Efficient solid-phase synthesis of cyclic RGD peptides under controlled microwave heating

Cyclic RGD peptides are potent antagonists for the α_vβ₃ integrin receptor. In this Letter, microwave-assisted solid-phase synthesis of cyclic RGD peptides is described. In a coupling reaction between Fmoc-Arg(Pbf)-OH and high-loading H-Gly-Trt(2-Cl) resin, multiple coupling reactions were required for completion under the conventional HBTU activation. We found that the use of COMU, a new coupling reagent, under microwave heating to 50 °C accelerated the reaction even inside the resin. This method was applicable to the synthesis of linear pentapeptides, H-Asp(OtBu)-Xxx-Yyy-Arg(Pbf)-Gly-OH (Xxx = d-Phe(p-Br) or d-Tyr, Yyy = Lys(Boc) or MeVal). Cyclization of these peptides followed by deprotection gave the desired cyclic RGD peptides with high purity.     

Fluorinated peptidomimetics: synthesis, conformational and biological features

Peptides modified with fluoroalkyl functions in key backbone positions have been scarcely studied so far. Thus, little is known about their synthesis, their structural and physico-chemical properties, and their biological features. Our interest in this field of research led to the development of stereocontrolled synthetic protocols, both in solution and in solid phase, for many different fluoroalkyl peptidomimetics, some of which are overviewed in this paper: (a) ψ[CH(CF₃)NH]-peptide mimics holding a great potential as hybrids between natural peptides and hydrolytic transition state analogs; (b) trifluoromethyl (Tfm) malic peptidomimetics as micromolar inhibitors of some matrix metalloproteinases; (c) bis-Tfm analogs of Pepstatin A, that are nanomolar and selective inhibitors of the protozoal aspartyl protease Plasmepsin II.     

Preparation of peptide thioesters using Fmoc strategy through hydroxyl side chain anchoring

In the course of the chemical synthesis of human protein mitogaligin, we present here a simple method to prepare peptide thioesters using Fmoc chemistry. The hydroxyl side chain of serine was reacted with a trichloroacetimidate Wang resin to anchor it on solid phase. After peptide elongation and orthogonal unmasking of the C-terminus, the amino thioester was introduced under optimized conditions to avoid epimerization.     

The role of the histidine residue in the coordination abilities of peptides with a multi-histidine sequence towards copper(II) ions

Cu²⁺ complexes with peptides containing three histidine residues have very specific metal binding abilities and can mimic the structures of various multi-histidine metal binding sites in proteins. The main goal of the work concerns the investigations of coordination abilities of the group of N-terminally protected Ac-His-Arg-His-Gly-His-Gly, Ac-His-Gly-His-Arg-His-Gly, Ac-Gly-His-His-Arg-His-Gly and Ac-His-His-Gly-His-Arg-Gly, and their unprotected analogs His-Arg-His-Gly-His-Gly, His-Gly-His-Arg-His-Gly, Gly-His-His-Arg-His-Gly and His-His-Gly-His-Arg-Gly towards Cu²⁺ ions. Detailed spectroscopic (UV/Vis, CD and EPR) and potentiometric studies have been made. The stoichiometry and binding mode for each ligand–Cu²⁺ system were determined.     

A novel and convenient route for the construction of 5-((1H-1,2,4-triazol-1-yl)methyl)-1H-indoles and its application in the synthesis of Rizatriptan

In this study, a novel and convenient route for the construction of 5-((1H-1,2,4-triazol-1-yl)methyl)-1H-indoles (8) is presented starting from (1H-1,2,4-triazol-1-yl)methanol (5) and indolines (6) under 98% H₂SO₄ at room temperature for 4–24 h, followed by deacetylation and dehydrogenation. Based on this finding, a novel route to synthesize Rizatriptan starting from tryptamine was designed and accomplished with 48.5% overall yield in 6 steps. Compared with operational art, the new route afforded higher yield and more pure products requiring no chromatographic purification, which may further be applied in industrialization.     

Efficient synthesis of phosphonodepsipeptides derived from norleucine

In the present work, we describe in detail an efficient solution synthesis of norleucine-derived phosphonopeptides mimicking the peptide sequences Nle-Gly(Ala) and Nle-Gly(Ala)-Val. The most efficient strategy involved use of the benzyl group. The synthesis was achieved through BOP-catalysed coupling of the monobenzyl ester of the N-Cbz-protected phosphonate derivative of norleucine with the hydroxyl moieties of derivatised l-lactic or glycolic acid. Subsequently, complete deprotection of the products was achieved in good yields by one-step Pd-catalysed hydrogenolysis. We also prepared the Fmoc-Nle-Ψ[PO(OH)O]-CH₂-COOH synthon and demonstrated that this precursor is a suitable building block for the solid-phase synthesis of cysteine-containing phosphonopeptides.     

Structural studies of Cu(II) binding to the novel peptidyl derivative of quinoxaline: N-(3-(2,3-di(pyridin-2-yl)quinoxalin-6-yl)alanyl)glycine

The coordination properties of the novel conjugate towards copper ions were investigated. The performed studies exhibited the unusual binding properties of the ligand molecule having two potential strong coordination sites, namely dipeptidic chain and pyridyl nitrogens. On the basis of potentiometric and spectroscopic studies the binding at the low pH values to the aromatic entity is suggested, while the rise of pH (including physiological one) yielded the dimeric head-to-tail complex formation. This stable species possesses three nitrogen donors involved in Cu(II) chelation: N(pirydyl), NH₂ and N⁻(amide).     

The acetyl CoA synthase paradigm for hybrid bio-organometallics: Quantitative measures for resin-bound Ni-Rh complexes

The active site of Acetyl CoA Synthase utilizes a square planar NiN₂S₂ complex in the form of Ni^II(CGC)²⁻ (CGC = the cysteine-glycine-cysteine tripeptide motif within the protein) to serve as a bidentate sulfur-donor ligand to chelate a second, catalytically active Ni atom responsible for the C-C and C-S coupling reactions for the production of Acetyl CoA. Metalloenzymes, such as this, which house stable catalytic complexes within intricately designed pockets accessible by solvent channels, have inspired design of resin-bound complexes. Through the use of TentaGel S-RAM^® resin beads, the O-Ni(CGC)²⁻ ligand has been synthesized and derivatized with the Rh^I(CO)₂ moiety. The identification of the adduct on these resin beads is afforded by attenuated total reflectance FTIR spectroscopy in the ν(CO) region and compared to solution analogues. The goal of this study is to establish a quantitative measure of the loading of nickel and rhodium on the tripeptide modified resin beads, O-(CGC). The extent of CGC derivatization was determined by Fmoc cleavage of the Fmoc protected O-(CGC). Nickel and rhodium loading were determined by Neutron Activation Analysis. This work provides evidence that the TentaGel S-RAM^® resin beads greatly decrease the air sensitivity of the Ni-Rh complex as compared to the unsupported solution phase analogue. The derivatized beads have also been studied for their ability to withstand a number of physical stresses, i.e., for leaching.     

Synthesis and characterization of a tetraruthenium butterfly cluster containing a quadruply-bridging ligand derived from an N,N′-dipyrid-2-ylurea

The tetraruthenium cluster complex [Ru₄(μ₄-κ⁴-dmpu)(CO)₁₀], H₂dmpu = N,N′-bis(6-methylpyrid-2-yl)urea, has been prepared by treating [Ru₃(CO)₁₂] with H₂dmpu in toluene at reflux temperature. An X-ray diffraction study has determined that this cluster has a butterfly metallic skeleton hold up by a doubly-deprotonated N,N′-bis(6-methylpyrid-2-yl)urea ligand (dmpu). This ligand has the pyridine N atoms attached to the wing-tip Ru atoms and the amido N atoms spanning Ru-Ru wing-edges, in such a way that the cluster has C₂ symmetry. The donor atoms of doubly-deprotonated N,N′-dipyrid-2-ylureas seem to be appropriately arranged to hold butterfly tetranuclear clusters.     

Dimolybdenum complexes containing anions of N,N′-bis(pyrimidine-2-yl)formamidine and N-(2-pyrimidinyl)formamide

The reactions of Mo₂(O₂CCH₃)₄ with different equivalents of N,N′-bis(pyrimidine-2-yl)formamidine (HL1) and N-(2-pyrimidinyl)formamide (HL2) afforded dimolybdenum complexes of the types Mo₂(O₂CCH₃)(L1)₂(L2) (1) trans-Mo₂(L1)₂(L2)₂ (2) cis-Mo₂(L1)₂(L2)₂ (3) and Mo₂(L2)₄ (4). Their UV–Vis and NMR spectra have been recorded and their structures determined by X-ray crystallography. Complexes 2 and 3 establish the first pair of trans and cis forms of dimolybdenum complexes containing formamidinate ligands. The L1 ligands in 1–3 are bridged to the metal centers through two central amine nitrogen atoms, while the L2 ligands in 1–4 are bridged to the metal centers via one pyrimidyl nitrogen atom and the amine nitrogen atom. The Mo–Mo distances of complexes 1 [2.0951(17) Å], 2 [2.103(1) Å] and 3 [2.1017(3) Å], which contain both Mo?N and Mo?O axial interactions, are slightly longer than those of complex 4 [2.0826(12)–2.0866(10) Å] which has only Mo?O interactions.     

Quinoxalines. Part 12: Synthesis and structural study of 1-(thiazol-2-yl)-1H-pyrazolo[3,4-b]quinoxalines—the dehydrogenative cyclization with hydroxylamine hydrochloride

Starting with 2-acetylquinoxaline a novel class of heterocyclic compounds, the 1-(thiazol-2-yl)-1H-pyrazolo[3,4-b]quinoxalines 4, were prepared by following two different synthetic procedures: 2-acetylquinoxaline reacted with thiosemicarbazide to the thiosemicarbazones 1a which was (i) cyclized with α-halogeno ketones to the thiazoles 3. These compounds were dehydrogenated in acidic medium to the title compounds 4. (ii) The thiosemicarbazone 1a could be also dehydrogenated using NH₂OH·HCl to the thioamide 5a and these, finally, were cyclized with α-halogeno ketones to the title compounds 4. Only thiazole 3a was isolated, the other thiazoles 3 were dehydrogenated in a one-pot procedure. From the thioamide 5a also both the compounds 9, by reacting with dibromodiacetyl, and 10, by treatment with dimethyl acetylenedicarboxylate, were obtained. The analysis of both the ¹H and ¹³C NMR spectra was not straightforward but could be attained finally by employing the whole arsenal of 1D and 2D NMR spectroscopy.     

Rapid access to 3-(N-substituted)-aminoquinolin-2(1H)-ones using palladium-catalyzed C-N bond coupling reaction

A series of 3-(N-substituted)-aminoquinolin-2(1H)-ones have been synthesized by the palladium-catalyzed C-N coupling reaction starting from 3-bromoquinolin-2-(1H)-ones. Various nucleophiles including amines, amides, sulfonamides, carbamates and ureas have been used successfully. In all the cases, the reactions take place rapidly in 1,4-dioxane and proceed in good to excellent yield using palladium acetate as a catalyst, Xantphos as a ligand and Cs₂CO₃ as a base.     

Dimeric and polymeric silver(I) saccharinato complexes of two bis(pyridine) ligands: Synthesis,structural, spectroscopic,fluorescent and thermal properties

The reaction of silver(I) with 1,2-bis[1-(pyridin-2-yl)ethylidene]hydrazine (bpeh) and N,N-bis(pyridin-2-ylmethyl)amine (bpma) in the presence of Na(sac) (sac = saccharinate) yielded [Ag₂(sac)₂(bpeh)] (1) and [Ag(sac)(bpma)]_n (2) with conformational chirality. Both complexes have been characterized by elemental analysis, IR, thermal analysis and X-ray single crystal diffraction. Complex 1 displays a binuclear composition, in which each silver(I) ion is bound to one monodentate sac ligand and one of the bidentate pyridylimino groups of the bpeh ligand in a distorted trigonal coordination geometry. Complex 2 is a one-dimensional helical polymer, in which silver(I) centers are bridged by tridentate bpma ligands, and each silver(I) ion is coordinated in a distorted tetrahedral geometry by one monodentate sac ligand, a bidentate pyridylamine group of one bpma ligand, and a py group of another bpma ligand. Weak intermolecular C–H?O hydrogen bonds and C–H?π interactions lead to assembly of 1 and 2 into three-dimensional supramolecular frameworks. Spectral and thermal analysis data for 1 and 2 are in agreement with the crystal structures. In addition, both complexes in the solid state display intraligand π–π∗ fluorescence.     

N-[1-(Benzotriazol-1-yl)alkyl]amides from N-acyl-α-amino acids or N-alkylamides

A variety of N-(1-methoxyalkyl)amides react with benzotriazole in the presence of PPh₃·HBF₄ and organic bases (Hünig's base, DBU or DABCO) or solid-state-supported bases (SiO₂-Pip or IRA-67) in CHCl₃ to give N-[1-(benzotriazol-1-yl)alkyl]amides in good yields. The most convenient and efficient procedure for obtaining N-[1-(benzotriazol-1-yl)alkyl]amides consists, however, of the addition of benzotriazole sodium salt to a solution of crude 1-(N-acylamino)alkyltriphenylphosphonium salt, obtained in situ from N-(1-methoxyalkyl)amides and PPh₃·HBF₄. A combination of these reactions with the recently described electrochemical decarboxylative α-methoxylation of N-acyl-α-amino acids in the presence of SiO₂-Pip enables an effective two-pot transformation of N-acyl-α-amino acids to N-[1-(benzotriazol-1-yl)alkyl]amides.     

Structure of N,C,N-chelated organotin(IV) fluorides

The set of starting tri-, di- and monoorganotin(IV) halides containing N,C,N-chelating ligand (L^NCN = {1,3-[(CH₃)₂NCH₂]₂C₆H₃}⁻) has been prepared (1-5) and two compounds structurally characterized ([L^NCNPh₂Sn]⁺I₃⁻ (1c), L^NCNSnBr₃ (5)) in the solid state. These compounds were reacted with KF with 18-crown-6, NH₄F or L^CNnBu₂SnF to give derivatives containing fluorine atom(s). Triorganotin(IV) fluorides L^NCNMe₂SnF (2a) and L^NCNnBu₂SnF (3a) revealed monomeric structural arrangement with covalent Sn-F bond both in the coordinating and non-coordinating solvents, except the behaviour of 3a that was ionized in the methanol solution at low temperature. The products of fluorination of L^NCNSnPhCl₂ (4) and 5 were described by NMR in solution as the ionic hypervalent fluorostannates or the oligomeric species reacting with chloroform, methanol or moisture to zwitterionic monomeric stannate L^NCN(H)⁺SnF₄⁻ (5c), which was confirmed by XRD analysis in the solid state.     

Microwave-assisted guanidinylation in solid phase peptide synthesis: comparison of various reagents

The guanidinylation of a peptide chain on a polymeric support under microwave conditions using derivatives of thioureas—S-alkylisothioureas, pyrazole-carboxamidine, and guanidine as guanidinylating reagents is described. The best results are obtained with N,N′-di-Z-S-methylisothiourea and N,N′-di-Z(2-Cl)-S-methylisothiourea. It is found that guanidinylation with reagents containing Boc groups is accompanied by side reactions.     

Reaction of 1-vinylpyrrole-2-carbaldehydes with phosphorus pentachloride: a stereoselective synthesis of E-2-(2-dichloromethylpyrrol-1-yl)vinylphosphonyl dichlorides

1-Vinylpyrrole-2-carbaldehydes react with phosphorus pentachloride (benzene, 10-15 °C) to afford E-2-(2-dichloromethylpyrrol-1-yl)vinylphosphonium hexachlorophosphates in up to 85% yield, which after treatment with SO₂ (benzene, rt) are converted into E-2-(2-dichloromethylpyrrol-1-yl)vinylphosphonyl dichlorides in 50-75% yields.     

A sensitive fluorescence reagent for the determination of aldehydes from alcoholic beverage using high-performance liquid chromatography with fluorescence detection and mass spectrometric identification

A pre-column derivatization method for the sensitive determination of aldehydes using the tagging reagent 2-[2-(7H-dibenzo[a,g] carbazol-7-yl)-ethoxy] ethyl carbonylhydrazine (DBCEEC) followed by high-performance liquid chromatography with fluorescence detection and APCI-MS identification has been developed. The chromophore of fluoren-9-methoxy-carbonylhydrazine (Fmoc-hydrazine) reagent was replaced by 2-[2-(7H-dibenzo[a,g] carbazol-7-yl)-ethoxy] ethyl functional group, which resulted in a sensitive fluorescence tagging reagent DBCEEC. DBCEEC could easily and quickly labeled aldehydes. The maximum excitation (300 nm) and emission (400 nm) wavelengths did not essentially change for all the aldehyde derivatives. Derivatives were sufficiently stable to be efficiently analyzed by high-performance liquid chromatography. The derivatives showed an intense protonated molecular ion corresponding m/z [M + (CH₂)_n]⁺ in positive-ion mode (M: molecular weight of DBCEEC, n: corresponding aldehyde carbon atom numbers). The collision-induced dissociation of protonated molecular ion formed fragment ions at m/z 294.6, m/z 338.6 and m/z 356.5. Studies on derivatization demonstrated excellent derivative yields in the presence of trichloroacetic acid (TCA) catalyst. Maximal yields close to 100% were observed with a 10 to 15-fold molar reagent excess. Separation of the derivatized aldehydes had been optimized on ZORBAX Eclipse XDB-C₈ column with aqueous acetonitrile as mobile phase in conjunction with a binary gradient elution. Excellent linear responses were observed at the concentration range of 0.01-10 nmol mL⁻¹ with coefficients of >0.9991. Detection limits obtained by the analysis of a derivatized standard containing 0.01 nmol mL⁻¹ of each aldehyde, were from 0.2 to 1.78 nmol L⁻¹ (at a signal-to-noise ratio of 3).     

Synthesis of 1H-pyrrolo[3,2-c]quinoline derivatives via palladium-catalyzed heteroannulation of 2-aryl-3-iodo-4-(phenylamino)quinolines and 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinolines

Palladium(0)/copper iodide catalyzed Sonogashira cross-coupling of 2-aryl-3-iodo-4-(phenylamino)quinolines with terminal alkynes afforded series of 1,2,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines in a single-step operation. Conversely, the 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinoline derivatives were found to undergo PdCl₂(PPh₃)₂/CuI catalyzed intramolecular Heck reaction to yield the corresponding 1,3,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines.     

A new enlargement methodology for the preparation of 2H-1- and 2H-3-benzazepin-2-one derivatives

An investigation of the one-carbon homologation of some 1-tribromomethyl-isoquinoline and 2-tribromomethyl-quinoline derivatives was conducted. Under the influence of an aqueous solution of silver nitrate in the presence of a nucleophilic species (MeOH, H₂O, EtNH₂), these derivatives led to the respective expanded heterocycles, 2H-1- and 2H-3-benzazepin-2-one derivatives. A mechanism for this novel ring enlargement involving initial formation of an aziridinium, and its subsequent opening to form a stabilized benzylic carbocation, is proposed to explain the results.