An improved procedure for the preparation of aminomethyl polystyrene resin and its use in solid phase (peptide) synthesis

2-Aminoethanol was used to successively replace hydrazine in the preparation of aminomethyl polystyrene resin thereby facilitating purification and by-product removal. The syntheses of the polypeptides ACP (65-74) and oxytocin demonstrated that the use of aminomethyl polystyrene resin prepared in this manner was equal to or better than that prepared using the hydrazine method.     

Solid-phase synthesis of lipidated peptides

A new flexible and efficient methodology for the solid-phase synthesis of lipidated peptides has been developed. The approach is based on the use of previously synthesized building blocks and overcomes the limitations of previously reported methods, since long doubly lipidated peptides can be synthesized by using this route. Furthermore, it was thus possible to prepare a large number of N- and H-Ras peptides bearing a wide range of reporter and/or linking groups--efficient tools for the investigation of biological processes. In terms of efficiency and flexibility this solid-phase method is superior to the solution-phase synthesis. It gives pure peptides in multimilligram amounts within a much shorter time and with superior overall yield.     

Efficient and direct solid phase synthesis of ketomethylenimino and ketomethylenamino peptides

The aim of this study is the synthesis of pseudopeptides on solid supports, in order to quickly obtain modified peptides. We report a convenient step-by-step synthesis of ketomethylenimino ψ[CO-CHN] and ketomethylenamino ψ[CO-CH₂-NH] peptides. The key is the reaction between the free amino terminus of the supported peptide and a glyoxal-modified amino acid, leading to a ketomethylenimino bond, which can be reduced to a ketomethylenamino bond.     

Hot or not—the influence of elevated temperature and microwave irradiation on the solid phase synthesis of an affibody

Despite the advances of solid phase peptide synthesis (SPPS) the synthesis of long peptides is still challenging. Microwave irradiation and conventional heating are considered to improve the efficiency of SPPS. It has been shown that conventional heating and heating by microwave irradiation improves the efficiency of solid phase synthesis of peptides that are prone to aggregation as compared to the synthesis at room temperature. In this Letter, the influence of elevated temperature and microwave irradiation on the homogeneity of the synthesis product of a 58-mer peptide affibody has been compared. A detailed analysis by high resolution HPLC and LC-MS mass spectrometry using a high-mass resolution Orbitrap Exactive mass spectrometer was performed. This study revealed that neither thermal heating nor microwave heating improves the yield and purity of the crude product as compared to the synthesis at room temperature. In contrast, the formation of undesirable side products rather increased by microwave irradiation. These results indicate that neither heating nor microwave enhancement of solid phase synthesis does allow a significant improvement of peptide sequences with a low aggregation potential.     

A traceless solid phase synthesis of thiomorpholin-3-ones

A novel synthesis of thiomorpholin-3-ones using a traceless solid phase approach is described, in which many kinds of thiomorpholin-3-ones were efficiently obtained in high purity based on an intramolecular alkylation of sulfides followed by an elimination of desired thiomorpholin-3-ones from the generated sulfonium salts.     

Application of microwave method to the solid phase synthesis of pseudopeptides containing ester bond

A new procedure was developed for reducing the reaction time and improving the yield of esterification reaction in solid phase synthesis of pseudopeptides containing an ester bond by utilizing microwave irradiation. We selected a pseudodipeptide (Fmoc-LysΨ[COO]Leu-NH₂) and optimized the microwave-assisted esterification reaction in solid phase synthesis using Fmoc chemistry. For this, microwave-assisted esterification reactions with different reaction time, temperature, and solvents were performed using 1,3-diisopropylcarbodiimide (DIC) as the coupling reagent. We synthesized several pseudodipeptides containing an ester bond by using the optimized microwave irradiation method. The purity and yield of the pseudodipeptides synthesized in this way were better than those obtained without microwave irradiation. Furthermore, we applied this methodology for synthesizing pseudopeptides (6- and 12-mer) corresponding to the α helical peptide. The microwave-assisted esterification reaction afforded the target pseudopeptides with high yield (∼80%) and purity within 12 min, whereas the reaction without microwave irradiation afforded the target compound with poor yield (∼45%) and low purity.     

Cystine mimetics--solid phase lanthionine synthesis

The total solid phase synthesis of an analogue of the B ring of nisin was achieved, in a biomimetic fashion, via the solid phase diastereoselective cyclisation of a dehydrothiol-containing peptide.     

Stepwise solid phase synthesis of uridylylated viral genome-linked peptides using uridylylated amino acid building blocks

The uridylylated amino acid building blocks 2-cyanoethyl-(N^α-9-fluorenylmethoxy-carbonyl-tyrosin-4-yl)-(2′,3′-di-O-acetyluridin-5′-yl) phosphate and 2-chlorophenyl-(N^α-fluorenyl-methoxycarbonyl-serin-3-yl)-(2′,3′-di-O-acetyluridin-5′-yl) phosphate have been used successfully in an on-line SPPS of the VPgpU from the polio, coxsackie and cowpea mosaic virus.     

Aromatic homolytic substitution using solid phase synthesis

Solid phase synthesis has been used to carry out intramolecular aromatic homolytic substitution with benzoimidazole precursors. The protocol attaches the radical precursors to the resins via the radical leaving groups (in the aromatic homolytic substitution). When the radical reactions are complete, the leaving group, unaltered starting material and reduced uncylised products remain attached to the resin, which facilitates easy separation of the cyclised products. Novel use of focussed microwave irradiation in solid phase radical reactions drastically shortens the reactions times. Tributylgermanium hydride has been used to replace the toxic and troublesome tributyltin hydride in the radical reactions.     

A convenient one-pot preparation and applications of high loading benzhydrylamine solid phase linkers

A rapid and convenient one-pot route to solid supported benzhydrylamine linkers with high chemical loading is described. Such linkers possess differing levels of acid lability, which could be exploited in solid phase synthesis applications. They have also been utilised to prepare novel and potentially useful N-methylated derivatives. We also report an effective on-resin purification strategy for reductive amination, which is facilitated by the varying acid lability of resin-linked secondary amines or tertiary amine by-products.     

Tricine as a convenient scaffold for the synthesis of C-terminally branched collagen-model peptides

A novel and convenient method for the synthesis of C-terminally branched collagen-model peptides has been achieved using tricine (N-[tris(hydroxymethyl)methyl]glycine) as a branching scaffold and 1,2-diaminoethane or 1,4-diaminobutane as a linker. The peptide sequence was incorporated directly onto the linker and scaffold during solid-phase synthesis without additional manipulations. The resulting branched triple-helical peptides exhibited comparable thermal stabilities to the parent, unbranched sequence, and served as substrates for matrix metalloproteinase-1 (MMP-1). The tricine-based branch reported herein represents the simplest synthetic scaffold for the convenient synthesis of covalently linked homomeric collagen-model triple-helical peptides.     

Transfer allyl esters to thioesters in solid phase condition: synthesis of peptide thioesters by Fmoc chemistry

A method to transfer allyl esters to thioesters under a solid phase condition has been developed to synthesize peptide thioesters. A Fmoc chemistry has been applied to synthesize the peptide allyl esters, which are selectively transferred to the expected peptide thioesters under solid phase synthesis conditions successfully.     

One pot solid phase synthesis of 2-substituted 2,3-dihydropyridin-4(1H)-ones on Rinkamide-resin

A novel solid phase synthesis of 2-substituted 2,3-dihydropyridin-4(1H)-ones using Rinkamide-polystyrene-resin is described. The key step involves a hetero-Diels-Alder reaction of Danishefsky's diene with solid phase bound imines, which was carefully optimized. Using this method even ketones are transformed into 2,2-disubstituted dihydropyridones.     

Facile solid phase synthesis of 1,2-disubstituted-6-nitro-1,4-dihydroquinazolines using a tetrafunctional scaffold

Solid phase synthesis of 1, 2-disubstituted-6-nitro-1,4-dihydroquinazolines is described. The new tetrafunctional scaffold N-Alloc-3-amino-3-(2-fluoro-5-nitrophenyl)propionic acid was prepared by nitration of 3-amino-3-(2-fluorophenyl)propionic acid. The scaffold was anchored to Rink resin via its carboxylic group and treated with primary amines to displace the arylfluorine followed by cyclization with aryl isothiocyanates in the presence of DIC upon Alloc deprotection to afford 1,2-disubstituted-6-nitro-1,4-dihydroquinazolines in high yield.     

Review: Sample preparation of catecholamines and biologically active peptides by solid phase extraction

This paper reviews solid phase extraction as applied to the sample preparation of catecholamines and biologically active peptides. The mechanisms used in solidphase extraction are: non-polar, polar, ion-exchange, and covalent.     

A convenient synthesis of new chromophoric tetracyanobutadiene-scaffolded peptides via a dipolar [2+2] cycloaddition-cycloreversion reaction

Herein, we report a novel approach for the synthesis of π-conjugated peptide-based donor-acceptor (D-π-A) chromophores, by reacting electron-rich alkynes with tetracyanoethylene. The desired tetracyanobutadiene-scaffolded peptides were obtained in good yields with various optical properties, λ_max: 321-492 nm, ε: 21,000-65,000 mol⁻¹ dm³ cm⁻¹ depending on the substitution pattern of the cyanobutadiene scaffold.     

One-pot solid phase synthesis of (E)-nitroalkenes

An efficient one-pot protocol for the synthesis of (E)-nitroalkenes by reaction of aldehydes and nitroalkanes in the presence of polymer-bound triphenylphosphine, iodine and imidazole is described. Although the reaction works with similar efficiency with triphenylphosphine and its polymer-bound version, easy removal of the unwanted polymer-bound triphenylphosphine oxide and its recovery as triphenylphosphine provide the edge for practical application of the method.     

An efficient protocol for solid phase aminothiazole synthesis

An efficient synthesis of 2,4-diamino-5-ketothiazoles under solid phase conditions has been achieved by the reaction of polymer supported amidinothioureas with α-haloketones. This novel synthetic approach involving traceless cleavage from the support is suited for automation, and allows solid phase combinatorial synthesis of 2,4-diamino-5-ketothiazoles in good yields and purities.     

Solid phase synthesis of mono- or disubstituted arginine containing peptides from an isothiocitrulline precursor

A method for the solid phase synthesis of substituted arginine containing peptides starting from an isothiocitrulline precursor is described. In this procedure, a peptide containing one or more protected ornithine residue(s) was assembled on a solid support. Following selective deprotection, ornithine residue(s) was (were) converted into S-methyl-isothiocitrulline in three steps. Subsequent reaction with primary or secondary amines afforded mono and disubstituted arginine-containing derivatives, respectively. Using lysine instead of ornithine afforded substituted homoarginine-containing derivatives.     

A faster solid phase peptide synthesis method using ultrasonic agitation

Solid phase-supported synthesis is a widely used strategy in peptide chemistry. A factor which limits the product purity is the individual stages yields. Here, we reported that the use of ultrasonic agitation allows to reduce tenfold the time of synthesis in the Fmoc strategy and improve the purity of the final product. Our method is a promising alternative to traditional synthetic methods and microwave synthesizers.