Catalytic, asymmetric synthesis of α,α-disubstituted amino acids

Copper(salen) complex 1 has been found to catalyse the asymmetric alkylation of enolates derived from a variety of amino acids. There is a clear relationship between the size of the side chain in the substrate and the enantioselectivity of the process, so that the enantioselectivity decreases in the order alanine>aminobutyric acid>allylglycine>leucine>phenylalanine>valine. A transition state model which accounts for the influence of the size of the side chain on the enantioselectivity of the reactions is presented.     

Reactions of organometallics with oximes. Synthesis of α-N-hydroxy amino acids

Reaction of organolithium reagents with glyoxylate and pyruvate derived oximes provides a direct route for the synthesis of unusual α-N-hydroxy amino acids.     

Glycoconjugates of amino acids. Preparation throughN-alkylation of amino acids withN-chloroacetyl-β-glycopyranosylamines

Monoalkylation of amino acids of different structural types withN-chloroacetyl-glycosylamines was shown to be applicable for the preparation of glycoconjugates containing β-d-galactose,N-acetyl-β-d-glucosamine, β-d-mannose, and lactose residues. The glycoconjugates were synthesized from amino acids with secondary (sarcosine,l-proline) or primary (l-2- and 4-aminobutyric acids,l-tryptophan) amino groups as well as from various amino dicarboxylic acids (N-methyl-dl-aspartic,dl-aspartic,l-glutamic, anddl-2-aminoadipic acids). The derivatives obtained may be of interest for glycotargeting of physiologically active compounds of this series. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1377–1380, July, 1999.     

Copper(II)salen catalysed, asymmetric synthesis of α,α-disubstituted amino acids

Cu(salen) complex 1 was found to be a versatile catalyst for the asymmetric alkylation of a range of enolates derived from α-amino acids, leading to α,α-disubstituted amino acids. The enantioselectivity of the process decreases as the size of the amino acid sidechain increases, but functionalized amino acids such as allylglycine and aspartic acid are substrates for the process. Benzylic bromides are found to be more enantioselective alkylating agents than propargylic bromides. As an example of the utility of this chemistry, an α-propargylic allylglycine derivative is prepared and subjected to ene-yne metathesis using Grubbs' catalyst to give a non-racemic cyclopentenyl amino acid.     

σ-Complexes of transition metals in organic synthesis. 9. Reactions of allyl organomanganese compounds with γ-bromine derivatives of esters of α, Β-unsaturated carboxylic acids

The allyl Mn(II) organic compounds R¹CH=C(R²)CH₂MnCl (R¹=H, Me; R²=H, Me, Bu), obtained in situ from Grignard reagents and Li₂MnCl₄, react with esters of 4-bromocrotonic, (2-bromobutylidene)-, (4-bromo-2-butenylidene)-, (2-bromoisobutylidene) malonic, and (2-bromoheptylidene)cyanoacetic acids in THF at –78 to +20C to give derivatives of substituted cyclopropanecarboxylic or cyclopropane-1, 1-dicarboxylic acids. These derivatives contain a fragment of the allyl type. When ethers of 2-(bromomethyl)acrylic, 4-bromo-2-methyl-, and 4-bromo-3-methyl-2-butenoic acids are used, cross-combination products result.For previous communication, see [1].Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 3, pp. 656–663, March, 1991.     

Study of the temperature effect on IR spectra of crystalline amino acids,dipeptids, and polyamino acids. III. α-Glycylglycine

The IR spectra of α-glycylglycine (H₃ ⁺N-CH₂-CO-NH-CH₂-COO^?) are studied in the temperature range of 93 to 413 K. Changes in the spectra due to temperature variation are correlated with the previously obtained X-ray diffraction data on anisotropic compression of the structure and changes in the parameters of hydrogen bonding. Changes in the vibrational frequencies of NH ₃ ⁺ and COO groups in the IR spectrum of α-glycylglycine are compared to changes in the vibrational frequencies of the same groups in the IR spectra of polymorphs of glycine, L- and DL-serine.     

Reactions of an aromatic σ,σ-biradical with amino acids and dipeptides in the gas phase

Gas-phase reactivity of a positively charged aromatic σ,σ-biradical (N-methyl-6,8-didehydroquinolinium) was examined toward six aliphatic amino acids and 15 dipeptides by using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR) and laser-induced acoustic desorption (LIAD). While previous studies have revealed that H-atom and NH₂ abstractions dominate the reactions of related monoradicals with aliphatic amino acids and small peptides, several additional, unprecedented reaction pathways were observed for the reactions of the biradical. For amino acids, these are 2H-atom abstraction, H₂O abstraction, addition — CO₂, addition — HCOOH, and formation of a stable adduct. The biradical reacts with aliphatic dipeptides similarly as with aliphatic amino acids, but undergoes also one additional reaction pathway, addition/C-terminal amino acid elimination (addition — CO — NHCHR_C). These reactions are initiated by H-atom abstraction by the biradical from the amino acid or peptide, or nucleophilic addition of an NH₂ or a HO group of the amino acid or peptide at the radical site at C-6 in the biradical. Reactions of the unquenched C-8 radical site then yield the products not observed for related monoradicals. The biradical reacts with aromatic dipeptides with an aromatic ring in N-terminus (i.e., Tyr-Leu, Phe-Val, and Phe-Pro) similarly as with aliphatic dipeptides. However, for those aromatic dipeptides that contain an aromatic ring in the C-terminus (i.e., Leu-Tyr and Ala-Phe), one additional pathway, addition/N-terminal amino acid elimination (addition — CO — NHCHR_N), was observed. This reaction is likely initiated by radical addition of the biradical at the aromatic ring in the C-terminus. Related monoradicals add to aromatic amino acids and small peptides, which is followed by Cα-Cβ bond cleavage, resulting in side-chain abstraction by the radical. For biradicals, with one unquenched radical site after the initial addition, the reaction ultimately results in the loss of the N-terminal amino acid. Similar to monoradicals, the C-S bond in amino acids and dipeptides was found to be especially susceptible to biradical attack.     

Reaction of aminoquinolines with unsaturated carboxylic acids. 2. Cyclization of N-quinolyl-β-alanines

The cyclization of N-(3-quinolyl)- and N-(6-quinolyl)--alanines was carried out to give uncondensed hexahydropyrimidine derivatives, while the cyclization of N-(5-quinolyl)- and N-(8-quinolyl)--alanines gave tetrahydrophenanthrolinone derivatives.Communication 1, see ref. [1].Kaunas Technological University, 3028 Kaunas, Lithuania, Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 653–657, May, 2000.     

Reactions of aminobenzoic acids with α,β-acetylenic γ-hydroxy nitriles: synthesis of functionalized amino acids and unusually facile esterification and acetylene hydration

2-Aminobenzoic acid 1 reacts with α,β-acetylenic γ-hydroxy nitriles 4 and 5 to afford 2-[(5-iminio-2,2-dialkyl-2,5-dihydro-3-furanyl)amino]benzenecarboxylates 7 and 8 (yield 73-74%), a new class of unnatural amino acids in a peculiar zwitterionic form, having the positive charge transferred to the remote imino group of the dihydrofuranyl substituent. 3- and 4-Aminobenzoic acids 2 and 3 with α,β-acetylenic γ-hydroxy nitriles 4-6 undergo entirely different transformations to deliver the esters of cyanomethylhydroxyalkyl ketones 9-12, which result from the unusually facile esterification of the hydroxyl function and simultaneous hydration of the triple bond. 4-Aminobenzoic acid 3 is found to be an active organic catalyst for the one-pot conversion of α,β-acetylenic γ-hydroxy nitrile 4 to 5-amino-2,2-dimethyl-3(2H)-furanone 13, in 80% yield.     

Asymmetric Strecker reaction of γ-keto acids. Facile entry to α-substituted and α,γ-disubstituted glutamic acids

The Strecker reaction of γ-keto acid derived sodium salts with (S)-phenylglycinol followed by treatment of the resultant α-amino nitriles with methanolic HCl and heating at 200 °C give bicyclic lactones 11 and 12. Hydrolysis and subsequent debenzylation of 11 and their alkylation products 17 furnish α-substituted and α,γ-disubstituted glutamic acids.     

Cleavage of hindered α-methylbenzylamides,intermediates in the resolution of carboxylic acids

α-Methylbenzylamides, useful intermediates in the resolution of carboxylic acids, are cleaved with a two step procedure; enolizable amides are not racemized.     

The preparation and alkylation of a butanedione-derived chiral glycine equivalent and its use for the synthesis of α-amino acids and α,α-disubstituted amino acids

A benzyloxycarbonyl protected glycine equivalent 2 has been prepared in enantiopure form and has been used in the synthesis of both α-substituted amino acids and α,α-disubstituted amino acids. The process involved deprotonation to form the corresponding enolates which underwent stereoselective alkylation with various electrophiles and upon hydrolysis gave the corresponding amino acid derivatives as enantiomerically pure products.     

Efficient, enantioselective synthesis of a β,β-disubstituted carboxylic acid by Ru-XylPhanePhos-catalyzed asymmetric hydrogenation

Enantioselective preparation of a key α_vβ₃ integrin antagonist intermediate was accomplished via catalytic asymmetric hydrogenation of the corresponding β,β-disubstituted α,β-unsaturated carboxylic acid bearing a 3-quinolinyl moiety. The successful application of a Ru-(R)-XylPhanePhos catalyst to this type of substrate is unprecedented. In situ NMR experiments of pre-catalyst formation/activation by CH₃CO₂H, and reaction parameter modification, revealed that [Ru(COD)(CF₃CO₂)₂]₂/(R)-XylPhanePhos is a highly active and efficient catalytic system.     

A one step synthesis of ω-hydroxyacetylenic carboxylic acids

A convenient chemioseLective method to prepare ω-hydroxyacetylenic carboxylic acids from unprotected ω-alkyn-1 ols and ω-bromo acids is described.     

Interaction of aminoquinolines with unsaturated carboxylic acids. 1. Synthesis of N-quinolyl-β-alanines and their biological activity

N-Quinolyl--alanines, and -methyl- and-methyl-N-quinolyl--alanines were prepared by reaction of aminoquinolines and acrylic, methacrylic, and crotonic acids. The corresponding hydrazides and benzylidenehydrazides were obtained. 4-Aminoquinoline with unsaturated acids in water gave betaines. The biological activity of sodium salts of -alanines was investigated.Kaunas University of Technology, Kaunas LT-3028, Lithuania; Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 504–511, April, 2000.     

Decarboxylative bromination of α,β-unsaturated carboxylic acids via an anodic oxidation

A novel bromination of α,β-unsaturated carboxylic acids was developed via a decarboxylation by virtue of a direct anodic electro-oxidation.In this method,ammonium bromide was employed as a bromine source and the reaction features transition-metal-free,short time,and no additional supporting electrolyte.     

Enamines of 3-acyltetramic acids from β-enamino amides and amino acids

A novel approach for the synthesis of enamine derivatives of N-protected 3-acyltetramic acids is described. The synthetic procedure relies on α-C-acylation of β-enamino amides with N-protected α-amino acids and subsequent cyclisation of the obtained intermediates in refluxing TFA. The tetramic derivatives are obtained with very good enantiopurity (e.r. ≥95:5). Ring-enlarged analogues (piperidine-2,4-diones) can also be obtained from β-amino acids.