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.     

Microwave-assisted solid-phase synthesis of phthalimides

[reaction: see text] A traceless solid-phase synthesis of substituted phthalimides is proposed. The target compounds are obtained within minutes by a microwave-assisted cyclative cleavage in good yields and excellent purities.     

Microwave-assisted solid-phase synthesis of peptoids

Microwave irradiation reduces the reaction time for the solid-phase synthesis of peptoids. Under these conditions, coupling of each residue requires only 1 min. The purity and yields of peptoids synthesized in this way are as good as or better than those achieved using standard methods. [reaction: see text]     

Microwave-assisted solid-phase synthesis of hydantoin derivatives

A microwave-assisted synthesis of 3,5- and 1,3,5-substituted hydantoins starting from various resins for solid-phase combinatorial chemistry has been developed. The hydantoins were synthesized from pre-loaded resins with amino acids via treatment with isocyanate or phenylisocyanate and subsequent intramolecular cyclization. Both reactions were performed under microwave irradiation. We studied the cyclative cleavage leading to hydantoin compounds dependent on the nature of the amino acid and the nucleofuge properties of the resin.     

Microwave-assisted solid-phase synthesis of 5-carboxamido-N-acetyltryptamine derivatives

[reaction: see text] The synthesis of the indole skeleton of new melatoninergic analogues was realized using solid-phase methodology in association with microwave irradiation. This combination speeds up the solid-phase drug discovery process in rigorously established conditions.     

Microwave-assisted, solid-phase synthesis of a chiral 1,2,3,4-tetrahydro-quinoline library

The synergy of a solution-phase preparation of scaffolds with a solid-phase combinatorial synthesis let to develop an efficient route to a small library of chiral, highly functionalized tetrahydroisoquinolines. Both loading on the Merrifield resin and the key acid-catalyzed Pictet-Spengler condensation were efficiently promoted by microwave irradiation. The library was designed such that up to five points of diversity would be potentially introduced, making the strategy in principle suitable for generation of a large number of compounds.     

含酰胺键的吡啶双子表面活性剂合成及性能

以间苯二甲酰氯、氨基吡啶、氯乙酰氯和长链伯胺(n为8、12、14、16)为原料,通过酰胺化反应合成了1,3-二[N-(3-吡啶基)]苯甲酰胺(中间体A)和N-烷基-2-氯乙酰胺(中间体B)。中间体A和中间体B通过季铵化反应,合成目标产物(I₈,I₁₂,I₁₄,I₁₆)。利用¹H-NMR、FTIR对产物及中间体结构进行表征。通过电导率法测定了目标产物在25℃、35℃、45℃的临界胶束浓度(CMC),进行热力学参数计算。用吊环法测定了25℃时目标产物的表面张力γ,计算了相关的表面性能参数。测定目标产物在25℃下的稳泡性及乳化能力。结果表明,合成表面活性剂具有良好的表面活性、稳泡性和乳化能力。     

Microwave-assisted solid-phase synthesis of 2,5-diketopiperazines: solvent and resin dependence

Solid-phase synthesis of diketopiperazines (DKPs) was preformed using various combinations of resins (polystyrene, TentaGel, ArgoGel, and PEGA) and solvents (toluene, tert-butyl alcohol, water, and toluene/2-butanol (1:4, v/v). The DKPs were synthesized from solid-phase bound dipeptides via intramolecular aminolysis. Both thermal and microwave-assisted solid-phase synthesis of DKPs gave high yields of products independently of resin and organic solvent used; however, only the PEGA resin resulted in high yields of DKPs in water independent of heating method. The short reaction times, high yields, and the possibility to run reactions in water when an appropriate resin is used makes the microwave-assisted solid-phase synthesis the method of choice. The method should be suitable for solid-phase synthesis of diketopiperazine-based libraries.     

Microwave-assisted solution- and solid-phase synthesis of 2-amino-4-arylpyrimidine derivatives

An efficient and rapid microwave-assisted solution-phase method for the synthesis of 2-amino-4-arylpyrimidine-5-carboxylic acid derivatives has been developed. The five-step linear protocol involves an initial Biginelli multicomponent reaction leading to dihydropyrimidine-2-thiones which are subsequently S-alkylated with methyl iodide. The resulting 2-methylthiodihydropyrimidines are sequentially oxidized first with manganese dioxide and then with Oxone to provide 2-methylsulfonyl-pyrimidines which serve as excellent precursors for the generation of a variety of 2-substituted pyrimidines via displacement of the reactive sulfonyl group with nitrogen, oxygen, sulfur, and carbon nucleophiles. A modified protocol using a solid-phase method has also been developed.     

Two dialkoxynaphthalene aldehydes as backbone amide linkers for solid-phase synthesis

Two new solid-phase handles for backbone amide anchoring based on regioisomeric dialkoxynaphthalene aldehydes (NALdehydes) were synthesized in five convenient steps from the corresponding commercially available dihydroxynaphthalenes. The two NALdehydes were coupled to an aminomethyl polystyrene support, the first monomer attached by efficient reductive amination, and the secondary amine acylated to form naphthalene amide linker (NAL-1 and NAL-2) anchoring. After on-resin synthesis, release of peptides was effected with TFA/H(2)O (95:5), TFA/DCM (50:50), or low TFA concentrations. The properties of the NAL handles were evaluated in the solid-phase synthesis of a series of peptides, in which NAL-2 showed the best cleavage properties.     

Microwave-assisted sequential amide bond formation and intramolecular amidation: a rapid entry to functionalized oxindoles

A general method has been developed for the synthesis of N-substituted oxindoles. The two-step process involves initial microwave-assisted amide bond formation between 2-halo-arylacetic acids and various alkylamines and anilines, followed by a palladium-catalyzed intramolecular amidation under aqueous conditions. In the case of alkylamines, the procedure can be carried out as a one-pot process without isolation of the intermediate amide. [structure: see text]     

Automated solid-phase synthesis of protected oligosaccharides containing beta-mannosidic linkages

For automated oligosaccharide synthesis to impact glycobiology, synthetic access to most carbohydrates has to become efficient and routine. Methods to install "difficult" glycosidic linkages have to be established and incorporated into the overall synthetic concept. Described here is the first automated solid-phase synthesis of oligosaccharides containing the challenging beta-mannosidic linkage. Carboxybenzyl mannoside building blocks proved effective beta-mannosylation agents and resulted in excellent conversion and good to moderate selectivities. [(Triisopropylsilyl)oxy]-methyl ether (Tom), served as an orthogonal, minimally intrusive, and readily cleavable protecting group for the elongation of the C3 position of mannose. The desired oligosaccharide products were readily separated from by-products containing unwanted stereoisomers using reverse-phase HPLC. The methods described here expand the scope of carbohydrates currently accessible by automation as many oligosaccharides of biological interest contain beta-mannosidic linkages.     

Control of enzyme hydration in penicillin amidase catalysed synthesis of amide bond

Penicillin amidase catalyses the synthesis of amide bond in very high yield (>98%), using equimolar concentrations of the amine and the phenylacetic components. In situ hydrated phosphates were employed for controlling the water activity in a benzene/water system (97:3 v/v), where the water is taken up by the salt with formation of the hydrated species.     

Simple synthesis of a terpenophenol—chlorin conjugate with an amide bond

A terpenophenol with a butylaminomethyl group was synthesized and conjugated to a chlorin macrocycle through formation of an amide bond without using activating reagents. __________ Translated from Khimiya Prirodnykh Soedinenii, No. 6, pp. 561–563, November–December, 2007.     

Efficient synthesis of a side-chain extended diaminodiacid for solid-phase synthesis of peptide disulfide bond mimics

Solid-phase incorporation of diaminodiacids is one of the most effective approaches for synthesis of peptide disulfide bond mimics. One of a limitation of current diaminodiacid toolbox is that only four-atom linkage mimics are available that may not fully meet the activity optimization requirement. In this work, we developed a new diaminodiacid that contains a five-atom thioether (C–C–S–C–C) bridge for the first time. With this diaminodiacid in hand, we successfully obtained oxytocin containing new disulfide bond mimic by solid phase peptide synthesis.     

Facile synthesis and cleavage of imidazolidines in a novel protection strategy for the preparation of peptides containing a reduced amide bioisostere

Unsymmetrical imidazolidines were obtained in 75-91% yield by treating monoalkoxycarbonyl vicinal diamines at room temperature with aqueous 37% formaldehyde in the presence of Montmorillonite KSF as a solid catalyst. The imidazolidines were shown to be useful intermediates in a novel protection strategy for the synthesis of peptide analogues containing a reduced glycine amide bioisostere. The imidazolidine intermediate was cleaved conveniently and efficiently by 50% TFA in methylene chloride.     

Microwave-assisted four-component reaction for the synthesis of a monothiohydantoin inhibitor of a fatty acid amide hydrolase

Monothiohydantoin 3a is made in seven steps from 1,4-diiodobenzene and is shown to be an inhibitor of fatty acid amide hydrolase (IC₅₀ = 23.4 ± 1.1 μM). The key step in the sequence involves a microwave-assisted four-component reaction that makes the 5,5′-disubstituted hydantoin nucleus by the sequential formation of two C-C and two C-N bonds.