Investigation for the cyclization efficiency of linear tetrapeptides: Synthesis of tentoxin B and dihydrotentoxin

Investigation of the cyclization efficiency of N-methyl linear tetrapeptides using a molecular modeling study and chemical synthesis is described. The linear peptide with two N-methyl groups, MeAla-Leu-MePhe-Gly, forms γ-turn like conformation with the amine at N-terminus and the carbonyl at C-terminus in closer proximity to give the desired cyclic tetrapeptide, dihydrotentoxin. In addition, synthesis of tentoxin B by the combination of Fmoc solid-phase peptide synthesis and cyclization in solution phase has been reported. An unusual amino acid, an L-N-methyl-β-hydroxyphenylalanine derivative, which was assembled on solid support, was prepared from ethyl cinnamate. Cyclic tetrapeptide formation and cleavage of benzyl ether were optimized with DIPCI/HOBt/DIPEA and Et₃SiH/Pd(OH)₂, respectively.     

Pyrolysis studies on polyalkylene phthalates

The synthesis and identification of pyrolysis products of five polyalkylene phthalates are reported. The pyrolysis products are separated in a capillary gas chromatograph and the products are identified using a mass selective detector. The major degradation products for the polyesters now investigated are phthalic anhydride and the appropriate diol. In nearly all the polyesters studied, cyclic ether from the diol and the cyclic diester formed from phthalic anhydride and the diol are detected. A wide variety of low molecular weight compounds and considerable quantities of complex mono- and diesters of phthalic acid are identified among the pyrolysis products. The mode of formation of the products identified by GC/MS analysis are discussed with reference to the general polyester degradation mechanism.     

Microcystin-LR and chemically degraded microcystin-LR electrochemical oxidation

Microcystins (MCs) are cyclic hepatotoxic heptapeptides produced by certain strains of freshwater cyanobacteria toxic for humans and animals. The electrochemical behaviour of microcystin-LR (MC-LR) at a glassy carbon electrode (GCE) was investigated using cyclic voltammetry (CV), square wave voltammetry (SWV) and differential pulse voltammetry (DPV). The oxidation of MC-LR is a diffusion-controlled irreversible and pH-independent process that occurs with the transfer of only one electron and does not involve the formation of any electroactive oxidation product. Upon incubation in different pH electrolytes, homogeneous degradation of MC-LR in solution was electrochemically detected by the appearance of a new oxidation peak at a lower potential. The electrochemical behaviour of chemically degraded MC-LR is an irreversible, pH-dependent process, and involves the formation of two redox products that undergo reversible oxidation. The formation of degradation products of MC-LR was confirmed by HPLC with UV detection at room temperature. Experiments were also carried out in solutions containing constituent MC-LR amino acids, which enabled the understanding of the MC-LR electron transfer reaction and degradation. An oxidation mechanism for MC-LR is proposed.     

Synthesis of cyclo-PLAI using a combination of solid- and solution-phase methods

Cyclo-PLAI was successfully synthesized using a combination of solid- and solution-phase methods. This current synthesis was found to be faster than the previously reported synthesis for the cyclic peptide. The linear precursor was synthesized on 2-chlorotrityl resin with Fmoc/t-Bu strategy. HATU/HOAt was employed as the coupling reagent in the amide bond formation on the resin. Cyclization of the linear precursor was experimented with HATU/HOAt reagents with different conditions. However, the linear precursor was best cyclized using HATU reagent in DIPEA by stirring the reaction mixture at 0?°C for 1?h and followed by stirring the reaction mixture at room temperature for 30?min, giving the cyclic product in 70% yield (calculated from the linear peptide). Both linear and cyclic products were characterized using HR-TOF-ESMS, ¹H-NMR, ¹³C-NMR, and compared with previously reported spectral data for the cyclic product.     

Design of a stabilized short helical peptide and its application to catalytic enantioselective epoxidation of (E)-chalcone

Stabilized short helical heptapeptides containing a combination of an α-aminoisobutyric acid as a helical promoter and l/d-serine derivatives to produce cross-linked units were synthesized. The cyclic peptide R₃,₇R-2, which had d-serine derivatives at its 3rd and 7th positions, formed a stable right-handed (P) α-helix in solution and the crystalline state. Furthermore, its N-terminal free helical peptide catalyzed the enantioselective epoxidation of (E)-chalcone to afford the epoxide in a high yield and moderate enantioselectivity.     

Euryjanicins E–G,poly-phenylalanine,and poly-proline cyclic heptapeptides from the Caribbean sponge Prosuberites laughlini

A new investigation of the active sponge extracts of Prosuberites laughlini collected off the West coast of Puerto Rico has yielded three new cyclic heptapeptides, namely euryjanicins E (1)–G (3), containing multiple phenylalanine and proline residues. In CDCl₃ solution, each euryjanicin F (2) and G (3) exists as an inseparable complex mixture of conformational isomers. The molecular structures of 1–3 were elucidated by a combination of chemical degradation, extensive ESI-MS/MSⁿ analyses, and 2D NMR methods. The elucidation of the absolute configuration was achieved by HPLC following analysis of the acid hydrolysates after derivatization with Marfey's reagent. When assayed against the National Cancer Institute 60 tumor cell line panel, the new cyclic peptides did not display significant in vitro cytotoxicity.     

Efficient photochemical synthesis of tricyclic keto‐indoles

Tricyclic keto‐indoles were synthesized by photocyclization of easily obtained enaminones in an electro‐cyclic photochemical reaction. The three methods reported were chosen according to the enaminone structure. The most general procedure using one‐step synthesis was carried out in a benzene‐methanol solution in the presence of sodium methylate. In the case of base sensitive substrates, the best method was photocyclization followed by oxidation. Besides, N‐unsubstituted indoles with a five‐membered ring were prepared by a photolysis reaction. All three methods are efficient and easy to perform.     

Enzymatic synthesis and characterization of a water-soluble, conducting poly(o-toluidine)

An enzymatic method for the synthesis of a water-soluble, conducting poly(o-toluidine) (POT) in the presence of sulfonated polystyrene (SPS) is presented. The enzyme horseradish peroxidase was used to polymerize o-toluidine to form a water-soluble, conducting POT/SPS complex, which exhibits moderate electrical conductivity. The synthesis is simple and the conditions are mild. The polymerization may be carried out at room temperature in pH 4.3 buffered aqueous solution with stoichiometric amount of monomer, SPS, hydrogen peroxide and catalytic amount of enzyme. The UV-Vis absorption spectra of the products display a distinct absorption peak at 740 nm at pH 4.3 that indicates the formation of the conducting, emeraldine salt form of POT. The structure and electrochemical behavior of the polymer was investigated with FT-IR and cyclic voltammetry method.     

First total synthesis of the β-carboline alkaloids trigonostemine A,trigonostemine B and a new synthesis of pityriacitrin and hyrtiosulawesine

The total synthesis of four natural products, trigonostemine A, trigonostemine B, pityriacitrin, and hyrtiosulawesine was accomplished. The key intermediates, variously substituted 1-formyl-β-carbolines, were prepared in five steps via a novel synthetic approach using readily available starting materials. These formyl derivatives were then further transformed, providing a general route for the synthesis of the four title alkaloids. The method reported herein represents the first total synthesis of the two trigonostemines and a new pathway to pityriacitrin and hyrtiosulawesine.     

Cyclic Heptapeptides Axinastatin 2, 3, and 4: Conformational analysis and evaluation of the biological potential

The conformational analysis of naturally occurring cytostatic cyclic heptapeptides axinastatin 2, 3, and 4 was carried out by two-dimensional NMR spectroscopy in combination with distance-geometry (DG) and molecular-dynamics (MD) calculations in explicit solvents. The synthesized secondary metabolites were examined in (D₆)DMSO. Axinastatin 2 was also investigated in CD₃OH. In all structures, Pro² is in the i + 1 position of a βI turn and Pro⁶ occupies the i + 2 position of a βVIa turn about the cis amide bond between residue 5 and Pro^6. In all peptides, a bifurcated H-bond occurs between residue 4 CO and the amide protons of residue 1 and 7. For axinastatin 2 and 3, an Asn I_g turn was found about Asn¹ and Pro^2. We compared these structures with conformations of cyclic heptapeptides obtained by X-ray and NMR studies. A β-bulge motif with two β turns and one bifurcated H-bond is found as the dominating backbone conformation of cyclic all-L-heptapeptides. Axinastatin 2, 3, and 4 can be characterized by six trans and one cis amide bond resulting in a β/βVI(a)-turn motif, a conformation found for many cyclic heptapeptides. Detailed biological tests of the synthetic compounds in different human cancer cell lines indicates these axinastatins to be inactive or of low activity.     

Facile solid-phase synthesis of cyclic decapeptide antibiotic streptocidins A-D

Total synthesis of decapeptide antibiotics streptocidins A-D from Streptomyces sp. Tü 6071 was accomplished for the first time by solid-phase peptide synthesis followed by traceless cyclization of the activated linear precursors, without protection of nucleophilic side chain. Synthetic products were equally active as the natural products isolated from the bacterial source and found to possess similar bacterial selectivity as other members in the amphipathic antimicrobial cyclic decapeptide family.     

Synthesis, structural aspects and cytotoxicity of the natural cyclopeptides yunnanins A, C and phakellistatins 1, 10

Yunnanins A and C, two cyclic heptapeptides occurring in the roots of Stellaria yunnanensis, and phakellistatins 1 and 10, a hepta- and an octacyclopeptide first isolated from marine sponges of the genus Phakellia, were efficiently synthesized using a combination of solid and solution-phase techniques. Structural analysis on the synthetic members of the yunnanin series showed that the synthetic sample of yunnanin A exhibited a configurational pattern at the Pro peptide linkages identical to the natural product (trans-Pro³, trans-Pro⁵), while yunnanin C was obtained as a complex mixture of geometric/conformational isomers; the major isomer (trans-Pro³) was indistinguishable from the natural cyclopeptide and co-occurred along with lower amounts of a mixture (1:1 ratio) of two different rotamers, both displaying cis geometry at the Pro³ linkage. In the phakellistatin series, the synthetic phakellistatin 1 (determined as cis-Pro¹, cis-Pro³, cis-Pro⁵) was identical to the natural one, while two different isomeric products of phakellistatin 10 could be obtained: a major one (trans-Pro¹, trans-Pro⁴, trans-Pro⁶) showing spectral properties superimposable with the natural metabolite, and a minor geometric isomer of the natural cyclopeptide. Interestingly, the synthetic cyclopeptides, although found to be chemically identical with their natural counterparts, did not display the same biological properties (in vitro cytotoxicity against a panel of cancer cell lines), leaving presently open the question whether or not the potent bioactivity reported in the literature should really be attributed to these natural cyclic peptides.     

Total synthesis of violaceimides A–E and consideration of the reported stereochemistry

Here we report the first total synthesis of violaceimides A–E, a family of sulfur-containing metabolites from Aspergillus violaceus, a sponge-associated fungus. A concise, convergent and enantioselective synthesis was developed for all five family members, from a common advanced intermediate. However, while the NMR spectral data matched that of the reported natural products, the optical rotations were of opposite sign. This result prompted the enantioselective synthesis of all four diastereomeric pairs of violaceimide E, and suggests that the stereochemistry might have been misassigned.     

Synthesis and NMR investigation of cyclic pentapeptide analogues of thymopentin

The synthesis of two cyclic pentapeptides cyclo (-Arg-Lys-Xxx-D-Val-Tyr-) (Xxx=Asp or Glu) with thymopentin-analogue sequences is described. Cyclization was achieved by the carbodiimide/DMAP method. The results of the NMR investigations performed on the protected pentapeptides suggest a βII′/γ-structure in DMSO solution.     

Facile approach to diverse range of 1,3-diaza-heterocycles: angular/linear selectivity paradigm and a remarkable intramolecular methyl migration

Starting from cyclic anhydrides and tert-butyl 2-aminobenzylcarbamate, simple and efficient synthesis of diverse range of kinetically controlled angular and thermodynamically controlled linear tricyclic and tetracyclic 1,3-diaza-heterocycles have been described via the intramolecular cyclizations of the corresponding imides/anilic acid esters. The effect of imide stability on the angular/linear product selectivity has also been described. The kinetically controlled angular products were successfully transformed to the corresponding thermodynamically controlled linear products by refluxing in methanol or methanol and acetic acid mixture. An interesting in situ 1,2-intramolecular methyl group migration has also been described.     

Synthesis of cyclic peptides via O-N-acyl migration

We describe here a novel and convenient synthesis of head-to-tail cyclic peptide avoiding racemization. Linear depsipeptides including a serine residue as the key element for ester bond formation and acyl transfer were synthesized on 2-chlorotrityl chloride resin. After cleavage from the resin, intramolecular head-to-tail cyclization was performed in solution by C-terminal activation of urethane protected O-acyl serine residue. After removal of the N^α-serine protecting group, the final step consisted in O-N-acyl migration reaction on the ‘switch’ or ‘click’ element to restore native cyclic peptides.     

Recent advances of Pd-π-allyl zwitterions in cycloaddition reactions

Palladium-catalyzed cycloaddition reactions via Pd-π-allyl zwitterions have been established as significant synthetic transformations to enable numerous carbon- or heterocycles compounds that are key constituents of various biologically active natural products and pharmaceuticals. In addition to the well-known Pd-π-allyl zwitterions, including palladium-trimethylenemethane and Pd-1,3/1,4-zwitterions, chemists have recently discovered new applications of several long ago reported but less-studied Pd-π-allyl zwitterions, which can straightforwardly and efficiently construct novel cyclic architectures. Meanwhile, some impressive newly designed zwitterions have been also developed. Those zwitterions are diverse and can serve as transient and highly reactive intermediates for the subsequent cyclization with various acceptors. In this review, we highlight recent advances in applications of these two types of zwitterions in the synthesis of complex polycyclics and medium-sized cyclic compounds.     

Modelling of prebiotic synthesis and selection of peptides under isothermal conditions and thermal cycling mode

The model peptide synthesis from mixtures of amino acids was carried out under the thermal cycling and isothermal modes. The compositions of the obtained mixtures of products and the primary amino acid sequence of the synthesized peptides were determined by Fourier transform ion cyclotron resonance mass spectrometry and tandem mass spectrometry in combination with high-performance liquid chromatography with the application of de novo sequencing of the synthesized products. The processes of abiogenous synthesis of peptides were shown to occur under relatively mild temperature conditions and give a substantially less number of peptides as compared with the possible statistical set. The evolution of the system takes place in the process of the synthesis in solid phase with the disappearance of a series of the most unstable peptides. The selection process with the formation of complementary peptides takes place in peptide synthesis under the thermal cyclic mode.     

Synthesis of aromatic trifluoromethyl compounds by ring expansion of cyclodienes

Chlorotrifluoromethyl-1-diazirine was used for a source of chlorotrifluoromethyl carbene. The carbene added to cyclic dienes to give trifluoromethylated six-membered aromatic compounds. Thus, pyrrole gave 3-(trifluoromethyl)pyridine and cyclopentadiene gave benzotrifluoride.In the course of out research to develop a new synthetic method for aromatic trifluoromethyl compounds [1], we planned to use the reaction of chlorotrifluoromethyl carbene (1) with a five-membered cyclic diene. The reaction of pyrrole with dichlorocarbene was reported to give 3-chloropyridine [2]. Therefore, we expected that the similar type of reaction of 1 with a five-membered cyclic diene would provide a new method for the syntheses of aromatic trifluoromethyl compounds. We chose chlorotrifluoromethyl-1-diazirine (2) [3] as the precursor of 1.First, we examined the reaction of 2 with cyclohexene to learn the reactivity of 1. Heating the solution of 2 in cyclohexene at 120° for 3 h gave two adducts (3 and 4). Both products were separated by the preparative g.l.c. using a DEGS column of 7 m at 60°C. 3: 36%; m/e 198 (M⁺); ¹H-NMR δ(CDCl₃) 0.88?2.60 (m); ¹⁹F-NMR δ [4] 10.2. 4: 10% m/e 198; ¹H-NMR δ(CDCl₃) 0.80?2.60; ¹⁹F-NMR δ ?1.2. Compound 3 reacted with silver trifluoroacetate to give 2-(trifluoromethyl)cyclohepten-3-yl trifluoroacetate, while 4 did not. This result established the Stereochemistry of both products as shown in Chart 1. This reaction showed that 2 was a good precursor of 1 and that 1 had a high reactivity to a double bond.To utilized this reaction for the synthesis of an aromatic trifluoromethyl compound, thermolysis of 2 with five-membered cyclic dienes was investigated. A solution of 2 (230 mg) in pyrrole (500 mg) was sealed in a Pyrex tube under vacuum and heated at 120°C for 2 h. The reaction mixture was purified by a trap-to-trap distillation. Analysis of the distillate by g.l.c. showed that 3-(trifluoromethyl)pyridine (5) was obtained in 35% yield based on 2. The g.l.c-mass spectrum and ¹⁹F-NMR of 5 were identical with those of the authentic sample [5]. Similar thermolysis and work-up of a solution of 2 (160 mg) in cyclopentadiene (550 mg) at 140°C for 3 h gave benzotrifluoride in 23% yield. All the results are summarized in Chart 1.The characteristic point of this procedure is that a trifluoromethyl group was introduced to a five membered ring with one carbon atom under ring expansion. Yields shown above were not optimized and this method can be used for synthesis of some aromatic trifluoromethyl compounds, which are difficult to synthesize by the usual methods.     

Cobalt boron nitride: A novel heterogeneous catalyst for the synthesis of medicinally important α-amino quinoline phosphonates

A novel cobalt supported on boron nitride (CoBNT) heterogeneous catalyst for the synthesis of α-amino quinoline phosphonates (AQPs) is reported in the present work. The CoBNT was synthesised by simply mixing boron nitride in a solution of cobalt acetate, under an inert atmosphere for 7 d followed by filtration; the yield was 94%. It exhibited excellent catalytic properties for the synthesis of 16 novel AQPs in a one pot mixture containing 2-methoxy 3-formyl quinoline, aniline derivatives and diethyl phosphite. Reactions were rapid, products were easily worked-up and were obtained in more than 90% yield. The CoBNT also exhibited higher catalytic activity than conventional catalysts and was re-used five times without significant decrease in catalytic activity.