Α-amino Acid Precursors Research Articles

Synthesis and Crystal Structure Analysis of Methyl 2-Hydroxyimino-3-phenyl-propionate

As precursors of α-amino acids, methyl 2-hydroxyimino-3-phenyl-propionate (F.W. 193.20) was synthesized, characterized by 1H NMR, IR, element analysis and confirmed by X-ray crystal structure analysis. This compound crystallizes in monoclinic class under the space group P21/c with cell parameters, a = 8.6435(17) A, b = 5.4957(11) A, c = 21.146(4) A; β = 97.12(3)°, and Z = 4. The structure exhibits inter-molecular hydrogen bonds of the type O–H···N, O–H···O, C–H···O. The title compound, methyl 2-hydroxyimino-3-phenyl-propionate was synthesized by nitrosation oximation of substituted malonic esters and its crystal structure was determined.

Biophysical and Structural Characterization of a Robust Octameric β-Peptide Bundle

Proteins composed of alpha-amino acids are essential components of the machinery required for life. Stanley Miller's renowned electric discharge experiment provided evidence that an environment of methane, ammonia, water, and hydrogen was sufficient to produce alpha-amino acids. This reaction also generated other potential protein building blocks such as the beta-amino acid beta-glycine (also known as beta-alanine); however, the potential of these species to form complex ordered structures that support functional roles has not been widely investigated. In this report we apply a variety of biophysical techniques, including circular dichroism, differential scanning calorimetry, analytical ultracentrifugation, NMR and X-ray crystallography, to characterize the oligomerization of two 12-mer beta3-peptides, Acid-1Y and Acid-1Y*. Like the previously reported beta3-peptide Zwit-1F, Acid-1Y and Acid-1Y* fold spontaneously into discrete, octameric quaternary structures that we refer to as beta-peptide bundles. Surprisingly, the Acid-1Y octamer is more stable than the analogous Zwit-1F octamer, in terms of both its thermodynamics and kinetics of unfolding. The structure of Acid-1Y, reported here to 2.3 A resolution, provides intriguing hypotheses for the increase in stability. To summarize, in this work we provide additional evidence that nonnatural beta-peptide oligomers can assemble into cooperatively folded structures with potential application in enzyme design, and as medical tools and nanomaterials. Furthermore, these studies suggest that nature's selection of alpha-amino acid precursors was not based solely on their ability to assemble into stable oligomeric structures.

Single-crystal analyses of a series of asymmetrically synthesized α-amino acid precursors

Three α-amino acid precursors and their common substrate were structurally analyzed by means of X-ray crystallography. Though the precursors were synthesized under asymmetric reaction conditions and showed certain optical activities, their single-crystals were in racemic forms. A systematic structural investigation on these precursors has been carried out by comparing their molecular conformations and crystal packing to that of the substrate.

Synthesis of α-Amino Acids via a Carbolithiation Reaction on Acyclic Ene-Carbamates and an Internal N→C Alkyloxycarbonyl Migration

A novel and efficient synthesis of precursors of α-amino acids is described. The key step involves a carbolithiation reaction on acyclic ene-carbamates generated from the corresponding vinylphosphates via a palladium cross-coupling reaction followed by a spontaneous internal N→C alkyloxycarbonyl migration.

Highly diastereoselective nucleophilic addition reactions of masked acyl cyanide reagents to tert-butanesulfiminides

Addition reactions of dicyanomethyl tert-butyldimethylsilyl ether (H–MAC–TBS) to optically active tert-butanesulfinimides afforded α-amino acid precursors in excellent yields and with high diastereoselectivities.

Synthesis of α-Amino Acid Precursors Directly from Aldehydes Using Masked Acyl Cyanide Reagents and N,O-Dialkylated Hydroxylamines

A synthetic methodology for the synthesis of alpha-amino acid precursors directly from the corresponding aldehydes using N,O-dialkylated hydroxylamines and masked acyl cyanide (MAC) reagents was developed. The one-pot reaction can be carried out under mild conditions and without a separate purification step of the imino species. The method was applied to the synthesis of optically pure (+)-4-methylphenylglycine and the derivatives by using an Abiko-Masamune's tricyclic 1,2-oxazolidine as the chiral auxiliary.

Tandem Addition/Cyclization of Alkynylzinc Reagents to Enantiopure 2‐tert‐Butyl‐3,5‐dimethyl‐2,3‐dihydroimidazol‐4‐one N‐Oxide: Potential Precursors of Quaternary α‐Amino Acids.

A new enantiopure cyclic nitrone, a potential electrophilic alanine synthon, has been prepared. Its reaction with alkynylzinc reagents led to a tandem addition/cyclization reaction with complete regio- and stereoselectivity. The adducts are potential precursors of quaternary α-amino acids. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Asymmetric synthesis of amino acids by Cr(II) complexes of natural amino acids

Stoichiometric reduction of the C,N double bond of oxime precursors of α-amino acids was performed in aqueous media by Cr(II) complexes of natural amino acids. The reduction of oximes of α-ketophenylacetic, α-keto-β-phenylpropionic and α-ketopropionic acids proceeded up to >90% conversion and 2–30% enantiomeric excess. 1:2 complexes of Cr(II) with l-alanine, l-valine, l-aspartic acid, l-histidine and l-phenylalanine were used as reducing agents. The reduction of α-(oximino)phenylacetic acid showed increasing e.e. (and decreasing conversion) with increasing temperature.

A convenient synthesis of tetrazole, precursors of α-dialkylated α-amino acids, by reaction of trimethylsilyl azide with α-dialkylated β-ketoesters

The Schmidt rearrangement using trimethylsilyl azide with various α-dialkylated β-keto esters affords a convenient synthesis of tetrazole, precursors of α-dialkylated α-amino acids.

Investigation of the Influence of pH on the Catalytic Asymmetric Hydrogenation in Aqueous Micellar Media

The influence of pH on the asymmetric hydrogenation of α-amino acid precursors was investigated in the presence of different types of amphiphiles in water as medium. Non-ionic, cationic and zwitterionic amphiphiles gave optimal results with respect to activity and enantioselectivity between pH 2 and pH 5. Anionic amphiphiles were effective in the range from pH 2 up to pH 8 (sometimes pH 9). Comparable results were obtained with cationic and anionic polymeric micelles. Some relationships exist between CH/CD exchange in D2O and the pH dependence of the hydrogenation. As a practical consequence the pH in micellar hydrogenation systems should be chosen between pH 2 and pH 4.

Preparation of α- and β-substituted alanine derivatives by α-amidoalkylation or Michael addition reactions under heterogeneous catalysis assisted by microwave irradiation

Abstract Silica-supported Lewis acids are useful catalysts in conjunction with microwave irradiation for the synthesis of a range of alanine derivatives. Reaction of methyl α-acetamidoacrylate ( 1 ) with different heterocycles, such as furan ( 2 ), pyrrole ( 3 ), N -benzylpyrrole ( 4 ), indole ( 5 ) and pyrazole ( 6 ) and the carbocycle 1,3,5-trihydroxybenzene ( 7 ), led to several α-amino acid precursors.

Asymmetric hydrogenation in a membrane reactor: recycling of the chiral catalyst by using a retainable micellar system

A micellar enlarged Rh-(2 S,4 S)- N- tert-butoxycarbonyl-4-diphenylphosphino-2-diphenyl-phosphino-methyl-pyrrolidine (BPPM) catalyst was used for the enantioselective hydrogenation of α-amino acid precursors in a membrane reactor, equipped with an ultrafiltration membrane. The chiral α-amino acid derivatives were obtained with good enantioselectivity and space–time yields. The catalyst, embedded in micelles, obtained from triblock copolymers as surfactants, was retained and reused several times without loss of activity and enantioselectivity. Only a minimal leaching of the catalyst components was found.

Electrophilic Amination of Ketone Enolates Mediated by the DiTOX Asymmetric Building Block: Enantioselective Formal Synthesis of α-Aminoacids

Diastereoselective electrophilic amination of enolates derived from 2-acyl-1,3-dithiane 1-oxides is used as the key step for an enantioselective synthesis of two α-hydrazido carboxylic acids, well-known precursors of α-amino acids.

Aziridine Carboxylates, Carboxamides and Lactones: New Methods for Their Preparation and Their Transformation into α- and β-Amino Acid Derivatives

The preparation of a variety of novel aziridine-γ-lactones (3) from carbohydrates is described. In contrast to aziridine-2-carboxylates, the lactones react regiospecifically at C-2 with soft nucleophiles to provide optically pure substituted β-amino acid precursors. Hard nucleophiles react exclusively at the C-3 position to provide α-amino acid precursors. The utility of this methodology was demonstrated by the preparation of (3S,4S)-dihydroxy-L-glutamic acid (DHGA) from the appropriate aziridine-γ-lactone. DHGA was subsequently shown to be a selective partial agonist of mGluR1 receptors. A more concise preparation of aziridine-γ-lactones was achieved by 1,4-Michael addition of benzylamine to 2-O-triflylbutenolides. Use of a 2-O-mesylbutenolide led, under the same conditions, to the corresponding aziridine-2-carboxamides or 2-carboxylates. Finally, a new Evanstype aziridinating agent, Ses-iminoiodinane, was developed and shown to react efficiently with unsaturated substrates to give the corresponding aziridines, whose N-Ses protecting groups can be removed under mild conditions.

Synthesis of Heterocyclic β-Aminoalcohol Precursors of Heterocyclic α-Aminoacids

Heterocyclic β-aminoalcohol precursors of heterocyclic α-aminoacids were obtained from biheterocyclic systems, prepared by 1,3-dipolar cycloaddition reaction of azido oxazoline with alkynes.

Ring expansion of N-acyl aziridine-2-imides to oxazoline-4-imides, useful precursors of pure β-Hydroxy α-aminoacids

Optically active N-acyl aziridine 2-imides or 2-carboxylates rearrange to oxazoline-4-imides or 4-carboxylates with high regio and stereo control. This ring expansion followed by mild hydrolisis allows the synthesis of enantiomerically pure β-hydroxy α-aminoacid precursors.

Catalytic osmylation of allenic compounds. Synthesis of α-hydroxyketo amino acid precursors

Osmium tetroxyde-catalyzed dihydroxylation of allenic compounds in the presence of N-Methylmorpholine Oxide leads to α-ketols. Regioselectivity of this oxidation procedure with allenic α-amino acid precursors is greatly influenced by the nature and the remoteness of the protected amino acid group.

Concise synthesis of α-alkyl α-amino acids and their incorporation into peptides viaβ-lactam-derived α-amino acid N-carboxy anhydrides

α-Hydroxy β-lactams in which C4 exists as a quaternary carbon are transformed in a single one-pot operation into α,α-dialkyl α-amino acid N-carboxy anhydrides providing a new approach to conformationally restricted peptide segments from non α-amino acid precursors.

Diels-Alder reactions of α-amino acid precursors by heterogeneous catalysis: Thermal vs. microwave activation

The Diels-Alder reactions of methyl and (−)-menthyl 2 acetamidoacrylates with cyclopentadiene, a key step in the synthesis of cyclic α-amino acids, are carried out in the presence of heterogeneous catalysts. Given the low reactivity of these dienophiles the best results are obtained when the reactions are carried out in the absence of a solvent. A close relationship between the relative catalytic activity of the different solids and the nature of the dienophile exists. The selectivities obtained are similar to those described for the reactions catalyzed by homogeneous Lewis acids, in particular a complete diastereofacial selectivity is obtained. Microwave activation increases the reaction rate without decreasing the selectivity. However, it is necessary to choose a suitable input power in order to avoid the decomposition of the 2-acetamidoacrylate.

Two effective procedures for the synthesis of trichloromethyl ketones, useful precursors of chiral α-amino and α-hydroxy acids

Trichloroacetic acid can been converted to trichloromethyl ketones in good yield by two practical new procedures, one involving the catalyzed reaction of trichloroacetic acid with aldehydes at 23 °C followed by oxidation and the other utilizing the coupling of organozinc intermediates with trichloroacetyl chloride