N-protected Α-amino Acids Research Articles

Chiral Oxime Ethers in Asymmetric Synthesis. 3.1 Asymmetric Synthesis of (R)-N-Protected α-Amino Acids by the Addition of Organometallic Reagents to the ROPHy Oxime of Cinnamaldehyde

A new asymmetric synthesis of α-amino acids is described in which the key step is the diastereoselective addition of organometallic reagents to (R)-O-(1-phenylbutyl)cinnamaldoxime 5 to give hydroxylamines 6. Subsequent reductive cleavage of the N−O bond in the hydroxylamine 6 followed by N-protection gave the carbamates 7, which upon oxidation with ruthenium(III) chloride/periodate gave the N-protected amino acids 8. The method was also adapted to the synthesis of a quaternary amino acid 15 from the ketoxime ether 9.

Solid-phase synthesis of N,N′-unsymmetrically substituted ureas: application to the synthesis of carbaza peptides

The synthesis of Boc- or Fmoc-monoprotected propylenediamine derivatives is reported starting from N-protected α-amino acids. The introduction of these building blocks on solid support via the formation of a urea moiety leads to a new pseudopeptide family (C αCH 2CH 2N α(R)CONHC α). Two carbonylating reagents, i.e N,N′-carbonyldiimidazole and triphosgene, as well as different coupling procedures, have been tested to optimize the Boc and Fmoc solid-phase synthesis of a model peptide incorporating this isosteric replacement.

DIRECT LIQUID CHROMATOGRAPHIC ENANTIOMER SEPARATION OF N-tert-BUTOXYCARBONYL AND N-BENZYL-OXYCARBONYL α-AMINO ACIDS USING POLYSACCHARIDE DERIVED CHIRAL STATIONARY PHASES[1

The direct enantioseparation of several N-protected t-BOC (tert-butoxycarbonyl) and CBZ (benzyloxycarbonyl) α-amino acids on polysaccharide derived chiral stationary phases (CSPs) is described. Good resolution of N-protected t-BOC and CBZ α-amino acids used in this study has been achieved. Chiralpak AD shows performance superior to other CSPs for the direct separation of the enantiomers of N-t-BOC as well as N-CBZ α-amino acids. The behavior of elution order and the effects of eluent composition for the resolution of N-t-BOC and N-CBZ α-amino acids have been investigated.

Synthesis of novel chiral lipophilic pyridyl-containing β-amino alcohol ligands and enantioselective hydrolysis of α-amino acid esters by chiral metallomicelles

Seven novel chiral lipophilic pyridyl-containing β-amino alcohol ligands have been synthesized by coupling of 6-alkoxymethyl-2-chloromethylpyridine 3 with the corresponding chiral β-amino alcohols or l-cysteine. Their metal ion complexes have been investigated as catalysts for the enantioselective hydrolysis of N-protected α-amino acid esters in aqueous comicellar solution. The results indicate that the hydrophobic interactions between substrate and metallocatalyst, the rigidity of the ligand, the hydroxyl group of the ligand acting as a nucleophile for the transacylation process, and the micellar microenvironment are important factors for the activity and enantioselectivity. Large rate accelerations (up to three orders of magnitude) and moderate enantioselectivities (up to 7.81 (k R/k S)) employing 4a–Cu 2+ have been observed.

Inulin polysaccharide having pendant amino acids: Synthesis and characterization

Inulin polysaccharide was esterified with N-protected α-amino acids (N,N′-di-benzylocarbonyl-L-lysine and N-benzylocarbonyl-glycine) under a mild condition (room temperature) and within short reaction times (6 h). The esterification reactions were conducted in the presence of dicyclohexylcarbodiimide and 4-(dimethylamino)pyridine as a catalyst. The optimal reaction time (6 h) was determined by monitoring the concentration of free carboxylic acid of the N-protected amino acids during the reaction. The degree of substitution per fructose unit was 0.95 for inulin-lysine and 1.01 for inulin-glycine. The resulting biopolymer was deprotected by catalytic transfer hydrogenation method using 1,4-cyclohexadiene as an effective hydrogen donor. The structures, molecular weight, and thermal properties of the amino acid esters of inulin were determined by Fourier transform infrared spectroscopy, 1H and 13C NMR, UV, viscosity, and dicyclohexylcarbodiimide. This new modified inulin polysaccharide would have the potential as a biomaterial for biomedical applications. © 1998 John Wiley & Sons, Inc. J. Appl. Polym. Sci. 70: 953–963, 1998

Benzotriazole-Mediated Stereoselective Olefination of Carboxylic Esters: Transformation of α-Amino Acid Esters into Chiral Allylamines

Diastereoselective trans-olefinations of carboxylic esters 3a−h have been accomplished using benzylic or allylic benzotriazole derivatives 1a−e to prepare α-(benzotriazol-1-yl) ketones 4a−i, for the subsequent reduction of 4a−i, and finally for low-valent titanium-effected dehydroxybenzotriazolylation.1 N-Protected α-amino acid esters 9a−c and 15 thus give allylamines 13a−e and 19 with virtually full retention of chirality. Mechanistic aspects of the dehydroxybenzotriazolylation are discussed.

A simple preparation of N-protected chiral α-aminonitriles from N-protected α-amino acid amides

N-protected α-amino-acid amides are dehydrated to N-protected α-aminonitriles in good yields and with excellent purities by reaction of the corresponding primary amides with cyanuric chloride in DMF.

Highly Practical Methodology for the Synthesis ofd- andl-α-Amino Acids,N-Protected α-Amino Acids, andN-Methyl-α-amino Acids

Full details are provided for an exceedingly practical method to synthesize d- and l-α-amino acids, N-protected α-amino acids, and N-methyl-α-amino acids, employing as a key step the asymmetric alkylation of pseudoephedrine glycinamide (1) or pseudoephedrine sarcosinamide (2). Practical procedures for the synthesis of 1 and 2 from pseudoephedrine and glycine methyl ester or sarcosine methyl ester, respectively, are presented. Optimum protocols for the enolization and subsequent alkylation of 1 and 2 are described. Alkylation reactions of 1 and 2 are found to be quite efficient with a wide range of alkyl halide substrates, and the products are formed with high diastereoselectivity. The products of these alkylation reactions are hydrolyzed efficiently and with little to no racemization simply by heating in water or water−dioxane mixtures. This protocol provides an exceedingly practical method for the preparation of salt-free α-amino acids of high enantiomeric purity. Alternatively, the alkylation products may be hydrolyzed in high yield and with little to no racemization by heating with aqueous sodium hydroxide. The alkaline hydrolyzate can then be treated with an acylating reagent to provide directly highly enantiomerically enriched N-protected derivatives such as N-Boc and N-Fmoc. Key features necessary for the successful execution of these experimental procedures are identified.

High-performance liquid chromatographic enantioseparation of N-protected ?-amino acids using nonporous silica modified by a quinine carbamate as chiral stationary phase

In this study, tert-butyl carbamoylated quinine as chiral selector was immobilized on nonporous silica (NPS) 1.5 μm particles developed by MICRA, and this new chiral stationary phase (CSP) was packed into a 3.3 cm column (4.6 mm ID). A series of various N-protected α-amino acids was chosen as chiral selectands, including 3.5-dinitrobenzyloxycarbonyl amino acids (DNZ-AAs). In order to optimize the chromatographic conditions with this novel CSP and to apply it to the resolution of acidic analytes the following parameters have been varied and studied: pH of the mobile phase, buffer concentration, and percentage of methanol or acetonitrile in the mobile phase. DryLabR software was applied to optimize enantioseparation by simulating chromatographic functions of experimental conditions for isocratic and/or gradient runs. Thus, we were able to resolve a set of test compounds within several minutes, whereby our attention was particularly drawn to the resolution of DNZ-AA derivatives. Chirality 9:157–161, 1997. © 1997 Wiley-Liss, Inc.

High‐performance liquid chromatographic enantioseparation of N‐protected α‐amino acids using nonporous silica modified by a quinine carbamate as chiral stationary phase

In this study, tert-butyl carbamoylated quinine as chiral selector was immobilized on nonporous silica (NPS) 1.5 μm particles developed by MICRA, and this new chiral stationary phase (CSP) was packed into a 3.3 cm column (4.6 mm ID). A series of various N-protected α-amino acids was chosen as chiral selectands, including 3.5-dinitrobenzyloxycarbonyl amino acids (DNZ-AAs). In order to optimize the chromatographic conditions with this novel CSP and to apply it to the resolution of acidic analytes the following parameters have been varied and studied: pH of the mobile phase, buffer concentration, and percentage of methanol or acetonitrile in the mobile phase. DryLabR software was applied to optimize enantioseparation by simulating chromatographic functions of experimental conditions for isocratic and/or gradient runs. Thus, we were able to resolve a set of test compounds within several minutes, whereby our attention was particularly drawn to the resolution of DNZ-AA derivatives. Chirality 9:157–161, 1997. © 1997 Wiley-Liss, Inc.

Enantioseparation of N-protected ?-amino acid derivatives by liquid-liquid extraction technique employing stereoselective ion-pair formation with a carbamoylated quinine derivative

Two-phase liquid-liquid extraction experiments were undertaken to study the enantioselective transport of the chiral N-protected α-amino acid derivatives from an aqueous buffer solution into an organic phase employing highly lipophilic carbamoylated quinine as chiral selector and phase transfer carrier, respectively. The chiral separation, derived from enantioselective ion-pair formation and differential solubility in the aqueous and organic phases of diastereomeric associates thus formed has been shown to be primarily dependent on the structure of the selectand, the nature of the organic solvent, the molar ratio of a given chiral selector to selectand in the two phases, and the pH of the aqueous phase. Extracted enantiomers were recovered by back-extraction using a relatively polar acidic medium in which the selector is barely insoluble. Thus, the enantiomeric purity of N-(3,5-dinitrobenzoyl)-leucine exceeded 95% enantiomeric excess with 70% overall yield with a single extraction and back-extraction step. Chirality 9:268–273, 1997. © 1997 Wiley-Liss, Inc.

Synthesis of Enantiopure N-and C-Protected homo-β-Amino Acids by Direct Homologation of α-Amino Acids ¶

Enantiopure N-and/or C-protected homo-β-amino acids are prepared readily and in good yields from N-protected α-amino acids with the same side chain, via reduction of the carboxyl function and conversion of the resulting N-protected β-amino alcohol into the corresponding β-amino iodide and then β-amino cyanide. The key step of this strategy is represented by the synthesis of the enantiopure N-protected β-amino iodides 2 and 3 that are smoothly obtained from the parent amino alcohols 1 by polymer bound triarylphosphine-I 2 complex in anhydrous dichloromethane.

The Synthesis of Optically Active Thiazoline and Thiazole Derived Peptides from N-Protected α-Amino Acids

The Synthesis of Optically Active Thiazoline and Thiazole Derived Peptides from N-Protected α-Amino Acids

Epimerisation-free peptide formation from carboxylic acid anhydrides and azido derivatives

Conversion of C-terminal carboxy groups of N-protected α-amino acids to the corresponding 3,5-dinitrobenzoyl mixed anhydrides, followed by treatment with α-azido esters and trialkylphosphines, affords good yields of peptides, without appreciable formation of epimers even for reactions involving Phe–Val and Val–Val couplings and/or N-benzoyl α-amino acids.

First synthesis of enantiomerically pure N-protected β-amino-α-keto esters from α-amino acids and dipeptides

A racemization-free route from N-protected α-amino acids and dipeptides to N-protected β-amino-α-keto esters is described, involving the sequence: diazoketone formation, Wolff rearrangement in methanol, diazo transfer, and oxidation with dimethyldioxirane.

Dehydrooligopeptides. XIV. Convenient Coupling of N-Carboxy-α-dehydroamino Acid Anhydride with Both Amine and Carboxyl Components

Abstract In order to further develop and expand the usefulness of N-carboxy-α-dehydroamino acid anhydride (ΔNCA), the optimum conditions of the acylation of ΔNCA with N-protected α-amino acids (AA) were thoroughly examined. Furthermore, various kinds of AA or dipeptides as a C-component were utilized in the acylation of ΔNCA, followed by condensation with an AA methyl ester as an N-component.

Peptide modification by incorporation of α-trifluoromethyl α-amino acids via trifluoromethyl-substituted acylimines

α-Trifluoromethyl-substituted α-amino acids can be introduced into the C-terminal position of peptides via acylimines obtained on reaction of trifluoropyruvates with N-protected α-amino acid amides and dipeptide amides, respectively.

Preparation, isolation and X-ray crystallographic structure determination of a stable, crystalline carbonic anhydride of an N-protected α-amino acid

The reaction of methyl (2S,3aR,8aS)-2-carboxy-8-phenylsulfonyl-1,2,3,3a,8,8a-hexahydropyrrolo-[2,3-b] indole-1 -carboxylate and isobutyl chloroformate in tetrahydrofuran at –15 °C in the presence of trimethylamine results in the formation of the corresponding mixed carboxylic–carbonic anhydride. This unusually stable mixed anhydride was isolated in the form of an analytically pure crystalline solid and its structure verified crystallographically.

A facile synthesis of chiral N-protected β-amino alcohols.

Chiral N-protected β-amino alcohols are easily obtained by NaBH 4 reduction of mixed anhydrides of N-protected α-amino acids in an organic/aqueous medium. The alcohols obtained from side chain or main chain reduction of N-protected aspartic acid are converted in good yields into lactones.

Preparation of N-protected α-amino alcohols by acetoxyborohydride reduction of N-protected α-amino acid esters

N-Protected α-amino alcohols were prepared by reduction of N-protected α-amino acid esters by sodium acetoxyborohydride in dioxane at elevated temperature. The reductions proceed with excellent yields and without racemisation. Reduction of the carbamate protecting groups was not observed.