability, limiting the use of aldehyde inhibitors as drugs. We have developed a novel class of self-masked aldehyde inhibitors (SMAIs) for cruzain, the major cysteine protease of the causative agent of Chagas disease - Trypanosoma cruzi. These SMAIs exerted potent, reversible inhibition of cruzain (Ki? = 18-350 nM) while apparently protecting the free aldehyde in cell-based assays. We synthesized prodrugs of the SMAIs that could potentially improve their pharmacokinetic properties. We also elucidated the kinetic and chemical mechanism of SMAIs and applied this strategy to the design of anti-SARS-CoV-2 inhibitors.
- Li, Linfeng,Chenna, Bala C.,Yang, Kai S.,Cole, Taylor R.,Goodall, Zachary T.,Giardini, Miriam,Moghadamchargari, Zahra,Hernandez, Elizabeth A.,Gomez, Jana,Calvet, Claudia M.,Bernatchez, Jean A.,Mellott, Drake M.,Zhu, Jiyun,Rademacher, Andrew,Thomas, Diane,Blankenship, Lauren R.,Drelich, Aleksandra,Laganowsky, Arthur,Tseng, Chien-Te K.,Liu, Wenshe R.,Wand, A. Joshua,Cruz-Reyes, Jorge,Siqueira-Neto, Jair L.,Meek, Thomas D.
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- Enantioselective synthesis of 2-substitued-tetrahydroisoquinolin-1-yl glycine derivatives via oxidative cross-dehydrogenative coupling of tertiary amines and chiral nickel(II) glycinate
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The asymmetric synthesis of 2-substituted-tetrahydroisoquinolin-1-yl glycines was achieved by an oxidative cross-dehydrogenative coupling (CDC) reaction. This method for activation of the α-C-H bonds of amines with chiral nickel(II) glycinate using o-chlo
- Zhou, Shengbin,Wang, Jiang,Lin, Daizong,Zhao, Fei,Liu, Hong
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- The formation of pyrroline and tetrahydropyridine rings in amino acids catalyzed by pyrrolysine synthase (PylD)
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The dehydrogenase PylD catalyzes the ultimate step of the pyrrolysine pathway by converting the isopeptide L-lysine-Nε-3R-methyl-D-ornithine to the 22nd proteinogenic amino acid. In this study, we demonstrate how PylD can be harnessed to oxidize various isopeptides to novel amino acids by combining chemical synthesis with enzyme kinetics and X-ray crystallography. The data enable a detailed description of the PylD reaction trajectory for the biosynthesis of pyrroline and tetrahydropyridine rings as constituents of pyrrolysine analogues.
- Quitterer, Felix,Beck, Philipp,Bacher, Adelbert,Groll, Michael
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- ASYMMETRIC SYNTHESIS OF ASPARTIC AND α-METHYLASPARTIC ACIDS VIA Ni(II) COMPLEXES WITH SCHIFF BASES OF GLYCINE AND ALANINE AND CHIRAL CARBONYL-CONTAINING REAGENTS
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We propose a method for the synthesis of aspartic and α-methylaspartic acids by alkylation with ethyl bromoacetate of the α-carbon atom of the amino acid moiety in Ni(II) complexes of Schiff bases of glycine with (S)-2-benzophenone and alanine with (S)-2-benzaldehyde, respectively.Attempts to synthesize α-methylaspartic acid by oxidative cleavage of the C=C bond to a COOH group in the complex of the Schiff base of α-allylalanine with (S)-2-benzophenone were unsuccessful.
- Belokon, Yu. N.,Tararov, V. I.,Maleev, V. I.,Motsishkite, S. M.,Vitt, S. V.,et al.
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- Synthesis of (2S,3S)-β-(trifluoromethyl)-α,β-diamino acid by Mannich addition of glycine Schiff base Ni(II) complexes to N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine
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A convenient access to (2S,3S)-β-(trifluoromethyl)-α,β-diamino acid is reported by using highly diastereoselective Mannich addition reactions of either chiral or achiral Ni(II) complexes derived from glycine Schiff bases to a chiral sulfinimine, N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine. Disassembly of the resultant Ni(II) complexes affords the target amino acid which was, for the first time, isolated in enantiomerically pure form and fully characterized.
- Kawamura, Akie,Moriwaki, Hiroki,R?schenthaler, Gerd-Volker,Kawada, Kosuke,Ace?a, José Luis,Soloshonok, Vadim A.
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- Rational Design and Synthesis of Modified Teixobactin Analogues: In Vitro Antibacterial Activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa
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Teixobactin, a recently discovered depsipeptide that binds to bacterial lipid II and lipid III, provides a promising molecular scaffold for the design of new antimicrobials. Herein, we describe the synthesis and antimicrobial evaluation of systematically modified teixobactin analogues. The replacement of the Ile11 residue with aliphatic isosteres, the modification of the guanidino group at residue 10 and the introduction of a rigidifying residue, that is, dehydroamino acid, into the macrocyclic ring generated useful structure–activity information. Extensive antimicrobial susceptibility assessment against a panel of clinically relevant Staphylococcus aureus and Propionibacterium acnes strains led to the identification of the new lead compound, [Arg(Me)10,Nle11]teixobactin, with an excellent bactericidal activity (minimum inhibitory concentration (MIC)=2–4 μg mL?1). Significantly, the antimicrobial activity of several of the teixobactin analogues against the pathogenic Gram-negative Pseudomonas aeruginosa was “restored” when combined with the sub-MIC concentration of the outer membrane-disruptive antibiotic colistin. The antimicrobial effectiveness of a [Tfn10,Nle11]teixobactin (32 μg mL?1)–colistin (2 μg mL?1; 0.5×MIC) combination against P. aeruginosa PAO1 reveals, for the first time, an alternative therapeutic option in the treatment of Gram-negative infections.
- Ng, Vivian,Kuehne, Sarah A.,Chan, Weng C.
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- Asymmetric Synthesis of (2S,3S)-α-(1-Oxoisoindolin-3-yl)glycines under Low-Basicity "kinetic" Control
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The previously illusive (2S,3S)-configured α-(1-oxoisoindolin-3-yl)glycines can be prepared under mild DBU-catalyzed, low-basicity conditions. The overall process includes a cascade of aldol addition, cyclization, rearrangement, and conjugate addition reactions, leading to the target products with moderate to good chemical yields and diastereoselectivity.
- Li, Tingting,Zhou, Shengbin,Wang, Jiang,Ace?a, José Luis,Soloshonok, Vadim A.,Liu, Hong
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- Asymmetric synthesis of novel highly sterically constrained (2S,3S)-3- methyl-3-trifluoromethyl- and (2S,3S,4R)-3-trifluoromethyl-4- methylpyroglutamic acids
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Asymmetric synthesis of the novel highly sterically constrained (2S,3S)- 3-methyl-3-trifluoromethyl-and (2S,3S,4R)-3-trifluoromethyl-4- methylpyroglutamic acids has been developed via diastereoselective Michael addition reactions between a Ni(II) complex of the chiral non-racemic Schiff base of glycine with (S)-o-[N-(N-benzylprolyl)amino]benzophenone (BPB) and the corresponding trifluoromethyl-containing crotonates. Of particular synthetic interest is the reaction of the glycine Ni-complex with ethyl 3- trifluoromethyl crotonate featuring excellent diastereoselectivity (>98% de) as a result of complete stereochemical discrimination between the methyl and trifluoromethyl groups. A mechanistic rationale for the observed kinetically controlled stereochemical outcome is discussed.
- Soloshonok, Vadim A.,Cai, Chaozhong,Hruby, Victor J.,Van Meervelt, Luc
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- Asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid by sequential SN2-SN2′ dialkylation of (R)-N-(benzyl)proline-derived glycine Schiff base Ni(ii) complex
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This work describes a new process for the asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid of high pharmaceutical importance. The sequence of the reactions includes PTC alkylation (SN2), homogeneous SN2′ cyclization followed by disassembly of the resultant Ni(ii) complex. All reactions are conducted under operationally convenient conditions and suitably scaled up to 6 g of the starting Ni(ii) complex. This journal is
- Kawashima, Aki,Xie, Chen,Mei, Haibo,Takeda, Ryosuke,Kawamura, Akie,Sato, Tatsunori,Moriwaki, Hiroki,Izawa, Kunisuke,Han, Jianlin,Acea, Jos Luis,Soloshonok, Vadim A.
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- Stereoselective synthesis of arylglycine derivatives via palladium-catalyzed α-arylation of a chiral nickel(II) glycinate
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A practical and efficient stereoselective synthesis of arylglycine derivatives was realized via palladium-catalyzed α-arylation of a chiral nickel(II) glycinate complex with aryl bromides. The structurally diverse arylglycine products were obtained in excellent isolated yields and with good diastereoselectivity. A simple acidic hydrolysis furnished optically pure arylglycines in high yield, and the chiral ligand (S)-BPB could be efficiently recovered and reused.
- Zhang, Fan,Sun, Hengzhi,Song, Zhuang,Zhou, Shuxi,Wen, Xiaoan,Xu, Qing-Long,Sun, Hongbin
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- Preparation of labeled aromatic amino acids: Via late-stage18F-fluorination of chiral nickel and copper complexes
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A general protocol for the preparation of 18F-labeled AAAs and α-methyl-AAAs applying alcohol-enhanced Cu-mediated radiofluorination of Bpin-substituted chiral complexes using Ni/Cu-BPX templates as double protecting groups is reported. The chiral auxiliaries are easily accessible from commercially available starting materials in a few synthetic steps. The versatility of the method was demonstrated by the high-yielding preparation of a series of [18F]F-AAAs and the successful implementation of the protocol into automated radiosynthesis modules. This journal is
- Craig, Austin,Kolks, Niklas,Urusova, Elizaveta A.,Zischler, Johannes,Brugger, Melanie,Endepols, Heike,Neumaier, Bernd,Zlatopolskiy, Boris D.
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supporting information
p. 9505 - 9508
(2020/09/03)
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- A reappraisal of the Ni-[(Benzylprolyl)amino]benzophenone complex in the synthesis of α,α-disubstituted amino acid derivatives
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α,α-Disubstituted alkenyl amino acid derivatives (e.g. Fmoc-S5-OH) are valuable monomers in the construction of stapled peptide derivatives. Synthetic access to these is possible using the Ni-[(Benzylprolyl)amino]benzophenone (BPB) complex as a chiral auxiliary. We discuss a reappraisal of the use of this, and demonstrate that epimerisation of the proline α-centre occurs during formation of the complex, leading to erosion in the enantiomeric excess of the final product. Modified conditions have been developed, providing the target compounds in high enantiomeric excess.
- Watson, Morag E.,Jamieson, Craig,Kennedy, Alan R.,Mason, Andrew M.
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- Synthesis of Chiral Spin-Labeled Amino Acids
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Spin-labeled amino acids (SLAAs) are often used to determine intermolecular distances and conformations in proteins via double electron-electron resonance. Currently available SLAAs can be difficult to incorporate selectively and have little resemblance to natural side chains in proteins. Enantioselective synthesis of three spin-labeled l-amino acids is described, starting from readily available 2,2,6,6-tetramethyl-4-piperidinone. These SLAAs better replicate canonical residues in proteins and aim for biological incorporation via genetic incorporation or solid-phase peptide synthesis.
- Vuong, Wayne,Mosquera-Guagua, Fabricio,Sanichar, Randy,McDonald, Tyler R.,Ernst, Oliver P.,Wang, Lei,Vederas, John C.
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supporting information
p. 10149 - 10153
(2019/12/24)
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- 2-[ 18 F]Fluorophenylalanine: Synthesis by Nucleophilic 18 F-Fluorination and Preliminary Biological Evaluation
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2-[ 18 F]Fluorophenylalanine (2-[ 18 F]FPhe), a promising PET tracer for imaging of cerebral infarction and tumors, was efficiently prepared from an easily accessible iodonium salt precursor using Cu-mediated radiofluorination under 'low base' or 'minimalist' conditions. Whereas significant racemization was initially observed if the 'minimalist' protocol was applied for radiolabeling, it was completely suppressed by the careful adjustment of 18 F - preprocessing. The initial biological study revealed a higher uptake of 2-[ 18 F]FPhe in different tumor cells in comparison to that of [ 18 F]FET. In contrast to 4-[ 18 F]FPhe, which suffered from rapid defluorination in vivo, 2-[ 18 F]FPhe demonstrated a sufficient in vivo stability. Conclusively, 2-[ 18 F]FPhe is a promising PET probe that is now readily available using Cu-mediated radiofluorination under 'minimalist' or 'low base' conditions. The simplicity of the translation of the proposed procedures to automated synthesis modules allows a broad biological evaluation of 2-[ 18 F]FPhe. Notably, a novel protocol for the preparation of N -Boc protected amino acids from the respective Ni-Schiff base complexes was developed that avoided application of strongly acidic conditions.
- Modemann, Daniel J.,Zlatopolskiy, Boris D.,Urusova, Elizaveta A.,Zischler, Johannes,Craig, Austin,Ermert, Johannes,Guliyev, Mehrab,Endepols, Heike,Neumaier, Bernd
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p. 664 - 676
(2019/01/23)
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- Synthesis method of R-2-[N-(N-benzyl prolamide)amino]benzophenone
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The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of R-2-[N-(N-benzyl prolamide)amino]benzophenone. The method comprises the steps thatS1, BOC-D-proline (I) and 2-aminobenzophenone take a condensation reaction in an organic solvent under the catalytic action of N-methylmorpholine and isobutyl chlorocarbonate to obtain an intermediateIII; S2, the intermediate III is taken and takes a BOC removal protection reaction in a hydrochloric acid ethyl acetate solvent to obtain an intermediate IV; S3, the intermediate IV is taken and is dissolved in the organic solvent; the pH is maintained to be 8 to 9 by triethylamine; benzyl chloride is added; the condensation reaction is performed to obtain a product V. The invention provides a novel synthesis path for synthetizing the R-2-[N-(N-benzyl prolamide)amino]benzophenone; the raw materials and solvents used in the test process are very common; the cost is very low; no pollution exists. The preparation method has the advantages that the process is simple; the conditions are mild; the consumed time is short; the yield is high; the synthesis method is suitable for industrial production.
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Paragraph 0037-0039
(2018/03/26)
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- The use of 4,4,4-trifluorothreonine to stabilize extended peptide structures and mimic β-strands
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Pentapeptides having the sequence R-HN-Ala-Val-X-Val-Leu-OMe, where the central residue X is L-serine, L-threonine, (2S, 3R)-L-CF3-threonine and (2S, 3S)-L-CF3-threonine were prepared. The capacity of (2S, 3S)- and (2S, 3R)-CF3
- Xu, Yaochun,Correia, Isabelle,Ha-Duong, Tap,Kihal, Nadjib,Soulier, Jean-Louis,Kaffy, Julia,Crousse, Beno?t,Lequin, Olivier,Ongeri, Sandrine
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supporting information
p. 2842 - 2853
(2018/01/17)
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- TRIAZOLE MACROCYCLE SYSTEMS
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The present invention provides novel peptidomimetic macrocycles and methods for their preparation and use, as well as amino acid analogs and macrocycle-forming linkers, and kits useful in their production.
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Paragraph 0272
(2016/02/22)
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- NEPRILYSIN INHIBITORS
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In one aspect, the invention relates to compounds having the formula I: where R1-R6 are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising these compounds; methods of using these compounds; and processes and intermediates for preparing these compounds.
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Paragraph 0231; 0293
(2015/08/04)
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- NEPRILYSIN INHIBITORS
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In one aspect, the invention relates to compounds having the formula (I): where R1-R6 are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising these compounds; methods of using these compounds; and processes and intermediates for preparing these compounds.
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Paragraph 77; 78
(2015/09/23)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF AUTONOMIC AND OTHER NEUROLOGICAL DISORDERS
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The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for the treatment of autonomic and other neurological disorders may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of neurogenic orthostatic hypotension (NOH), as well as NOH associated with multiple system atrophy (MSA), familial amyloid polyneuropathy (FAP), pure autonomic failure (PAF), and Parkinson's disease (PD), intradialytic hypotension (IDH) or hemodialysis-induced hypotension, hypotension associated with fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS).
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Paragraph 0111; 0112
(2015/08/04)
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- NEPRILYSIN INHIBITORS
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In one aspect, the invention relates to compounds having the formula: where R1-R5 and X are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and processes and intermediates for preparing such compounds.
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Paragraph 0299
(2014/09/29)
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- DISUBSTITUTED AMINO ACIDS AND METHODS OF PREPARATION AND USE THEREOF
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Provided are crystalline α, α-disubstituted amino acids and their crystalline salts containing a terminal alkene on one of their side chains, as well as optionally crystalline halogenated and deuterated analogs of the α, α-disubstituted amino acids and their salts; methods of making these, and methods of using these.
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- Asymmetric synthesis of chiral heterocyclic amino acids via the alkylation of the Ni(II) complex of glycine and alkyl halides
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An investigation into the reactivity profile of alkyl halides has led to the development of a new method for the asymmetric synthesis of chiral heterocyclic amino acids. This protocol involves the asymmetric alkylation of the Ni(II) complex of glycine to form an intermediate, which then decomposes to form a series of valuable chiral amino acids in high yields and with excellent diastereoselectivity. The chiral amino acids underwent a smooth intramolecular cyclization process to afford the valuable chiral heterocyclic amino acids in high yields and enantioselectivities. This result paves the way for the development of a new synthetic method for chiral heterocyclic amino acids.
- Chen, Hui,Wang, Jiang,Zhou, Shengbin,Liu, Hong
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p. 7872 - 7879
(2015/03/18)
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- NEPRILYSIN INHIBITORS
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In one aspect, the invention relates to compounds having the formula: where R1-R6, a, b, and Z are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and processes and intermediates for preparing such compounds.
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Paragraph 0351
(2013/05/09)
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- Asymmetric synthesis of new β-heterocyclic (S)-α-aminopropionic acids
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The asymmetric synthesis of novel non-proteinogenic β-heterocyclic α-amino acids via the diastereoselective conjugate addition of heterocyclic nucleophiles to the dehydroalanine moiety of chiral Ni(II) complexes has been studied. The complexes were formed from the Schiff base of dehydroalanine using (S)-2-N-(N-benzylprolyl)aminobenzophenone as a chiral auxiliary. After decomposition of the complexes, the α-amino acids were isolated with 30-99% ee.
- Saghyan, Ashot S.,Simonyan, Hayarpi M.,Stepanyan, Lala A.,Ghazaryan, Samvel G.,Geolchanyan, Arpine V.,Manasyan, Luiza L.,Ghochikyan, Vahe T.,Ghochikyan, Tariel V.,Hovhannisyan, Nelli A.,Gevorgyan, Ashot,Iaroshenko, Viktor O.,Langer, Peter
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scheme or table
p. 891 - 897
(2012/09/22)
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- Enhanced stereoselectivity of a Cu(II) complex chiral auxiliary in the synthesis of Fmoc-L-γ-carboxyglutamic acid
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L-γ-Carboxyglutamic acid (Gla) is an uncommon amino acid that binds avidly to mineral surfaces and metal ions. Herein, we report the synthesis of N-R-Fmoc-L-γ-carboxyglutamic acid γ, γ0-tert-butyl ester (Fmoc-Gla(OtBu)2-OH), a suitably protected analogue for Fmoc-based solid-phase peptide synthesis. The residue was synthesized using a novel chiral Cu(II) complex, whose structurebased design was inspired by the blue copper protein rusticyanin. The five-coordinate complex is formed by Shiff base formation between glycine and the novel ligand (S)-2-(N-(2-methylthio)benzylprolyl) aminobenzophenone in the presence of copper. Michael addition of di-tert-butyl methylenemalonate to the R-carbon of the glycine portion of the complex occurs in a diastereoselective fashion. The resulting (S,S)-complex diastereomer can be easily purified by chromatography. Metal complex decomposition followed by Fmoc protection affords the enantiomerically pure amino acid. With the use of this novel chiral complex, the asymmetric synthesis of Fmoc-Gla(OtBu)2-OH was completed in nine steps from thiosalicylic acid in 14.5% overall yield.
- Smith, Daniel J.,Yap, Glenn P.A.,Kelley, James A.,Schneider, Joel P.
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p. 1513 - 1520
(2011/06/20)
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- NOVEL CYCLIC BORONATE INHIBITORS OF HCV REPLICATION
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Compounds of formula (I) or a salt thereof are provided; wherein R1, R2, R3, R4, R6, R8, R20, R30, Y, Z and n are as defined in the description. Uses of the compounds as medicaments, and in the manufacture of medicaments for treating viral infection, especially HCV infection are also disclosed. The invention further comprises processes to make these compounds and pharmaceutical formulations thereof.
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Page/Page column 73-75
(2009/05/29)
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- Nα-Fmoc-protected ω-azido- and ω-alkynyl-L- amino acids as building blocks for the synthesis of "clickable" peptides
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The growing interest in the 1,4-disubstituted-1,2,3-triazolyl moiety as an amide bond surrogate and its formation through very mild, chemoselective, and bioorthogonal CuI-catalyzed Huisgen 1,3-dipolar [3+2] cycloaddition of an alkynyl to an azi
- Isaad, Alexandra Le Chevalier,Barbetti, Francesca,Rovero, Paolo,D'Ursi, Anna Maria,Chelli, Mario,Chorev, Michael,Papini, Anna Maria
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experimental part
p. 5308 - 5314
(2009/06/18)
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- Preparation and conformational study of CF3-containing enkephalin-derived oligopeptide
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Incorporation of (2S,3S)-4,4,4-trifluorothreonine (F3-Thr) instead of Thr in the enkephalin-derived hexapeptide led to the apparent conformational alteration due to the strong electron-withdrawing effect of the trifluoromethyl group by comparison with the original compound on the basis of their various NMR measurements.
- Kitamoto, Takamasa,Marubayashi, Shunsuke,Yamazaki, Takashi
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p. 1888 - 1894
(2008/09/18)
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- Highly enantio- and diastereoselective mannich reactions of chiral Ni(II) glycinates with amino sulfones. Efficient asymmetric synthesis of aromatic αβ-diamino acids
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(Chemical Equation Presented) This paper describes a practical, enantio- and diastereoselective Mannich reaction between a chiral Ni(II) complex of glycine 1 and α-amino sulfones 2, involving the creation of a carbon-carbon bond and two stereogenic centers in a single operation; it represents an attractive route to the synthesis α,β-diamino acids.
- Wang, Jiang,Shi, Ting,Deng, Guanghui,Jiang, Hualiang,Liu, Hong
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experimental part
p. 8563 - 8570
(2009/04/04)
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- Operationally convenient, efficient asymmetric synthesis of enantiomerically pure 4-aminoglutamic acids via methylene dimerization of chiral glycine equivalents with dichloromethane
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This paper presents a practical and efficient asymmetric synthesis of enantiomerically pure 4-aminoglutamic acids using a quite unusual methylene dimerization of chiral nucleophilic glycine equivalents with dichloromethane under phase-transfer catalysis (
- Soloshonok, Vadim A.,Yamada, Takeshi,Ueki, Hisanori,Moore, Anna M.,Cook, Tanner K.,Arbogast, Kelsey L.,Soloshonok, Anatolii V.,Martin, Collin H.,Ohfune, Yasufumi
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p. 6412 - 6419
(2007/10/03)
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- METHOD OF PREPARING OPTICALLY ACTIVE SERINE DERIVATIVE
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A method of preparing L-threo-(2S,3R)-3-(3.4-dihydroxyphenyl)serine or a salt thereof and an immediate obtained in the preparation of the serine derivative are provided. The method includes decomposing an asymmetric aldol condensate of a chiral metal complex in a polar organic solvent using an acid and hydrogenating the resulting product.
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Page/Page column 7-8; 11
(2010/02/14)
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- METHOD FOR PRODUCING OPTICALLY ACTIVE SERINE DERIVATIVE
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PROBLEM TO BE SOLVED: To provide a method for producing optically active L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine or salts thereof, and to provide an intermediate thereof. SOLUTION: The method for producing L-threo-(2S,3R)-3-(3,4-dihydroxyphenyl)serine or salts thereof comprises a step in which asymmetric aldol condensation products of chiral metal complex are decomposed to acids in a polar organic solvent, and a step in which hydroxylation reaction of the obtained products is performed. The chiral metal complex of a production intermediate of the optically active compound is e.g. 1-hydroxy-1-(3,4,-dibenzyloxyphenyl)glycine-Ni-D-2-[N(N'-benzylprolyl)amino]benzophenone.
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Page/Page column 16
(2010/02/14)
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- Asymmetric synthesis of all six regioisomers of N-boc-dimethylphenylalanines
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All possible regioisomers of dimethyl-substituted (S)-phenylalanine were efficiently synthesized by reacting the Ni(II)-complex of the chiral Schiff base of glycine with (S)-2-N-(N-benzylprolyl)-aminobenzophenone.
- Ouchi, Hidekazu,Kumagai, Midori,Sakurada, Shinobu,Takahata, Hiroki
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p. 505 - 514
(2007/10/03)
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- Stereochemically defined C-substituted glutamic acids and their derivatives. 1. An efficient asymmetric synthesis of (2S,3S)-3-methyl- and - 3-trifluoromethylpyroglutamic acids
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An efficient asymmetric synthesis of biologically important (2S,3S)-3- methyl- and (2S,3S)-3-trifluoromethylpyroglutamic acid has been developed. The method consists of diastereoselective Michael addition reaction between ethyl crotonate or ethyl 4,4,4-trifluorocrotonate and a Ni(II) complex of the chiral non-racemic Schiff base of glycine with (S)-o-[N-(N- benzylprolyl)amino]benzophenone (BPB) followed by decomposition of the addition products by aq. HCl and treatment of the resultant glutamic acid derivatives with NH4OH to afford the target pyroglutamic acids along with recovery of the chiral auxiliary BPB. The stereochemical outcome of the addition reactions was found to be subjected to kinetic control. A mechanistic rationale for the observed stereochemical preferences is discussed.
- Soloshonok, Vadim A.,Cai, Chaozhong,Hruby, Victor J.,Van Meervelt, Luc,Mischenko, Nikolai
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p. 12031 - 12044
(2007/10/03)
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- ASYMMETRIC SYNTHESIS OF HETEROORGANIC ANALOGS OF NATURAL COMPOUNDS. 4. DIASTEREO- AND ENANTIOSELECTIVE SYNTHESIS OF (2S,3S)-4,4,4-TRIFLUOROTHREONINE AND (2S,3S)-β-PERFLUOROALKYLSERINES
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Perfluorinated aliphatic aldehydes react with the Ni(II) complex of the glycine Schiff base with (S)-2-benzophenone in the presence of MeONa to give (2S,3S)-perfluoroalkylserines, while alkanals react to form (2R,3S)-diastereomers
- Soloshonok, V. A.,Kukhar, V. P.,Batsanov, A. S.,Galakhov, M. A.,Belokon, Yu. N.,Struchkov, Yu. T.
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p. 1366 - 1372
(2007/10/02)
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- Synthesis of a Chiral Nickel(II) Complex of an Electrophilic Glycinate, and its Use for Asymmetric Preparation of α-Amino Acids
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A chiral NiII complex of a Schiff's base derived from (S)-o-benzophenone and α-bromoglycine has been obtained and its stereoselective reaction with nucleophiles studied; the synthesis of aspartic acid with 80percent optical purity is described.
- Belokon', Yuri N.,Popkov, Aleksander N.,Chernoglazova, Nina I.,Saporovskaya, Marina B.,Bakhmutov, Vladimir I.,Belikov, Vasili M.
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p. 1336 - 1338
(2007/10/02)
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- Synthesis of Enantio- and Diastereo-isomerically Pure β- and γ-Substituted Glutamic Acids via Glycine Condensation with Activated Olefins
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The glycine fragment in the nickel(II) complex formed from the Schiff base of glycine and (S)-o-benzophenone undergoes base-catalysed Michael addition in methanol in the presence of MeONa to the activated olefins methyl acrylate, acrylonitrile, methyl methacrylate, acrolein, and methyl trans-cinnamate.Complexes of substituted (S)-glutamic acid or its derivatives were formed in good chemical yields with almost complete diastereoselection at the α-carbon atom of the amino acid moiety.Diastereoselection at the β- and γ-atoms was not significant, but the isomeric complexes could be easily separated chromatogrphically.Cleavage of the pure diastereoisomers with aqueous HCl gave, in good yields, optically pure glutamic acids and regenerated the original chiral reagent.The configurations of the amino acid β- and γ-carbon atoms were determined by 1H n. m. r. spectroscopy and crystal structure X-ray analysis of the corresponding original complexes.The addition to acrolein, catalysed by triethylamine in methanol, leads to the 1,4-adduct exclusively.The amino acid thus obtained could be converted into (S)-proline by reduction with NaBH4.
- Belokon, Yuri N.,Bulychev, Aleksandr G.,Ryzhov, Mikhail G.,Vitt, Sergei V.,Batsanov, Andrei S.,et al.
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p. 1865 - 1872
(2007/10/02)
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- General Method of Diastereo- and Enantioselective Synthesis of β-Hydroxy-α-amino Acids by Condensation of Aldehydes and Ketones with Glycine
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The condensation of formaldehyde with a Ni(II) complex of glicyne Schiff base with (S)-2-acetophenone (1) or (S)-2-benzophenone (2) in CH3OH at 25 deg C in the presence of Et3N yields (S)-Ser with an enantiomeric excess (ee) of 80-90percent.The same reaction gives rise to (R)-Ser with an ee greater than 80percent in the presence of more than 0.2 N CH3ONa, α-(hydroxymethyl) serine being formed in negligible quantities.The reaction of benzaldehyde, 3,4-(methilenedioxy)benzaldehyde, and acetaldehyde with these Gly complexes in 0.2 N CH3ONa at 25 deg C yields β-hydroxy-α-amino acids: (R)-β-phenylserine, (R)-3,4-(methylenedioxy)-β-phenylserine, and (R)-threonine, respectively, with a threo/allo ratio ranging from 10:1 up to over 50:1 and ee more than 80percent.Condensation with acetone yields (R)-β-hydroxyvaline with an enantiomeric purity of 70percent.The enantiomerically pure β-hydroxy-α-amino acids can be obtained from pure diastereomers, isolated by chromatography on silica or Toyopearl HW-60.The initial reagents 1 and 2 were recovered with 60-98percent yield.The stereochemical mechanism of the reaction is discussed.
- Belokon, Yuri N.,Bulychev, Alexander G.,Vitt, Sergei V.,Struchkov, Yuri T.,Batsanov, Andrei S.,et al.
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p. 4252 - 4259
(2007/10/02)
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