N-protected Amino Acid Esters Research Articles

Theoretical Mechanistic Investigation of the Dynamic Kinetic Resolution of N-Protected Amino Acid Esters using Phase-Transfer Catalysts.

A detailed theoretical mechanistic investigation on the dynamic kinetic resolution of N-protected amino acid esters using phase-transfer catalysts is described. Semiautomatic exhaustive conformation search of transition state (TS)-like structures were carried out using the ConFinder program and the pseudo-TS conformational search (PTSCS) method. This conformational search method successfully provided reasonable TS structures for determining the stereoselectivity in the asymmetric base hydrolysis of hexafluoroisopropyl (HFIP) esters as well as the racemization mechanism. Furthermore, the independent gradient model (IGM) analysis of the TS structures suggested that the H-bonding interactions with the oxyanion hole and π-stacking interactions are the common important features of the proposed TS structures that determine the stereoselectivity.

Dynamic Kinetic Resolution of N-Protected Amino Acid Esters via Phase-Transfer Catalytic Base Hydrolysis

Asymmetric base hydrolysis of α-chiral esters with synthetic small-molecule catalysts is described. Quaternary ammonium salts derived from quinine were used as chiral phase-transfer catalysts to promote the base hydrolysis of N-protected amino acid hexafluoroisopropyl esters in a CHCl3/NaOH (aq) via dynamic kinetic resolution, providing the corresponding products in moderate to good yields (up to 99%) with up to 96:4 er. Experimental and computational mechanistic studies using DFT calculation and pseudotransition state (pseudo-TS) conformational search afforded a TS model accounting for the origin of the stereoselectivity. The model suggested π-stacking and H-bonding interactions play essential roles in stabilizing the TS structures.

Synthesis of 5H-Pyrrolo[3,4-b]pyrazine-Based Peptidomimetics

A range of 5<i>H</i>-pyrrolo[3,4-<i>b</i>]pyrazine-based peptidomimetics were designed, and their efficient synthesis starting from 5-imino-5<i>H</i>-pyrrolo[3,4-<i>b</i>]pyrazin-7-amine by subsequent interaction with N-protected amino acid hydrazides and amino acid esters with <i>N</i>,<i>N</i>-carbonyldiimidazole as the coupling agent was elaborated.

Catalyst and solvent-free amidation of inactive esters of N-protected amino acids

A catalyst free procedure for the preparation of amides from inactive esters of N-protected amino acids and various amines is demonstrated under mild reaction conditions. Our effort to recover excess amine and generated alcohol is an approach towards environment friendly and cost effective synthesis under easy operational conditions.

Synthesis of dipeptides from N-hydroxy-3-azaspiro[5,5]undecane-2,4-dione activated α-amino acids

A simple two step procedure for the synthesis of a dipeptide from N-hydroxy-3-azaspiro[5,5]undecane-2,4-dione (HO-ASUD) activated α-amino acids is described. In presence of DCC, N-hydroxy-3-azaspiro[5,5]undecane-2,4-dione readily esterifies the carboxylic acid group of all the N-protected amino acids to yield crystalline N-hydroxy-3-aza spiro[5,5]undecane-2,4-dione activated carboxy ester. The N-hydroxy-3-aza spiro[5,5]undecane-2,4-dione activated carboxy esters of N-protected amino acids readily condensed with other amino acids and gave a dipeptide. This new method is effective for the DCC coupling of a variety of chiral amino acids without loss of enantiomeric purity. Synthesis of fifteen dipeptides including the hitherto unreported Fmoc-l-Orn(Boc)-Val-OMe, Fmoc-l-Cys(trt)-Gly-OEt and Boc-l-Tyr-Gly-OEt is presented.

ChemInform Abstract: Synthesis of C‐Propargylic Esters of N‐Protected Amino Acids and Peptides.

AbstractThe method works well for Boc‐ and Cbz‐protected substrates.

ChemInform Abstract: Activation of Carboxylic Acids by Pyrocarbonates. Synthesis of Symmetric Anhydrides and Esters of N-Protected Amino Acids Using Dialkyl Pyrocarbonates as Condensing Reagents.

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Synthesis of C-Propargylic Esters of N-Protected Amino Acids and Peptides

Recent years have seen a huge surge of interest in the application of alkyne-derived motifs for so-called "click" chemistry. Given the critical importance of amino acids in organic synthesis as well as their myriad of applications in "click" chemistry it is interesting to note that the synthesis of C-propargyl derived amino acid esters has not been particularly well served. We report a convenient, straightforward, and high-yielding synthesis of structurally diverse C-propargyl-derived N-protected amino acid esters.

Study of the removal of allyl esters by Candida antarctica lipase B (CAL-B) and pig liver esterase (PLE)

A number of allyl esters of various carboxylic acids and N-protected amino acids were synthesized and their hydrolysis by Candida antarctica lipase B and pig liver esterase was studied. In order to test the selectivity, the enzymatic hydrolysis of the corresponding methyl and ethyl esters was also examined. Both enzymes easily remove the allyl esters of monocarboxylates. The chemo- and regio-selectivity for the hydrolysis of glutamate diesters was studied, too, and it was found that the preference for the hydrolysis of a particular ester group depends not only on the ease of the hydrolysis observed for the esters of monocarboxylic acids, but also on the position (α- or γ-).

New antituberculotics originated from salicylanilides with promising in vitro activity against atypical mycobacterial strains

A new series of 30 N-protected amino acid esters were prepared as a part of ongoing search for new anti-tuberculosis active salicylanilides. The esters possess high in vitro activity against Mycobacterium tuberculosis, Mycobacterium avium, and two strains of Mycobacterium kansasii, where one is an isolate from the patient, with MIC in the range 1–32 μmol/L for all tested strains. The prepared esters can be considered as prodrugs with better bio-availability and as more efficient transport forms through the mycobacterial cell membranes due to the higher lipophilicity. The experimental and calculated lipophilicity, stability, antituberculotic activity, cytotoxicity as well as the quantitative structure–activity relationships (QSARs) explored by the Intelligent Problem Solver (IPS) in Trajan Neural Network Simulator 6.0 are presented.

Salicylanilide esters of N-protected amino acids as novel antimicrobial agents

A series of novel, highly antimicrobial salicylanilide esters of N-protected amino acids were synthesized and characterized. Their in vitro antimicrobial activity against eight fungal strains and Mycobacterium tuberculosis was determined. The compounds had the highest level of activity against Aspergillus fumigatus, Absidia corymbifera and Trichophyton mentagrophytes, and these levels were higher than that of the standard drug fluconazole. In addition, three compounds showed interesting antituberculosis activity, with inhibition ranging from 89% to 99%. ( S)-4-Chloro-2-(4-trifluoromethylphenylcarbamoyl)-phenyl 2-benzyloxy-carbonylamino-propionate had the highest level of both antifungal and antimycobacterial activity. The structure–activity relationships of the new compounds are discussed.

Facile Synthesis of N-protected Amino Acid Esters Assisted by Microwave Irradiation

A highly efficient and safe methodology for synthesis of various N-protected amino acid ethyl esters have been established in this study. This methodology employs orthoesters as both esterification reagent and solvent for protected amino acids. The reactions were carried out under microwave irradiation in neutral conditions for only 2 min, resulting in highly pure crude products in most cases. This strategy works with a variety of N-protecting groups, such as acid labile protecting group: BOC and tBu; base labile protecting group: Fmoc; hydrogenation labile protecting group: Z and Na/NH3 labile protecting group: Tos, thus providing facile access to numerous valuable building blocks for solid phase synthesis. Further reduction of the crude protected amino acid ethyl ester by sodium borohydride under mild conditions led to the corresponding protected β-amino alcohols with excellent yield, as demonstrated by three examples.

Lipase-catalyzed enantioselective hydrolysis of N-protected racemic non-protein amino acid esters

Porcine pancreatic lipase (PPL)-catalyzed enantioselective hydrolysis of N-benzyloxycarbonyl-dl-amino acid esters (Z-dl-AA-ORs) was studied for the optical resolution of a variety of non-protein amino acids. The ester moiety (R) of the substrate affected the rate of hydrolysis significantly. The glyceryl (Gl) and carbamoylmethyl (Cam) esters were found to be highly reactive substrates. The hydrolysis of the Gl esters (Z-dl-AA-OGls) of both aliphatic and aromatic amino acids was examined in acetonitrile containing 70% (v/v) of 0.02 M phosphate buffer (pH 7.0) at 30°C. With all amino acids tested, the corresponding l-enantiomers were hydrolyzed preferentially. PPL favored aromatic amino acids, such as phenylalanine and p-chlorophenylalanine, leading to completion of the hydrolysis within 20 min with excellent enantioselectivities (E>100). The PPL-catalyzed hydrolysis of the corresponding Cam esters (Z-dl-AA-OCams) was also examined under the same reaction conditions. Although the hydrolysis of the Cam esters was rapid, the l-enantioselectivities were rather poor with aromatic amino acids, such as 2-phenylglycine and homophenylalanine.

An Improved Method for the Protection of Carboxylic Acids as 1,1-Dimethylallyl Esters

1,1-Dimethylallyl (DMA) esters of various N-protected amino acids have been synthesized using prenyldimethylsulfonium tetrafluroborate, a reagent that can be readily made and stored, in conjunction with catalytic CuBr. These reactions were complete within several hours and afforded DMA esters in high yields. As has been previously shown in our group, DMA esters represent a palladium-labile proctecting group for carboxylic acids that resists nucleophilic attack as a tert-butyl ester would.

Resolution of non-protein amino acids via the microbial protease-catalyzed enantioselective hydrolysis of their N-unprotected esters

In the Aspergillus oryzae protease-catalyzed ester hydrolysis, substitution of N-unprotected amino acid esters for the corresponding N-protected amino acid esters resulted in a large enhancement of the hydrolysis rate, while the enantioselectivity was deteriorated strikingly when the substrates employed were the conventional methyl esters. This difficulty was overcome by employing esters bearing a longer alkyl chain such as the isobutyl ester. Utilizing this ester, amino acids carrying an aromatic side chain were resolved with excellent enantioselectivities ( E=50 to >200). With amino acids bearing an aliphatic side chain also, good results in terms of the hydrolysis rate and enantioselectivity were obtained by employing such an ester as the isobutyl ester. Moreover, the enantioselectivity proved to be enhanced further by conducting the reaction at low temperature. This procedure was applicable to the case where the enantioselectivity was not high enough even by the use of the isobutyl ester.

Synthesis of structural analogs of the 13 – 19 sequence of human growth hormone releasing factor

Development of the principles of synthesis of bioregulators responsible for the secretion of natural hormones in the organism is among currently important tasks. One particular basic problem consists in finding previously unknown peptide agents stimulating the secretion of insulin, a hormone playing a key role in the regulation of metabolic processes in higher mammals and humans. One possible approach to solving this problem is via the synthesis of peptide structures capable of participating in hormone – receptor interactions and enhancing insulin secretion by cells in Largenhans’ islets in the pancreas. A real pathway to such peptide stimulators of insulin secretion can be based on the synthesis of previously unknown structural analogs of the amino end region of somatoliberin, the hypothalamic releasing factor of human growth hormone [1, 2]. Our previous investigations showed that this R-factor is capable of indirectly influencing insulin biosynthesis and secretion by pancreatic islet cells. However, from the standpoint of pharmacology, a significant disadvantage of using natural somatoliberin as a bioregulator of insulin secretion is its relatively low activity and insufficient selectivity. In addition to weakly stimulating the secretion of insulin, natural somatoliberin enhances (to a much greater extent) production of growth hormone and activates the secretion of glucagon. For this reason, much better prospects in solving the problem under consideration can be related to the amino end region of somatoliberin. This conclusion agrees with the results of computer simulation of hormone – receptor interactions involved in the biosynthesis and secretion of insulin. In this context, we have undertaken a special investigation aimed at the development of a method for the synthesis of previously unknown structural analogs of the amino end region of somatoliberin, which can be of interest as potential stimulators of insulin secretion. After a series of preliminary experiments and a comparative analysis of the results, it was concluded that the most promising approach is that based on the use of activated esters of N-protected amino acids. This approach leads to a high yield of the target compounds, excludes undesired side reactions, allows effective control over the racemization processes, and is less tedious than the other possible schemes. As a result, we have developed an effective method for the synthesis of previously unreported structural analogs of the 13 – 19 somatoliberin peptide sequence, which is a part of the amino end of somatoliberin. Distinguishing features of the proposed method are as follows: (i) use of benzyl esters of oligopeptides as amino components; (ii) use of p-nitrophenyl or pentafluorophenyl esters of N-protected amino acids as carboxy components; (iii) use of an acid-labile tert-butyloxycarbonyl protection for masking -amino groups in the carboxy components; (iv) stepwise peptide synthesis in the C N direction. An important advantage of the proposed method is the possibility of using protected derivatives of trifunctional amino acids for the synthesis of hydrophobic analogs of somatoliberin. It was also established that the isolation of target compounds from the reaction mixtures is considerably simplified by conducting the condensation stage in DMF. In this case, the target peptides can be isolated in a crystalline state and purified by recrystallization. The structure of peptides obtained using the proposed scheme is uniquely determined by the scheme of synthesis. The synthetic analogs of the terminal region of somatoliberin can be obtained in an analytically pure form.

Separation of Enantiomers of N-Protected Non-Protein Amino Acid Esters by Chiral High-Performance Liquid Chromatography

The high-performance liquid chromatographic separation of enantiomers of N-protected non-protein amino acid esters was investigated by using a cellulose tris(3,5-dimethylphenylcarbamate) chiral stationary phase column (Daicel Chiracel OD). The effect of the N-protecting groups and the ester groups on chiral discrimination was examined. The benzyloxycarbonyl (Z), 4-methoxybenzyloxycarbonyl, and 9-fluorenylmethoxycarbonyl derivatives gave good enantiomeric separations, while the formyl and t-butoxycarbonyl groups marred them. Almost all the alkyl esters examined and the benzyl ester gave enantiomeric separations better than or of the same order as the methyl ester. The N-Z-protected methyl esters of a number of non-protein α-amino acids were well resolved using hexane–2-propanol as a mobile phase. The resolution of β-amino acid derivatives was inferior to that of the isomeric α-amino acid derivatives.

Bacillus licheniformis protease-catalyzed peptide synthesisvia the kinetically controlled approach using the carbamoylmethyl ester as an acyl donor in anhydrous acetonitrile

The couplings of N-protected amino acid esters with amino acid amides proved to be carried out in anhydrous acetonitrile in the presence of Bacillus licheniformis protease (subtilisin Carlsberg) immobilized on Celite. The maximal peptide yields were obtained with the immobilized enzyme prepared through lyophilization from a pH 10.7 buffer solution. A series of dipeptide syntheses and several segment condensations were achieved generally in high yields by the combined use of the immobilized enzyme prepared from this pH and the carbamoylmethyl ester as the acyl donor.

SYNTHESIS OF N-PROTECTED PEPTIDE ALCOHOLS CATALYZED BY SUBTILISIN OR α-CHYMOTRYPSIN IN ORGANIC SOLVENTS

ABSTRACT A series of N-protected peptide alcohols were synthesized using amino alcohols with unprotected hydroxy groups as amino components by the catalysis of subtilisin or α-chymotrypsin in organic solvents. N-protected aromatic amino acid esters were more suitable as acyl donors for subtilisin. The influences of different N-protecting groups, organic solvents, and content of water on synthesis of N-protected peptide alcohols were systematically studied.

Dihalomethylation of N-protected phenylalanine esters

Dihalomethylation of several N-protected amino acid esters gave N-protected α-aminoalkyl-α′-dihalomethylketones, which are useful intermediates for the synthesis of erythro β-amino-α-hydroxycarboxylic acids, in good yield. The dihalomethylketones were successfully converted to N-protected α-aminoalkyl-α′-halomethylketones by selective catalytic hydrogenation.