Stereochemically defined C-substituted glutamic acids and their derivatives. 1. An efficient asymmetric synthesis of (2S,3S)-3-methyl- and -3-trifluoromethylpyroglutamic acids

Soloshonok, Vadim A.; Cai, Chaozhong; Hruby, Victor J.; Meervelt, Luc Van; Mischenko, N

doi:10.1016/s0040-4020(99)00711-5

Cited by 84 publications

(50 citation statements)

References 37 publications

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“…Initially, Michael additions of the glycinate (BPB-Ni-Gly) to di- tert -butyl methylenemalonate 14 32 were optimized around conditions described in the literature. 21,22,33 The selectivity of the addition reaction was assessed by decomposing the resulting metal complex to free the amino acid, whose enantiomeric excess was measured using Marfey’s reagent (Table 1, note b). The diastereomeric ratio of the products favoring the ( S , S ) configuration was consistent with reports discussed earlier.…”

Section: Resultsmentioning

confidence: 99%

Enhanced Stereoselectivity of a Cu(II) Complex Chiral Auxiliary in the Synthesis of Fmoc-l-γ-carboxyglutamic Acid

2011

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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-α-Fmoc-L-γ-carboxyglutamic acid-γ,γ’-tert-butyl ester (Fmoc-Gla(OtBu)2-OH), a suitably protected analog for Fmoc-based solid phase peptide synthesis. The residue was synthesized using a novel chiral Cu(II) complex, whose structure-based 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 α-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.

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Section: Resultsmentioning

confidence: 99%

Enhanced Stereoselectivity of a Cu(II) Complex Chiral Auxiliary in the Synthesis of Fmoc-l-γ-carboxyglutamic Acid

2011

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“…[13] This complex has been used for the synthesis of 2-substituted glutamic and pyroglutamic acids also by a Michael addition to β-substituted acrylates using a substoichiometric amount of DBU in DMF at room temperature to give, after separation trans-3-substituted pyroglutamic acids as the major diastereomers. [14] High diastereoselectivity has been obtained in the case of 3-trifluoromethylcontaining crotonate (Ͼ98% de) by using an excess of DBU and olefin to afford, after hydrolysis, (2S,3S)-3-methyl-3-trifluoromethylpyroglutamic acid. [15] The pyridoxal-derived alanine imines 11 (R 1 ϭ Me), [16a] bearing a chiral side-chain composed of a chiral glycerol structure, have been diastereoselectively alkylated with pnitrobenzyl bromide under PTC conditions (NaOH, CH 2 Cl 2 , 0°C) to give the dialkylated derivatives in 32% yield and 26% ee.…”

Section: Acyclic Chiral Imine Reagentsmentioning

confidence: 99%

“…[14] High diastereoselectivity has been obtained in the case of 3-trifluoromethylcontaining crotonate (Ͼ98% de) by using an excess of DBU and olefin to afford, after hydrolysis, (2S,3S)-3-methyl-3-trifluoromethylpyroglutamic acid. [15] The pyridoxal-derived alanine imines 11 (R 1 ϭ Me), [16a] bearing a chiral side-chain composed of a chiral glycerol structure, have been diastereoselectively alkylated with pnitrobenzyl bromide under PTC conditions (NaOH, CH 2 Cl 2 , 0°C) to give the dialkylated derivatives in 32% yield and 26% ee. [16b] Better chemical and optical yields (up to 86%) have been obtained with NaH or NaHMDS at low temperature and with activated alkyl halides as electrophiles.…”

Section: Acyclic Chiral Imine Reagentsmentioning

confidence: 99%

Glycine and Alanine Imines as Templates for Asymmetric Synthesis of α-Amino Acids

et al. 2000

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Keywords: Imines / Asymmetric synthesis / Amino acids / Schiff bases / α,β-Didehydro-α-amino acidsThe present paper is an overview of new methods for the asymmetric synthesis of different types of α-amino acids. These methods are based on alkylation and condensation reactions of glycine and alanine imine derivatives, which can be carried out under very mild and simple reaction conditions. The enolates generated from these types of reagents are very soft and can be alkylated in a highly diastereoselective manner, even at room temperature, by using chiral templates or asymmetric PTC conditions. These methodologies

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“…The reactions were conducted in a solution of DMF, at ambient temperature, using 15 mol% of organic base DBU. Owing to the high electrophilicity of the trifluoromethyl acrylates 81-83, the reaction rates were exceptionally fast, leading to the completion of the addition within a few minutes [124][125][126]. The observed stereochemical outcome was reasonably good, affording, after disassembly of the corresponding intermediate derivatives, the major diastereomeric products (2S,3S)-84, (2S,3S)-85 and (2S,3S,4R)-86 in isolated yields greater than 50%.…”

Section: Addition Reactionsmentioning

confidence: 99%

Practical Synthesis of Fluorine-Containing α- and β-Amino Acids: Recipes from Kiev, Ukraine

2009

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Naturally occurring compounds containing a C-F bond are extremely rare; only a handful of fluorine-containing carboxylic acids have been described so far. By contrast, man-made fluorine-containing derivatives of all major classes of biologically important compounds are extremely promising medicinal targets used in the elucidation of biochemical, metabolic transformations and the development of new pharmaceuticals. Among the fluorine-containing derivatives of natural products, fluorinated analogs of amino acids are of particular interest and medicinal potential. This article presents a concise review of various synthetic methods, developed by the Kiev's school of bioorganic chemistry, for the preparation of fluorine-containing analogs of α- and β-amino acids, α-hydroxy acids, amines, as well as their phosphorus and sulfur-derived compounds, in enantiomerically pure form. One of the major methodological goals of the study was practicality, which is understood by us as stereochemical generality, operational convenience and synthetic affordance for each reaction step and isolation of the target products. The synthetic methods developed by our group can be roughly divided in two general categories: fluorine-adaptation of known synthetic approaches and discovery of new reactions. The former approach is most prominently represented by asymmetric homologation of nucleophilic glycine equivalents using fluorinated substrates via alkyl halide alkylations, aldol and Michael addition reactions. A plethora of discovered unexpected reaction outcomes, in particular stereochemical, are emphasized in this review and the particular role of fluorine, in altering the 'normal' reaction result, is explained. The latter direction is notably represented by the novel 1,3-proton shift reaction, a biomimetic reductive amination of fluorinated carbonyl compounds to the corresponding amines and amino acids, as well as the development of α-fluoroalkyl epoxides as true fluorinated synthons for generalized asymmetric synthesis of various biologically relevant compounds. Despite the highly anticipated potential of fluorine-containing amino compounds, their medicinal chemistry still remains underexplored. The major obstacle, in our opinion, is that these selectively fluorinated compounds are generally unavailable to the medicinal chemists for comprehensive, systematic study. We hope this review of synthetic methods will highlight and bring attention to particular types of fluorinated amino acids and related compounds readily available on a laboratory scale using methods developed by our group.

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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

Cited by 84 publications

References 37 publications

Enhanced Stereoselectivity of a Cu(II) Complex Chiral Auxiliary in the Synthesis of Fmoc-l-γ-carboxyglutamic Acid

Enhanced Stereoselectivity of a Cu(II) Complex Chiral Auxiliary in the Synthesis of Fmoc-l-γ-carboxyglutamic Acid

Glycine and Alanine Imines as Templates for Asymmetric Synthesis of α-Amino Acids

Practical Synthesis of Fluorine-Containing α- and β-Amino Acids: Recipes from Kiev, Ukraine

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