Cyclic Amino Acids Research Articles

Stereoselective synthesis of cyclic amino acidsvia asymmetric phase-transfer catalytic alkylation

An asymmetric synthesis of cyclic amino acids having piperidine and azepane core structures was realized starting from readily available glycine and alanine esters by combination of phase-transfer catalyzed asymmetric alkylation and subsequent reductive amination.

Cyclobutene Ring-Opening of Bicyclo[4.2.0]octa-1,6-dienes: Access to CF3-Substituted 5,6,7,8-Tetrahydro-1,7-naphthyridines

An efficient method for the synthesis of novel CF(3)-substituted tetrahydro-1,7-naphthyridines including cyclic α-amino acid derivatives has been developed. The method is based on unusual cyclobutene ring-opening of bicyclo[4.2.0]octa-1,6-dienes with pyrrolidine to afford the corresponding 1,5-diketones followed by their heterocyclization. A convenient one-pot procedure has been also elaborated starting from readily available trifluoromethylated 1,6-allenynes.

Comparative canine Pharmacokinetics–Pharmacodynamics of Fospropofol Disodium Injection, Propofol Eemulsion, and Cyclodextrin-Enabled Propofol Solution Following Bolus Parenteral Administration

The pharmacokinetics and pharmacodynamics of fospropofol (FP) disodium injection, propofol emulsion (PE), and cyclodextrin-enabled propofol (CDP) solution following bolus parenteral administration in dogs was evaluated. Three healthy male beagle dogs were treated in a three-way cross-over study (14 day washout period) with 6 mg/kg propofol equivalents. Blood samples were collected predose and at 16 points postdose through 1440 min and analyzed for propofol and FP, when appropriate. From 5 min predose to 30 min postdose, brain electrical activity [electroencephalography (EEG)] was recorded and analyzed by power spectrum analysis techniques. Each formulation appeared to be well tolerated with transient discomfort observed in the PE and CDP animals and minor excitability in the FP animals prior to loss of consciousness. Blood propofol followed three-compartment pharmacokinetic behavior and derived parameters were not statistically different except for elimination half-life from the CDP formulation and onset, and duration of anesthesia from the FP formulation. The effect site concentrations at 50% the maximum EEG effect for the FP and CDP formulations were approximately one-half that of the PE formulation. Onset and duration of anesthesia are correlated with modeled effect site propofol concentrations. The implications of formulation on pain on injection and propofol activity are discussed.

Preparation, Characterisation and Some Reactions of Organocatalysts Immobilised Between the Layers of a CaFe-Layered Double Hydroxide

Five- and six-membered cyclic α-amino acid anions with secondary nitrogen in the ring (l-prolinate and dl-pipecolinate) were immobilised in Ca3Fe-L(ayered)D(ouble)H(ydroxide) by the dehydration-rehydration method. The resulting organic–inorganic hybrids were characterised by various instrumental methods (powder X-ray diffraction, scanning electron microscopy, energy dispersive X-ray fluorescence with elemental mapping, and analytical techniques for determining the iron as well as the organic contents) and molecular modelling. The immobilised organocatalysts were tested in the cross-aldol dimerization-condensation reaction between benzaldehyde and acetone and found to be active and enantioselectivity in the dimerization was also observed.

Synthesis of bicyclic 2,6-diketopiperazines via a three-step sequence involving an Ugi five-center, four-component reaction

A three-step sequence involving an Ugi five-center, four-component reaction (U-5C-4CR), amide N-detertbutylation and cyclocondensation has been developed for easy access to diverse bicyclic 2,6-diketopiperazine (2,6-DKP) derivatives. In the key step, aromatic aldehydes were successfully coupled with cyclic α-amino acids and isocyanides in the course of U-5C-4CR. Boron trifluoride-acetic acid complex was developed as a new N-detertbutylating agent effective at rt.

Synthesis of Enantiopure 7‐Substituted Azepane‐2‐carboxylic Acids as Templates for Conformationally Constrained Peptidomimetics

AbstractThe introduction of a cyclic amino acid in a peptide is one of the best methods to rigidify a strand. A general approach towards a new class of seven‐membered ring amino acids is described starting from (S)‐tribenzyl glutamic acid γ‐aldehyde, which reacts with β‐keto phosphonates to generate the Horner–Wadsworth–Emmons product. In the presence of H2 and a Pd catalyst, a four‐step process occurs involving double‐bond hydrogenation, hydrogenolysis of three benzyl protecting groups, imine formation, and reductive amination to produce the 7‐substituted azepane carboxylic acid in good overall yield and with good to excellent diastereomeric ratios. An amino function can be introduced in the 7‐position as an additional orthogonal chemical handle for readily generating diversity on the cyclic amino acid scaffold by using a β‐keto phosphonate derived from amino acids. A cyclic RGD (Arg‐Gly‐Asp) pentapeptide analogue containing this new class of noncoded amino acids was also prepared by microwave‐assisted cyclization, showing a promising activity as αvβ3 integrin inhibitor.

Cyclic α-amino acids as precursors for synthesis of 2-amino-3-hetarylpyrrolin-4-ones and their spiro derivatives

α-Aminoisobutanoic acid and some representatives of cyclic α-amino acids were converted to corresponding 1-phthalimido- and N-trifluoroacylated acid chlorides. Treatment of 2-(1H-benzimidazol-2-yl)acetonitrile with 1-phthalimidoacid chlorides in DMF unexpectedly gave 2-(1H-benzimidazol-2-yl)-3-(dimethylamino)-2-propenenitrile. On the other hand, the reaction of hetarylacetonitriles with N-trifluoroacylated acid chlorides gave the desired (3-cyano-2-oxo-3-hetarylpropyl)-2,2,2-trifluoroacetamides that upon detrifluoroacetylation provided the target 2-amino-3-hetarylpyrrolin-4-ones. The acylation of benzoimidazolylaminopyrrolinones by benzoyl chloride leads to formation of 3-benzoyl-2,3-dihydro-5-phenyl-1H-benzo[4,5]imidazo[1,2-c]pyrrolo[3,2-e]pyrimidin-1-ones.

One‐Handed Helical Screw Direction of Homopeptide Foldamer Exclusively Induced by Cyclic α‐Amino Acid Side‐Chain Chiral Centers

Chiral cyclic α,α-disubstituted amino acids, (3S,4S)- and (3R,4R)-1-amino-3,4-(dialkoxy)cyclopentanecarboxylic acids ((S,S)- and (R,R)-Ac(5)c(dOR); R: methyl, methoxymethyl), were synthesized from dimethyl L-(+)- or D-(-)-tartrate, and their homochiral homoligomers were prepared by solution-phase methods. The preferred secondary structure of the (S,S)-Ac(5)c(dOMe) hexapeptide was a left-handed (M) 3(10) helix, whereas those of the (S,S)-Ac(5)c(dOMe) octa- and decapeptides were left-handed (M) α helices, both in solution and in the crystal state. The octa- and decapeptides can be well dissolved in pure water and are more α helical in water than in 2,2,2-trifluoroethanol solution. The left-handed (M) helices of the (S,S)-Ac(5)c(dOMe) homochiral homopeptides were exclusively controlled by the side-chain chiral centers, because the cyclic amino acid (S,S)-Ac(5)c(dOMe) does not have an α-carbon chiral center but has side-chain γ-carbon chiral centers.

ChemInform Abstract: Base‐Promoted Reaction of Methyl 4,6‐O‐Benzylidene‐3‐deoxy‐hexopyranosid‐2‐ulose and Various Arylamines.

AbstractTreatment of the ulose derivative (I) with p‐anisidine in NaOH/CHCl3 does not produce the expected cyclic amino acid structure but enaminoketone (IIIa).

Hydrothermal Treatment (HTT) of Microalgae: Detailed Molecular Characterization of HTT Oil in View of HTT Mechanism Elucidation

The understanding of the chemical nature of the oil is important for both the optimization of the process and the design of upgrading strategies for further use as an energy carrier or toward transportation fuels. Hydrothermal treatment (HTT) oil is a complex matrix, whose composition is strongly affected by the feedstock type and by the HTT experimental conditions. In the present work, HTT oil from Desmodesmus sp. was subjected to a detailed chemical analysis. Various characterization techniques (silica gel chromatography, methanolysis, size exclusion chromatography, analytical pyrolysis, elemental analysis, and thermogravimetric techniques) were coupled to gather clearer information on the chemical nature of HTT oil obtained at different reaction times, temperatures, and slurry concentrations. Special attention was paid to the fate of N in the HTT process and the nature of the N-containing species in the oil. By cross-checking results from the chemical characterization of the oil with process data, it was finally possible to identify some different competitive reactions involved in the formation of HTT oil at different conditions. Results show that main compounds obtained at low temperature are still classifiable as lipids, which are extractable without the HTT, together with some short chain algaenan and some hydrophobic protein fragments that end up in the organic solvent phase. At higher temperature (300–375 °C), proteins and cellulose started to break down, giving cyclic dipeptides and amino acids side chains (by pyrolysis-like reactions), carbohydrates derivatives (e.g., furans) and products from the cross reaction of proteins and carbohydrates (e.g., formation of alkyl-pyrrolidinones, pyrazines, pyrroles and melanoidin-like materials). This phenomenon is responsible for the observed increase in oil mass yield with increasing processing temperature, as well as the increase in nitrogen content of the oil. Optimization of the production of fuels and fuel precursors by HTT should be done in conjunction with evaluation of downstream processing options and/or the possibility to recycle unconverted material to the algae cultivation.

Cyclic amino acid linkers stabilizing key loops of brain derived neurotrophic factor

Based on β-turn-like BDNF loops 2 and 4, involved in receptor interaction, cyclic peptide replicas were designed, synthesized and tested. In addition to the native turn residues, the cyclic peptides include a linker unit between the N- and C-termini, selected by molecular modeling among various non-proteinogenic cyclic amino acids. NMR conformational studies showed that most of the cyclic peptides were able to adopt turn-like structures. Several of the analogues displayed significant inhibition of the BDNF-induced TrkB receptor phosphorylation, and hence could be useful templates for developing improved antagonists for this receptor.

Thermal [2+2] Cycloaddition of CF3-Substituted Allenynes: Access to Novel Cyclobutene-Containing α-Amino Acids

An efficient approach for the preparation of novel CF3-substituted cyclic α-amino acid derivatives fused with cyclobutene ring has been developed. The method is based on intramolecular thermal [2+2] cycloaddition of amino acid containing allenynes with internal triple bond obtained by successive [2,3]-sigmatropic rearrangement of propargyl-containing nitrogen CF3-ylides and ­Sonogashira derivatization of the triple bond.

Substrate Recognition and Specificity of the NisB Protein, the Lantibiotic Dehydratase Involved in Nisin Biosynthesis

Nisin is a posttranslationally modified antimicrobial peptide containing the cyclic thioether amino acids lanthionine and methyllanthionine. Although much is known about its antimicrobial activity and mode of action, knowledge about the nisin modification process is still rather limited. The dehydratase NisB is believed to be the initial interaction partner in modification. NisB dehydrates specific serine and threonine residues in prenisin, whereas the cyclase NisC catalyzes the (methyl)lanthionine formation. The fully modified prenisin is exported and the leader peptide is cleaved off by the extracellular protease NisP. Light scattering analysis demonstrated that purified NisB is a dimer in solution. Using size exclusion chromatography and surface plasmon resonance, the interaction of NisB and prenisin, including several of its modified derivatives, was studied. Unmodified prenisin binds to NisB with an affinity of 1.05 ± 0.25 μm, whereas the dehydrated and the fully modified derivatives bind with respective affinities of 0.31 ± 0.07 and 10.5 ± 1.7 μm. The much lower affinity for the fully modified prenisin was related to a >20-fold higher off-rate. For all three peptides the stoichiometry of binding was 1:1. Active nisin, which is the equivalent of fully modified prenisin lacking the leader peptide did not bind to NisB, nor did prenisin in which the highly conserved FNLD box within the leader peptide was mutated to AAAA. Taken together our data indicate that the leader peptide is essential for initial recognition and binding of prenisin to NisB.

3-Aminopyrrolidine-4-carboxylic acid as versatile handle for internal labeling of pyrrolidinyl PNA

Conformationally restricted pyrrolidinyl PNAs with an α/β-dipeptide backbone consisting of a nucleobase-modified proline and a cyclic five-membered amino acid spacer such as (1S,2S)-2-aminocyclopentanecarboxylic acid (ACPC) (acpcPNA) can form very stable hybrids with DNA with high Watson-Crick base pairing specificity. This work aims to explore the effect of incorporating 3-aminopyrrolidine-4-carboxylic acid (APC), which is isosteric to the ACPC spacer, into the acpcPNA. It is expected that the modification should not negatively affect the DNA binding properties, and that the additional nitrogen atom in the APC should provide a handle for internal modification. Orthogonally-protected (N(3)-Fmoc/N(1)-Boc and N(3)-Fmoc/N(1)-Tfa) APC monomers have been successfully synthesized and incorporated into the acpcPNA by Fmoc-solid-phase peptide synthesis. T(m), UV and CD spectroscopy confirmed that the (3R,4S)-APC could substitute the (1S,2S)-ACPC spacer in the acpcPNA with only slightly decreasing the stability of the hybrids formed between the modified acpc/apcPNA and DNA. In contrast, the (3S,4R) enantiomer of APC caused substantial destabilization of the hybrids. Furthermore, a successful on-solid-support internal labeling of the acpc/apcPNA via amide bond formation between pyrene-1-carboxylic acid or 4-(pyrene-1-yl) butyric acid and the pyrrolidine nitrogen atom of the APC spacer has been demonstrated. Fluorescence properties of the pyrene-labeled acpc/apcPNAs are sensitive to their hybridization states and can readily distinguish between complementary and single-mismatched DNA targets.

Study of redox behavior of Cd(II) and interaction of Cd(II) with proline in the aqueous medium using cyclic voltammetry

The redox behavior of Cd(II) and the interaction of Cd(II) with cyclic amino acid, proline, have been studied in 0.1 M KCl, 0.1 M NaClO4 and acetate buffer of different pH. The CVs were recorded at glassy carbon electrode within the potential window 200 and −1500 mV. The reference and counter electrode used were Ag/AgCl and Pt wire, respectively. The cyclic voltammograms show one pair of cathodic and anodic peaks for the Cd(II)/Cd(0) system indicating the involvement of two electron transfer processes. The peak potential shift and charge transfer rate constant (kf) values strongly support the interaction between metal and ligand. The higher value of peak current ratio and peak potential separation (ΔE) indicate that the systems are quasireversible. The effect of supporting electrolyte and concentration of electro active species on the interaction were also studied.

Synthesis of α-CN and α-CF3 N-Heterocycles through Tandem Nucleophilic Additions

Using a readily available secondary aminoalkyne as starting material, a powerful strategy was discovered to prepare precursors of biologically important unnatural cyclic aminoacids and fluorinated N-heterocycles with important ring sizes (e.g., 5-7) in a one-pot reaction using two nucleophilic additions in a tandem fashion.

A straightforward route to enantiopure 2-substituted-3,4-dehydro-β-proline via ring closing metathesis

The synthesis of unusual cyclic amino acids, that may be envisaged as proline analogs, is an area of great interest for their potential applications as scaffolds for the design of bioactive peptidomimetics or units for the creation of novel foldamers. We have carried out the preparation of cyclic dehydro-β-amino acids starting from allylic carbonates via a two-step allylic amination/ring closing metathesis (RCM) protocol. The introduction of the allylamino moiety has been carried out either without a catalyst, through an S(N)2' reaction, or in the presence of iridium complexes. The backbone of the allylamino intermediates contains two unsaturations, thus suggesting that RCM could be a valuable tool for the preparation of dihydropyrrole scaffolds. A similar reaction has been already reported in the literature for racemic aromatic-substituted substrates, but no examples of enantiopure derivatives bearing aliphatic chains have been reported. The reaction was optimized by testing different Grubbs' catalysts and carbamate nitrogen protecting groups. Moreover, in view of a future application of these dehydro-β-amino acids as central core of peptidomimetics, the malonate chain was also used to protect nitrogen prior to RCM.

Kinetics and Mechanism of the Kmn04-Oxidative Catalysed Condensation Reaction of L-Proline to a Diketopiperazine: Evidence for Delayed Autocatalytic Behaviour

The kinetics and mechanism of the KMn04-oxidative catalysed condensation reaction of L-proline, as a cyclic secondary amino acid, has been investigated spectrophotometrically. Product analysis has revealed, that in contrast to the usual reaction of α-amino acids, which results in an aldehyde species, a valuable diketopiperazine, namely cyclo(L-pro-L-pro), is obtained as the main product, providing a cheap, simple, efficient, and novel method. Conclusive evidence has demonstrated delayed autocatalytic activity involving Mn2+in this reaction, analogous to that shown by chain primary a-amino acids. It has been revealed that such activity can emerge when a certain concentration of Mn2 +is built up in the medium, to which we refer as the “critical concentration”. Moreover, the “critical concentration” for the appearance of “autocatalytic behaviour” in this oxidative process is affected by the nature of the amino acid used, as reported in previous studies, while the magnitude of the critical concentration depends on the sulfuric acid concentration. In considering “delayed autocatalytic behaviour” of Mn2+ions, rate equations satisfying experimental data for both catalytic and non- catalytic routes have been presented. The reaction shows a first-order dependence on permanganate ion concentration, both in the catalytic and non-catalytic pathways, and an apparent first-order dependence on Mn2 +ions in the catalytic pathway. The correspondence of the pseudo-order rate constants of the catalytic and non-catalytic pathways to the Arrhenius and Eyring laws verified both the “critical concentration” and “delayed autocatalytic behaviour” concepts. The activation parameters associated with the reaction pseudo-rate constants k, and k2are computed and discussed. Proposed mechanisms for both catalytic and non- catalytic routes include a diacyclperoxide intermediate, which leads to a C-2-symmetric chiral product having a diketopiperazine skeleton.

Unexpected property of ectoine synthase and its application for synthesis of the engineered compatible solute ADPC

A new cyclic amino acid was detected in a deletion mutant of the moderately halophilic bacterium Halomonas elongata deficient in ectoine synthesis. Using mass spectroscopy (MS) and nuclear magnetic resonance (NMR) techniques, the substance was identified as 5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate (ADPC). We were able to demonstrate that ADPC is the product of a side reaction of lone ectoine synthase (EC 4.2.1.108), which forms ADPC by cyclic condensation of glutamine. This reaction was shown to be reversible. Subsequently, a number of ectoine derivatives, in particular 4,5-dihydro-2-methylimidazole-4-carboxylate (DHMICA) and homoectoine, were also shown to be cleaved by ectoine synthase, which is classified as a hydro-lyase. This study thus reports for the first time that ectoine synthase accepts more than one substrate and is a reversible enzyme able to catalyze both the intramolecular condensation into and the hydrolytic cleavage of cyclic amino acid derivatives. As ADPC supports growth of bacteria under salt stress conditions and stabilizes enzymes against freeze-thaw denaturation, it displays typical properties of compatible solutes. As ADPC has not yet been described as a natural compound, it is presented here as the first man-made compatible solute created through genetic engineering.

Recent Advances in the Synthesis of Fluorinated Amino Acids

AbstractIntroduction of fluorine atoms or fluorine‐containing groups into amino acids has attracted much attention from bioorganic and medicinal chemists because the resulting fluorinated amino acids have found wide application as potential enzyme inhibitors and antitumor (antibacterial) agents. Additionally, it is well known that replacement of naturally occurring amino acid(s) in some peptide chains with their fluorinated counterparts can significantly increase specific protein–ligand or protein–protein interactions, leading to increases in the proteolytic and thermal stabilities of peptide compounds and, as a result, promote their therapeutic properties. This microreview summarizes important advances in the synthesis of fluorinated amino acids since 2005. The contents are simply divided into three groups on the basis of amino acid types: fluorinated α‐amino acids (F‐αAAs), fluorinated β‐amino acids (F‐βAAs), and fluorinated cyclic amino acids (F‐CAAs).