Click chemistry to functionalise peptidomimetics

Sharpless modified Huisgen’s [2+3] cycloaddition of azide and acetylenic derivatives was employed as an efficient and simple method to conjugate azabicycloalkane amino acids, mimics of a homoSer-Pro dipeptide, with biologically relevant partners.     

Synthesis of crosslinking amino acids by click chemistry

Crosslinking amino acids are naturally existing protein crosslinkers. Herein, we described the synthesis of several novel bis-amino acids constituted of serine, alanine, lysine, and tyrosine with click chemistry. The Huisgen 1,3-dipolar cycloadditions between azido- and alkyne-functionalized amino acids can be easily realized in the presence of catalytic amount of CuSO₄ and Na ascorbate. In addition, fluorescent bis-amino acid derivatives have also been prepared using anthracene, fluorescein, and benzothiadiazole as fluorophores. With symmetrical bis-alkyne benzothiadiazole, it was possible to synthesize asymmetrical derivative bearing two different amino acid moieties.     

Synthesis of tetrazole analogues of amino acids using Fmoc chemistry: isolation of amino free tetrazoles and their incorporation into peptides

An efficient synthesis of tetrazole analogues of amino acids starting from N^α-Fmoc amino acid in a three-step protocol is reported. The free amino tetrazoles were obtained in good yields and with excellent purity after removal of the Fmoc group. The synthesis of analogues of aspartic and glutamic acids in which the 5-tetrazolyl moiety is inserted at the β/γ carboxyl group starting from Fmoc-Asn and Fmoc-Gln and the incorporation of these tetrazoles into peptides are also described.     

Chemo-, regio- and stereospecific addition of amino acids to acylacetylenes: a facile synthesis of new N-acylvinyl derivatives of amino acids

The one-pot reaction of natural amino acids (glycine, β-alanine, γ-aminobutyric and ?-aminocapronic acids, d,l-valine, d,l-leucine, anthranilic acid) with bielectrophilic acylacetylenes proceeds chemo-, regio- and stereospecifically in the presence of NaOH (45-50 °C, 4 h, EtOH-H₂O) to give (after treatment of the reaction mixture with aqueous HCl) Z-isomers of N-acylvinyl derivatives of amino acids in 87-94% yield.     

"Click chemistry" inspired synthesis of pseudo-oligosaccharides and amino acid glycoconjugates

[reaction: see text] Various pseudo-oligosacchardies and amino acid glycoconjugates were synthesized via an intermolecular 1,3-dipolar cycloaddition ("click") reaction using easily accessible carbohydrate and amino acid derived azides and alkynes as building blocks. It is pertinent to mention that the conjugation reaction is highly regioselective and high yielding and can be carried out under mild reaction conditions.     

Electrochemil investigation of the photodecomposition of selected ferrocene derivatives

The photostability of nine ferrocene derivatives of varying functionality was investigated using cyclic voltammetry. Derivatives with carbonyl groups (aldehyde or ketone) directly attached to the cyclopentadiene ring system were found to decompose in aqueous (pH 7.4) solution over a period of 10 min when exposed to light. The kinetics of the photodecomposition process were investigated and the relative values of the rate constants for the photodecomposition tabulated. The implications for biosensor applications are assessed.     

Enantioselective synthesis of non-natural aromatic alpha-amino acids

We present two complementary methods for the stereoselective synthesis of non-natural alpha-amino acids with aromatic or heteroaromatic side chains. One approach is based on the chemical transformation of methionine, whereas the other applies the stereoselective Myers alkylation of glycine. The resulting product types differ in the linker length between glycine and the aromatic substituent. Since methionine and pseudoephedrine are available in both absolute configurations, R- or S-configured enantiopure amino acids with either C(2) or C(3) linkers can be obtained on gram scales. In each case the key step of the synthesis is hydroboration of the unsaturated building blocks 9 and 17, followed by palladium-catalyzed Suzuki cross-coupling with aryl halides. Attention must in certain cases be paid to the stereochemical integrity when basic Suzuki conditions are applied. Our initial difficulties are reported as well as the final "racemization-proof" procedures. The protecting groups chosen for the alpha-amino acids should be compatible with solid-phase peptide synthesis. This was confirmed by the successful synthesis of a series of tripeptides.     

High resolution capillary gas chromatography and gas chromatography–mass spectrometry of protein and non-protein amino acids,amino alcohols,and hydroxycarboxylic acids as their tert-butyldimethylsilyl derivatives

A simple, single-step derivatization technique is presented for capillary GC-FID and GC-MS separation and identification of common protein and non-protein constituents of natural peptides as their tert-butyldimethylsilyl (TBDMS) derivatives. The tert-butyldimethyl-silylation of more than sixty compounds was accomplished with high yields and a single peak observed for each component. The TBDMS derivatives of both the protein and non-protein substances, moreover, exhibit excellent separation on apolar capillary columns and can be resolved completely using a polydimethylsiloxane or 5 % phenyl polydimethylsiloxane column and, complementarily, a 50 % phenyl polydimethylsiloxane column. Retention data and molar responses of the TBDMS derivatives on the polydimethylsiloxane column are compiled. Direct coupling of the 5 % phenyl polydimethylsiloxane column to an ion trap mass spectrometer enabled fast separation and identification of the investigated components, at nanomole to picomole levels, on the basis of retention and mass spectral data. The general usefulness of the method is demonstrated by research into new biologically active peptides isolated from entomopathogenic fungi.     

Benzophenone Schiff bases of glycine derivatives: Versatile starting materials for the synthesis of amino acids and their derivatives

This review focuses on the introduction and early development, in solution, of phase-transfer catalyzed (PTC) reactions to afford racemic or enantioenriched natural and unnatural amino acids. To form monosubstituted amino acids alkylation reactions are performed on the benzophenone Schiff base of glycine. For α,α-disubstituted amino acids the activated intermediate is an aldimine derivative of the monosubstituted amino acid. Enantioenriched products are produced by organocatalysis using derivatives of Cinchona alkaloids as the phase-transfer catalyst. Selectivity for monoalkylatation and lack of product racemization depend on the acidities of the glycine imines, and dialkylated products are formed from aldimine esters of monoalkyl amino acids. The racemic and catalytic enantioselective reactions of a cationic glycine equivalent with organoboranes, organometallics and malonate anion are discussed as are other reactions of these versatile Schiff bases derivatives.     

Stereoconversion of amino acids and peptides in uryl-pendant binol schiff bases

(S)-2-Hydroxy-2'-(3-phenyluryl-benzyl)-1,1'-binaphthyl-3-carboxaldehyde (1) forms Schiff bases with a wide range of nonderivatized amino acids, including unnatural ones. Multiple hydrogen bonds, including resonance-assisted ones, fix the whole orientation of the imine and provoke structural rigidity around the imine C==N bond. Due to the structural difference and the increase in acidity of the alpha proton of the amino acid, the imine formed with an L-amino acid (1-l-aa) is converted into the imine of the D-amino acid (1-D-aa), with a D/L ratio of more than 10 for most amino acids at equilibrium. N-terminal amino acids in dipeptides are also predominantly epimerized to the D form upon imine formation with 1. Density functional theory calculations show that 1-D-Ala is more stable than 1-L-Ala by 1.64 kcal mol(-1), a value that is in qualitative agreement with the experimental result. Deuterium exchange of the alpha proton of alanine in the imine form was studied by (1)H NMR spectroscopy and the results support a stepwise mechanism in the L-into-D conversion rather than a concerted one; that is, deprotonation and protonation take place in a sequential manner. The deprotonation rate of L-Ala is approximately 16 times faster than that of D-Ala. The protonation step, however, appears to favor L-amino acid production, which prevents a much higher predominance of the D form in the imine. Receptor 1 and the predominantly D-form amino acid can be recovered from the imine by simple extraction under acidic conditions. Hence, 1 is a useful auxiliary to produce D-amino acids of industrial interest by the conversion of naturally occurring L-amino acids or relatively easily obtainable racemic amino acids.     

Chiral separation of benzothiazole derivatives of amino acids using capillary zone electrophoresis

A method for the separation of enantiomers of leucine and phenylalanine benzothiazole derivatives as potential antimicrobial agents was developed using capillary zone electrophoresis with a dual cyclodextrin (CD) system. The best resolution of enantiomers was achieved in 100 mmol/L phosphate background electrolyte (pH 3.5) with the dual CD system consisting of 10 mmol/L of β‐CD with 10 mmol/L of 2‐hydroxypropyl‐β‐cyclodextrin for leucine derivative and 10 mmol/L of 2‐hydroxypropyl‐γ‐cyclodextrin for phenylalanine derivative, respectively. Under the optimal conditions, the highest enantioresolution of 1.25 was achieved in a noncoated‐fused silica capillary at 17°C and 24 kV applied voltage.     

Click chemistry for the synthesis of 5-substituted 1H-tetrazoles from boron-azides and nitriles

A novel and metal free catalysis of synthesizing 5-substituted 1H-tetrazoles through 1,3-dipolar cycloaddition of boron-azides and nitriles is reported with broad substrate scope and excellent yields.     

Synthesis and structural characterization of metallated bioconjugates: C-terminal labeling of amino acids with aminoferrocene

Aminoferrocene, H₂N-Fc, has been substituted to the C-terminus of six amino acids using the HBTU/HOBt coupling protocol. The synthesized bioconjugates Boc-Aaa-NH-Fc, Aaa = Gly (1), Leu (2), Phe (3), Val (4), Cys(Acm) (5), Tyr(^tBu) (6) (Acm = acetamidomethyl, ^tBu = tert-butyl), have been characterized by ¹H NMR, ¹³C NMR, EI-MS, EI-HRMS, UV and CD spectroscopies. In addition, a VT NMR study on 4 and the X-ray structure of 1 are presented.     

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.     

A recyclable/reusable hydrotalcite supported copper nano catalyst for 1,4-disubstituted-1,2,3-triazole synthesis via click chemistry approach

Using hydrotalcite as solid support, copper nano particles were synthesized and used in azide-alkyne cycloaddition reaction en route to the synthesis of 1,4-disubstituted-1,2,3-triazoles. The catalyst is heterogeneous and can be recycled and reused easily. Room temperature reaction condition and the use of ethylene glycol as solvent make it an environment friendly system.     

A facile synthesis of ferrocene grafted N-methyl-spiropyrrolidines through 1,3-dipolar cycloaddition of azomethine ylides

One-pot synthesis of novel ferrocene grafted N-methyl-spiropyrrolidines has been accomplished in good yields through a facile 1,3-dipolar cycloaddition reaction of various azomethine ylide derived from ninhydrin and sarcosine with various ferrocene derivatives as dipolarophile. The regiochemical and stereochemical outcome of the cycloaddition reaction is ascertained by X-ray crystallographic studies of one of the cycloadducts.     

Synthesis and physiological activity of trialkyl phosphorothioates and trialkyl phosphorodithioates containing fragments of N-acylated amino acids

A series of S-[N-acyl-N-(alkoxycarbonylalkyl)aminomethyl] O,O-dialkyl phosphorothioates and -dithioates were prepared by the reactions of the corresponding alkali salts of dialkyl phosphorothioates or dialkyl phosphorodithioates with esters of N-acyl-N-(chloromethyl)glycine or N-acyl-N-(chloromethyl)--alanine and by the reactions of dialkylphosphorothioic or dialkylphosphorodithioic acids with N-acylated amino acids or their esters and paraformaldehyde in the presence of gaseous HCl. Some of the resulting compounds proved to be active permethrine synergists.     

Unnatural benz-X-azolyl asparagine derivatives as novel fluorescent amino acids: synthesis and photophysical characterization

A family of new asparagine derivatives bearing benzothiazole and benzimidazole units, functionalised with electron donor or acceptor groups, were synthesized in good to excellent yields. The photophysical characterization of these new heterocyclic amino acids was performed by UV-visible absorption and fluorescence emission studies and revealed that the compounds displayed remarkably high fluorescence quantum yields and Stokes' shifts, making them good candidates for application as fluorescent probes by incorporation into peptidic frameworks.     

Zwitterionic chiral stationary phases based on cinchona and chiral sulfonic acids for the direct stereoselective separation of amino acids and other amphoteric compounds

An extensive series of free amino acids and analogs were directly resolved into enantiomers (and stereoisomers where appropriate) by HPLC on zwitterionic chiral stationary phases (Chiralpak ZWIX(+) and Chiralpak ZWIX(?)). The interaction and chiral recognition mechanisms were based on the synergistic double ion‐paring process between the analyte and the chiral selectors. The chiral separation and elution order were found to be predictable for primary α‐amino acids with apolar aliphatic side chains. A systematic investigation was undertaken to gain an insight into the influence of the structural features on the enantiorecognition. The presence of polar and/or aromatic groups in the analyte structure is believed to tune the double ion‐paring equilibrium by the involvement of the secondary interaction forces such as hydrogen bonding, Van der Waals forces and π–π stacking in concert with steric parameters. The ZWIX chiral columns were able to separate enantiomers and stereoisomers of various amphoteric compounds with no need for precolumn derivatization. Column switching between ZWIX(+) and ZWIX(?) is believed to be an instrumental tool to reverse or control the enantiomers elution order, due to the complementarity of the applied chiral selectors.     

Click chemistry and biocatalysis for the preparation of pancratistatin analogs

Tricyclic compounds that are advanced precursors for the synthesis of analogs of the antitumoral alkaloid pancratistatin were prepared by a short sequence that involved enzymatic dihydroxylation, epoxidation, and intramolecular Huisgen cycloaddition.