Introduction of the Aib-Pro unit into peptides by means of the ‘azirine/oxazolone method’ on solid phase

A method for the direct introduction of Aib-Pro into peptides on solid phase was developed. The Aib-Pro unit was introduced by means of the ‘azirine/oxazolone method’ using allyl N-(2,2-dimethyl-2H-azirin-3-yl)-l-prolinate as the synthon. After the reaction of the resin-bound amino or peptide acid with allyl N-(2,2-dimethyl-2H-azirin-3-yl)-l-prolinate, the allyl protecting group of the resulting extended peptide could be removed by a mild Pd⁰-promoted procedure. Cleavage of the peptide from the resin was performed with UV light at 352 nm and yielded C-terminal protected peptides. The method found a successful application in the syntheses of different Aib-Pro containing peptaibol segments. Furthermore, a protected derivative of the peptide antibiotic Trichovirin I 1B was prepared by segment condensation.     

Side Reactions in Peptide Synthesis: Failure of Coupling in Solid-Phase Automatic Synthesis of a Fragment (Sequence 65-74) of the Acyl Carrier Protein

Two major side-products and a desired peptide (each was one-third) were found in analysis of a synthesized fragment (65-74) of the acyl carrier protein by a solid-phase automatic peptide synthesizer. The peptide mixtures were separated and collected by HPLC. Each isolated peptide was characterized via amino-acid composition analysis, mass spectra and specific peptide-bond cleavage to prove the sequence. Each by-product had one amino-acid missing (⁷²Ile and ⁷³Asn, respectively) from the sequence of ACP(65-74).     

A new procedure for the synthesis of peptide-derived Amadori products on a solid support

A new and straightforward solid-phase synthesis of a series of site-specific Amadori-modified peptides is described. The method involves reductive alkylation of the ε-amino groups of lysine with 2,3:4,5-di-O-isopropylidene-β-d-arabino-hexos-2-ulo-2,6-pyranose in the presence of sodium cyanoborohydride on a solid support.     

A support for the identification of non-tryptic peptides based on low resolution tandem and sequential mass spectrometry data: The INSPIRE software

A simple software, to be used as an aid in the identification of non-tryptic peptides based on low resolution (3D-ion trap) tandem (MS/MS) and sequential (MS³) mass spectrometry data, is presented.     

Carboncarbon bond formation on solid support. Application of the classical Julia-Lythgoe olefination

Reductive elimination of β-benzoyloxysulfones, obtained via solid-phase organic synthesis, with samarium diiodide in the presence of DMPU favors the formation of trans-alkenes.     

Hydrolysis of amide bond in histidine-containing peptides promoted by chelated amino acid palladium(II) complexes: dependence of hydrolytic pathway on the coordination modes of the peptides

Hydrolytic reactions between cis-[Pd( -Ala-N,O)Cl₂]⁻ and cis-[Pd( -Ala-N,O)(H₂O)₂]⁺, in which -Ala is alanine coordinated through N and O atoms, and N-acetylated peptides -histidylglycine (MeCO-His-Gly), glycyl- -histidine (MeCO-Gly-His), glycylglycyl- -histidine (MeCO-Gly-Gly-His) and glycyl- -histidylglycine (MeCO-Gly-His-Gly) were studied by ¹H NMR spectroscopy. All reactions were carried out in the pH range 2.0–2.5 and two different temperatures, 22 and 60°C. In the reactions of these two palladium(II) complexes with MeCO-His-Gly, complete hydrolysis of the amide bond involving carboxylic group of histidine occurs in less than 24 h. The cleavage is regioselective. With peptides containing free a carboxylic group of histidine, MeCO-Gly-His and MeCO-Gly-Gly-His, palladium(II) complex promote the cleavage of the MeCO–Gly and Gly–Gly amide bonds. No cleavage of the Gly–His amide bond was observed. The mechanism of these hydrolytic reactions involves release of -Ala ligand and aquation of the palladium(II) complex chelated to the substrate through the imidazole N-3 atom and deprotonated nitrogen atom of the amide bond involving amino group of histidine. This aqua complex represents a catalytically active form different from the initially added catalytically inactive complex. In the reactions of palladium(II) complexes with tripeptide MeCO-Gly-His-Gly, two amide bonds, MeCO–Gly and His–Gly, were cleaved. The mechanism of the cleavage of these amide bonds is correlated with two different palladium(II)–substrate catalytically active forms. These findings contribute to the better understanding of selective cleavage of peptides and proteins and must be taken into consideration in designing new reagents for this purpose.     

Facile method for the synthesis of triazole- and tetrazole-containing peptoids on a solid support

The late-stage functionalization of a biomimetic foldamer such as a peptoid is a useful tool to achieve structural diversity. Herein, a facile method for the synthesis of triazole- or tetrazole-containing peptoids using post-synthetic modifications has been reported. On a resin-bound peptoid with a chloroalkyl side chain(s), substitution with nucleophiles (azide or cyanide) and the subsequent [3?+?2]-cycloaddition reaction were optimized. Peptoids with azide, triazole, and tetrazole functional groups could be readily synthesized and could potentially be utilized further for orthogonal bioconjugation or metal recognition.     

[N]-Isotopic labeling: a suitable tool to study the reactivity of bis lactams

The unexpected reactivity of 2,5-diketopiperazines under basic conditions, thanks to N-Boc activation, allows access to valuable pharmacological scaffolds, such as original statine derivatives. Toward this transannular rearrangement of activated lactams (TRAL), we report here the study of bis lactam reactivity using [¹⁵N]-isotopic labeling.     

Synthesis of a diverse set of phosphorus ligands on solid support and their screening in the Heck reaction

Representative members from five different families of supported phosphine and phosphinite ligands have been prepared from common templates—polymer-bound aminoalcohols. These include β-aminophosphines, N,β-diphosphinoamines, α,β-diphosphinoamines, β-aminophosphinites and N-phosphino-β-aminophosphinites. Representatives of each family of ligands were complexed with Pd(OAc)₂ and screened in the Heck reaction of iodo- and bromobenzene. While the reaction of iodoarenes is ligand-independent, the reaction of bromoarenes is ligand-sensitive. The rationale for this behavior is suggested. Lead ligands for the reaction of bromoarenes were determined.     

Specific ion effects on the electrophoretic mobility of small,highly charged peptides: A modeling study

In this work, we use coarse‐grained modeling to study the free solution electrophoretic mobility of small highly charged peptides (lysine, arginine, and short oligos thereof (up to nonapeptides)) in NaCl and Na₂SO₄ aqueous solutions at neutral pH and room temperature. The experimental data are taken from the literature. A bead modeling methodology that treats the electrostatics at the level of the nonlinear Poisson Boltzmann equation developed previously in our laboratory is able to account for the mobility of all peptides in NaCl, but not Na₂SO₄. The peptide mobilities in Na₂SO₄ can be accounted for by including sulfate binding in the model and this is proposed as one possible explanation for the discrepancy. Oligo arginine peptides bind more sulfate than oligo lysines and sulfate binding increases with the oligo length.     

FRET-based assay of the processing reaction kinetics of stimulus-responsive peptides: influence of amino acid sequence on reaction kinetics

In the field of chemical biology, methods for controlling peptidyl function by a stimulus are attracting increasing attention. Recently, we reported a stimulus-responsive peptide, which can be cleaved after exposure to a stimulus. In this study, we developed a FRET-based assay system to estimate the kinetics of the stimulus-induced processing (peptide bond cleavage) reaction. Based on the FRET system, it was clarified that introduction of a sterically less-hindered or polar residue at the position adjacent to the stimulus-responsive amino acid accelerates the processing reaction.     

alpha-Ketocarbonyl peptides: a general approach to reactive resin-bound intermediates in the synthesis of peptide isosteres for protease inhibitor screening on solid support.

alpha-Ketocarbonyl peptides were generated from peptide precursors on solid support via a metal-ion-catalyzed transamination. The reaction proceeded to completion within 2 h with glyoxylate as electrophile and copper(II) ions as catalyst in an aqueous acetate buffer at pH 5.5-6.0. The variety of naturally occurring alpha-amino acid substrates gave rise to a diverse set of differentially functionalized ketones. The highly reactive terminal ketocarbonyls were prone to aldol-type dimerization and could be transferred into stable moieties by oxime formation, reduction to the alcohol, or reductive amination, respectively. The alpha-ketocarbonyl peptides were efficient in nucleophilic addition of C-nucleophiles such as phosphono-ylides and allylsilanes.     

Investigation of the catalytic activity of metal complexes fixed on a solid support. 10. Selective hydrogenation of allylbenzene in the presence of heterogeneous Pt-Sn-citrate complexes

New heterogeneous catalysts based on the complexes of platinum with tin(II) citrate were prepared. The catalysts exhibit high selectivity in the hydrogenation of allylbenzene to propylbenzene without increasing the rate of isomerization of the C=C bond. The activity of the complexes depends on the conditions and decreases with increase in the Sn:Pt ratio.N. D. Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, 117913 Moscow. St. Petersburg Technological Institute. Translated fromIzvestiya Akademii Nauk, Seriya Khimicheskaya, No. 6, pp. 1287–1290, June, 1992.     

Nano-Fe3O4@silica sulfuric acid as a reusable and magnetically separable potent solid acid catalyst in Biginelli-type reaction for the one-pot multicomponent synthesis of fused dihydropyrimidine derivatives: A greener NOSE and SFRC approach

An efficient, highly product selective, eco-friendly, one-pot multicomponent synthesis of dihydropyrimidine derivatives via Biginelli reaction has been described. The reaction was developed by greener nanoparticle-catalyzed organic synthesis enhancement (NOSE) chemistry and solvent free reaction condition (SFRC) approaches, which helped us in making the procedure greener. The reaction went smoothly with a diverse range of aromatic, aliphatic, hetero-aromatic aldehydes, different amine sources, as well as various β-dicarbonyl compounds, showing the flexibility of this methodology. Magnetically separable nano-Fe₃O₄@SiO₂@SO₃H, which acts as a potent solid acid catalyst, was characterized by FT-IR, SEM, EDX and TEM, VSM, and TGA analyses. The catalyst was recycled from the reaction mixture easily by an external magnet and reused in five more consecutive runs without much decrease in catalytic activity. Its catalytic efficiency was compared to other nano and bulk solid acid catalyst in order to ascertain the best combination for the conversion.     

The Major/Minor Concept: Dependence of the Selectivity of Homogeneously Catalyzed Reactions on Reactivity Ratio and Concentration Ratio of the Intermediates

The homogeneously catalyzed asymmetric hydrogenation of prochiral olefins with cationic Rh^I complexes is one of the best‐understood selection processes. For some of the catalyst/substrate complexes, experimental proof points out the validation of the major/minor principle; the concentration‐deficient minor substrate complex, which has very high reactivity, yields the excess enantiomer. As exemplified by the reaction system of [Rh(dipamp)(MeOH)₂]⁺/methyl (Z)‐α‐acetamidocinnamate (dipamp=1,2‐bis((o‐methoxyphenyl)phenylphosphino)ethane), all six of the characteristic reaction rate constants have been previously identified. Recently, it was found that the major substrate complex can also yield the major enantiomer (lock‐and‐key principle). The differential equation system that results from the reaction sequence can be solved numerically for different hydrogen partial pressures by including the known equilibrium constants. The result displays the concentration–time dependence of all species that exist in the catalytic cycle. On the basis of the known constants as well as further experimental evidence, this work focuses on the examination of all principal possibilities resulting from the reaction sequence and leading to different results for the stereochemical outcome. From the simulation, the following conclusions can be drawn: 1) When an intermediate has extreme reactivity, its stationary concentration can become so small that it can no longer be the source of product selectivity; 2) in principle, the major/minor and lock‐and‐key principles can coexist depending on the applied pressure; 3) thermodynamically determined intermediate ratios can be completely converted under reaction conditions for a selection process; and 4) the increase in enantioselectivity with increasing hydrogen partial pressure, a phenomenon that is experimentally proven but theoretically far from being well‐understood, can be explained by applying both the lock‐and‐key as well as the major/minor principle.     

Synthetic studies on taxanes: construction of the tricyclic skeleton on the basis of a [6+2] cycloaddition reaction

The stereoselective synthesis of a tricyclic model compound of taxane diterpenes was achieved. The eight-membered B ring was constructed on the basis of a [6+2] cycloaddition reaction of a dicobalt acetylene complex with an enol silyl ether of cyclohexanone. After conversion of the cobalt complex moiety to an epoxide and introduction of a 3-cyanopropyl group, the A ring was formed via an intramolecular cyclization reaction under basic conditions.