Synthesis of Boc-Amino Tetrazoles Derived from α-Amino Acids

A simple route for the synthesis of Boc-protected tetrazole analogs of amino acids starting from N ^α-Boc amino acids has been described. The [2 + 3] cycloaddition of Boc-α-amino nitrile and sodium azide in the presence of a catalytic amount of zinc bromide yielded the desired tetrazoles in good yields and purity. All the compounds obtained have been characterized by ¹H and ¹³C-NMR and mass spectral studies.     

A reasonably stereospecific multistep conversion of Boc-protected α-amino acids to Phth-protected β-amino acids

A method for the synthesis of β³-amino acids starting from α-amino acids is described. This conversion can be effected by an eight-step procedure which involves the transformation of the carboxylic group into an alkyne followed by a selenium-mediated conversion of the carbon-carbon triple bond to a Se-phenyl selenocarboxylate intermediate. The reactive Se-phenyl selenocarboxylate intermediates can be trapped with water, alcohols or the amine of an amino acid derivative to give β³-amino acids, β³-amino esters or mixed peptides, respectively. The whole transformations of the carboxylic group into an alkyne and of the alkyne group into β³-amino acids may not require purification of the intermediate products but a work-up and isolation procedure of crude materials.     

Stereoselective synthesis of the various isomers of 3,4-dideoxy furanoid sugar amino acids with methyl substitution at the C6 position

Various isomers of C6-methyl-containing chiral 3,4-dideoxy furanoid sugar amino acids were synthesized following a common strategy, in which the C2 and C6 chiral centres were derived from the chiralities of the two starting materials, glyceraldehyde acetonide and N,N-dibenzylalaninal, respectively, and the C5 centre was fixed by standard diastereoselective transformations.     

Synthesis and complexation properties towards amino acids of mono-substituted p-sulphonato-calix-[n]-arenes

A series of mono-hydroxy functionalised calix-[n]-arenes, and p-sulphonato-calix-[n]-arenes where n=4, 6 and 8, have been synthesised, with the pendant functions being ethoxycarbonyl methoxy group, 2-carboxy methoxy group, 2-amido methoxy group or 2-amino ethoxy group. With calix-[4]-arene and calix-[6]-arenes the compounds are obtained in good yield by treatment of the relevant p-H-calix-[n]-arene with a suitable metal carbonate, as a weak base, in the presence of one equivalent of the corresponding alkyl bromide. However in the case of calix-[8]-arene, the extremely low solubility of p-H-calix-[8]-arene prevented its use and p-tBu-calix-[8]-arene was used in the monosubstitution reactions. The corresponding sulphonate derivatives were prepared in the case of the 2-carboxy methoxy group, 2-amido methoxy group and 2-amino ethoxy group systems, either by sulphonation of the para-H derivatives or by ipso-sulphonation of the tert-butyl derivatives. The complexation properties of the water-soluble p-sulphonato-derivatives with regard to 11 amino acids have been studied by ¹H NMR titration experiments. The obtained association constants show a 1:1 stoichiometry. The presence of a pendant group at the lower rim of calix strongly modifies the observed association constant as compared to the parent p-sulphonato-calix-[n]-arenes. While generally, the cationic amino acids lysine and arginine bind strongly to all the derivatives, the binding of other amino acids is dependant on the nature of the pendant functions, in particular pendant arm-lateral chain function leads to strong binding with aspartic acid, serine and tryptophan.     

Synthesis of (S)-5,6-dibromo-tryptophan derivatives as building blocks for peptide chemistry

5,6-Dibromo-tryptophan is an interesting amino acid whose derivatives and analogues are found in a variety of highly bioactive natural compounds. Notwithstanding its relevance no data concerning this compound are found in the literature. Here an efficient pathway for the synthesis of 5,6-dibromo-tryptophan derivatives is reported. The reaction is performed by using 6-Br-isatin as starting material. Selective bromination at position 5 was followed by BH₃ reduction of the intermediate α-keto-amide and alkylation with Ser-OH in Ac₂O/AcOH. Optical resolution was effected by enzymatic de-acetylation of the obtained racemic mixture. Finally, in situ N^α-Boc protection of the optically pure S form yielded the desired N^α-Boc-(S)-5,6-dibromo-tryptophan.     

Silicon amino acids

The existence and gas phase stability of silicon analogues of three natural amino acids (i.e., silicon glycine, silicon alanine, and silicon valine) belonging to the novel class of compounds termed silicon amino acids (SiAA) are investigated theoretically on the basis of ab initio QCISD/aug‐cc‐pVTZ and MP2/aug‐cc‐pVTZ calculations. All molecules studied (in their gas phase canonical forms) are structurally comparable to their proteinogenic counterparts (i.e., glycine, l ‐alanine, and l ‐valine) and capable of forming several structural isomers as such. These higher energy isomers are characterized by small relative energies (not exceeding 4 kcal mol⁻¹). The simulated IR spectra of the Si‐Gly, Si‐Ala, and Si‐Val global minima are also presented and discussed.     

Improved synthesis of unnatural amino acids for peptide stapling

The procedures for the synthesis of various α-alkenyl and alkyne amino acids were systematically optimized in light of enhancing atom economy, reducing hazardous reagent usage, and simplifying workup. By starting with Boc-Pro-OH and coupling with EDCI/DMAP followed by alkylation, chiral auxiliary was synthesized with high yield and enantioselectivity. For alkylation of the chiral complex, tBuONa was found and proved by quantitative calculation to be superior to tBuOK in generating more nucleophilic enolate salt, thereby can significantly enhance yield under room temperature. Final Fmoc protection was also dramatically facilitated in one-pot sequential manner by adding EDTA-2Na as the nickel chelator. Synthesis of α-bisalkenyl amino acid was also accomplished by achiral complex approach with high yield and efficacy. Accordingly, five most commonly used N-Fmoc protected α-alkenyl and alkynyl amino acids were synthesized and characterized.     

New strategy for the identification of amino acids by TLE and TLC using basic or buffered mobile phases

Summary Direct, simple and reliable means for characterization of the common amino acids, using mixtures of structural analogues of amino acids and combinations of low-voltage electrophoresis (1.04 mol dm^–3 formic acid) and chromatography (tert-butanol/methanol/pyridine/formic acid/water, 33:43:9.6:0.4:20, v/v, methanol/pyridine/formic acid/water, 70:9.6:0.4:20, v/v, or tertpentanol/methylethylketone/pyridine/water, 37.5:37.5:5:20, v/v) on amorphous cellulose thin-layer are given. The efficiency of the procedures is evaluated in various examples.Abbreviations used: TLC = thin-layer chromatography, TLE = thin-layer electrophoresis, TLP = thin-layer plate; other abbreviations: see Table I and end of text.for structural analogues of amino acids and glucosamine, see Table I.     

The artificial binaphthyl amino acid 6-amino-6′-carboxyethyl-2-methoxy-2′-hydroxy-1,1′-binaphthyl (Bna): synthesis and assembly of Bna peptides

The new binaphthyl-based amino acid 6-amino-6′-carboxyethyl-2-methoxy-2′-hydroxy-1,1′-binaphthyl (Bna) is presented, which combines the axially chiral binaphthyl core, a phenolic OH-group as well as terminating amino and carboxyl groups in one structure. The large aromatic rings of the compound provide molecular spacing and π-surface attraction in assembled Bna oligoamides. The synthesis of Bna derivatives is reported, both with the (R)- and with the (S)-binaphthyl skeleton. Several dipeptides of (R)- or (S)-Bna units combined with natural amino acids, were prepared as ‘building blocks’ for the synthesis of extended Bna peptides. The tetrapeptide Boc-(S)-Val-(S)-Bna(OH)-(S)-Val-(S)-Bna(OPiv)-O-n-But (12) and the pentapeptide Boc-(S)-Val-(S)-Bna(OH)-(S)-Val-(S)-Bna(OH)-Gly-OH (13) were prepared via conventional solution phase synthesis and solid phase synthetic techniques, respectively. Compound 12 shows an interesting dynamic ¹H NMR spectrum suggesting compact and aggregated forms in dichloromethane. Compound 13 accelerates the enolisation of acetone. The use of more complex Bna peptides as organo catalysts is proposed.     

Expedient synthesis of a novel class of pseudoaromatic amino acids: tetrahydroindazol-3-yl- and tetrahydrobenzisoxazol-3-ylalanine derivatives

A concise synthesis of novel homochiral aromatic amino acid surrogates comprising a tetrahydroindazole or a benzisoxazole system was developed via the acylation of a cyclic 1,3-diketone by the side-chain carboxyl functionality of either Boc-Asp-OtBu or Boc-Glu-OtBu followed by regioselective condensation with hydrazine, N-benzylhydrazine and hydroxylamine. The tetrahydroindazole nucleus was also constructed by the condensation of Boc-Asp-OtBu with the enamine, 1-pyrrolidino-1-cyclohexene followed by acid-hydrolytic treatment and reaction with hydrazines. Further functional group transformations gave N^α-Fmoc-protected derivatives as useful building blocks for solid-phase peptide assembly.     

Quaternary β2,2‐Amino Acids: Catalytic Asymmetric Synthesis and Incorporation into Peptides by Fmoc‐Based Solid‐Phase Peptide Synthesis

β‐Amino acid incorporation has emerged as a promising approach to enhance the stability of parent peptides and to improve their biological activity. Owing to the lack of reliable access to β^2,2‐amino acids in a setting suitable for peptide synthesis, most contemporary research efforts focus on the use of β³‐ and certain β^2,3‐amino acids. Herein, we report the catalytic asymmetric synthesis of β^2,2‐amino acids and their incorporation into peptides by Fmoc‐based solid‐phase peptide synthesis (Fmoc‐SPPS). A quaternary carbon center was constructed by the palladium‐catalyzed decarboxylative allylation of 4‐substituted isoxazolidin‐5‐ones. The N?O bond in the products not only acts as a traceless protecting group for β‐amino acids but also undergoes amide formation with α‐ketoacids derived from Fmoc‐protected α‐amino acids, thus providing expeditious access to α‐β^2,2‐dipeptides ready for Fmoc‐SPPS.     

Evaluating electronic structure methods for accurate calculation of 19F chemical shifts in fluorinated amino acids

The ability of electronic structure methods (11 density functionals, HF, and MP2 calculations; two basis sets and two solvation models) to accurately calculate the ¹⁹F chemical shifts of 31 structures of fluorinated amino acids and analogues with known experimental ¹⁹F NMR spectra has been evaluated. For this task, BHandHLYP, ωB97X, and Hartree–Fock with scaling factors (provided within) are most accurate. Additionally, the accuracy of methods to calculate relative changes in fluorine shielding across 23 sets of structural variants, such as zwitterionic amino acids versus side chains only, was also determined. This latter criterion may be a better indicator of reliable methods for the ultimate goal of assigning and interpreting chemical shifts of fluorinated amino acids in proteins. It was found that MP2 and M062X calculations most accurately assess changes in shielding among analogues. These results serve as a guide for computational developments to calculate ¹⁹F chemical shifts in biomolecular environments. © 2017 Wiley Periodicals, Inc.     

Covalent sidewall functionalization of single-walled carbon nanotubes by amino acids

Single-walled carbon nanotubes (SWNTs) with amino acids covalently attached to their side walls, viz., “nanotube-aminoacids,” have been prepared starting from colloidal solutions of fluorinated SWNTs (F-SWNTs) and amino acids in o-dichlorobenzene and heating at 80–150 °C in the presence of pyridine. The syntheses were carried out with the F-SWNTs of approximately 2: 1 (C: F) stoichiometry and several natural α-aino acids with both pro-tected and unprotected carboxyl groups, such as glycine ethyl ester hydrochloride, L-serine ethyl ester hydrochloride, l-cysteine, and trans-4-hydroxy-l-proline. The nanotube-aminoacids have been characterized by Raman and FTIR spectroscopy, atomic force, scanning, and transmission electron microscopies, and thermal gravimetric analysis (TGA). Based on TGA data, the degree of sidewall functionalization in the synthesized SWNT derivatives was estimated to be in the range from one of 32 to one of 8 carbon atoms, depending on the amino acid nature and reaction conditions used. The amino acid-functionalized SWNTs, prepared in this work by simple and inexpensive one-step method, can be valuable precursors for peptide synthesis and targeted drug delivery, design and fabrication of nanocomposites and fibers, and other biomedical and engineering applications. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1035–1043, May, 2008.     

Benzylidene Acetal Protecting Group as Carboxylic Acid Surrogate: Synthesis of Functionalized Uronic Acids and Sugar Amino Acids

Direct oxidation of the 4,6‐O‐benzylidene acetal protecting group to C‐6 carboxylic acid has been developed that provides an easy access to a wide range of biologically important and synthetically challenging uronic acid and sugar amino acid derivatives in good yields. The RuCl₃–NaIO₄‐mediated oxidative cleavage method eliminates protection and deprotection steps and the reaction takes place under mild conditions. The dual role of the benzylidene acetal, as a protecting group and source of carboxylic acid, was exploited in the efficient synthesis of six‐carbon sialic acid analogues and disaccharides bearing uronic acids, including glycosaminoglycan analogues.     

ESI‐MS/MS analysis of protonated N‐methyl amino acids and their immonium ions

Methylation is one of the important posttranslational modifications of biological systems. At the metabolite level, the methylation process is expected to convert bioactive compounds such as amino acids, fatty acids, lipids, sugars, and other organic acids into their methylated forms. A few of the methylated amino acids are identified and have been proved as potential biomarkers for several metabolic disorders by using mass spectrometry–based metabolomics workstation. As it is possible to encounter all the N‐methyl forms of the proteinogenic amino acids in plant/biological systems, it is essential to have analytical data of all N‐methyl amino acids for their detection and identification. In earlier studies, we have reported the ESI‐MS/MS data of all methylated proteinogenic amino acids, except that of mono‐N‐methyl amino acids. In this study, the N‐methyl amino acids of all the amino acids ( 1 ‐ 21 ; including one isomeric pair) were synthesized and characterized by ESI‐MS/MS, LC/MS/MS, and HRMS. These data could be useful for detection and identification of N‐methyl amino acids in biological systems for future metabolomics studies. The MS/MS spectra of [M + H]⁺ ions of most N‐methyl amino acids showed respective immonium ions by the loss of (H₂O, CO). The other most common product ions detected were [MH‐(NH₂CH₃]⁺, [MH‐(RH)]⁺ (where R = side chain group) ions, and the selective structure indicative product ions due to side chain and N‐methyl group. The isomeric/isobaric N‐methyl amino acids could easily be differentiated by their distinct MS/MS spectra. Further, the MS/MS of immonium ions inferred side chain structure and methyl group on α‐nitrogen of the N‐methyl amino acids.     

Copolymerization of amino acid and amino ester functionalized norbornenes via living ring‐opening metathesis polymerization

The block and random copolymerization of a series of amino acid and amino ester functionalized norbornenes by ring‐opening metathesis polymerization (ROMP) induced by the well‐defined molybdenum [Mo(?N‐2,6‐ⁱPr? C₆H₃)(?CHCMe₂)Ph)(OCMe₃)₂] or ruthenium [Ru(PCy)₂Cl₂(?CHPh)] based initiators is described. The monomers are derived from the amino acids glycine, alanine, and isoleucine or the methyl esters of these amino acids and either endo‐ or exo‐norborn‐5‐ene‐2,3‐dicarboxylic anhydride. Enantiomerically pure monomers afforded optically active polymers, and the mechanism and kinetics of the copolymerizations are investigated. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 7985–7995, 2008     

Synthesis of 4-monofluoromethylenyl- and cis-4-monofluoromethyl-l-pyroglutamic acids via a novel dehydrofluorination

Novel dehydrofluorination reactions accidentally found were used to synthesize terminal monofluoro olefin lactam analogues in good yield. The following hydrogenation of the resulting defluorinated product was systematically investigated. Two important fluorinated amino acids: 4-monofluoromethylenyl-l-pyroglutamic acid 16 and cis-4-monofluoromethyl-l-pyroglutamic acid 17 were synthesized using the methodology.     

A simple protocol for the synthesis of 2-arylbenzoxazoles by oxidation with o-iodoxybenzoic acid (IBX) and its application in the synthesis of arylbenzoxazole-containing amino acids

A simple protocol for the preparation of 2-arylbenzoxazoles has been developed based on the oxidation of phenolic Schiff bases with o-iodoxybenzoic acid (IBX), wherein the oxidant can be recycled. The robustness of this new protocol has been demonstrated in the synthesis of arylbenzoxazole-containing amino acids.     

3′-Amino-5′-carboxymethyl-3′,5′-dideoxy nucleosides for the synthesis of fully amide-linked RNA mimics

A convenient protocol is developed for the synthesis of 3′-[N-(fluorenylmethoxycarbonyl)-amino]-5′-carboxymethyl derivatives of all four natural ribonucleosides from cheap chiral pool compound glucose. Synthesis of fully amide-linked RNA analogues of small oligonucleotides containing, for the first time, all four nucleoside amino acids using standard solid phase Fmoc-chemistry is described.     

Efficient copper-catalyzed synthesis of poly-N-heterocycles containing amino acid residues

An efficient copper-catalyzed method has been developed for the synthesis of poly-N-heterocycles containing amino acid residues. The protocol uses readily available 2-halobenzamides containing amino acids and their methyl esters, substituted phenylacetonitriles, and malononitrile as the starting materials and the reactions were performed well under mild conditions. The method should provide a novel and useful strategy for synthesis of N-heterocyclic compounds.