Application of an automated synthesis suite to parallel solution-phase peptide synthesis

An in-house developed automated synthesis suite was used to prepare a library of 72 tetrapeptide derivatives, the starting materials for pharmaceutically attractive pentapeptides, employing a convergent strategy. An initial set of 18 dipeptides were synthesized on a large-scale (100-1000 g) using automated synthesis workstations, and then 72 tetrapeptides were synthesized on a medium scale (5-10 g) using an automated system. Each di- or tetrapeptide was prepared in a single operating cycle using a modified methanesulfonic acid method, then a sub-library of 56 pentapeptides were synthesized in parallel, on a small-scale (100 mg-1 g) using a robotic workstation.     

Synthesis of di- and trisubstituted 1,2,4-triazoles containing indole fragments

The reaction of imino esters of indole-series acids with acid hydrazides gave N₍₁₎-acylamidrazones, which, during heating, were converted to 3,5-disubstituted 1H-1,2,4-triazoles containing indole fragments. Compounds of this type were also synthesized by the reaction of indolyl-containing 2,5-disubstituted 1,3,4-oxadiazoles with formamide. Condensation of 2,5-disubstituted 1,3,4-oxadiazoles with aniline gave 3,4,5-trisubstituted 4H-1,2,4-triazoles containing indolyl radicals. Cyclocondensation of N₍₁₎-phenylamidrazones of indole-series acids with benzoyl chloride gave 1,3,5-trisubstituted 1H-1,2,4-triazoles.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 189–196, February, 1993.     

The synthesis of 4-vinyl-1,2,4-triazoles

The reaction of 1,2,4-triazole and 5-methyl-1,2,4-triazole with acetylene gives 4-vinyl derivatives. 1,2,4-Triazole-3-thione and its 5-methyl derivative gives N⁴,S-divinyl monomers.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 4, pp. 928–931, April, 1990.     

Solid-phase synthesis of 3-alkylamino-1,2,4-triazoles

[reaction: see text] A solid-phase synthesis of trisubstituted 3-alkylamino-1,2,4-triazoles has been developed. The synthesis utilizes immobilized N-acyl-1H-benzotriazole-1-carboximidamides as key intermediates. Cyclization with hydrazines under mild conditions furnishes the title compounds with regioselectivity and high purity.     

Solid-phase synthesis of 3-amino-1,2,4-triazoles

A solid-phase synthesis of 3-amino-1,2,4-triazoles is described. Reaction of resin bound S-methylisothiourea 2 with carboxylic acids yielded resin-bound S-methyl-N-acylisothioureas 3, which reacted with hydrazines under mild conditions to afford the corresponding resin-bound 3-amino-1,2,4-triazoles 4 with regioselectivity. Following cleavage, the desired products 5 were obtained in good yields and purities.     

Fluorous electrophilic scavengers for solution-phase parallel synthesis

A fluorous isatoic anhydride and isocyanate are synthesized and used as scavengers for amines in solution-phase parallel synthesis of urea, thiourea, and β-hydroxyamine analogs. The resulting fluorous derivatives are readily separated from the reaction mixture by solid-phase extractions (SPE) over FluoroFlash™ cartridges to give products with good purity. The SPE cartridges can be reused.     

Rapid parallel synthesis of combinatorial libraries of substituted 3-thio-1,2,4-triazoles and 2-thioimidazoles

Combinatorial libraries of substituted 3-thio-1,2,4-triazoles and 2-thioimidazoles were synthesized in good yield by alkylation of the products via the reaction of isothiocyanates and carboxylic acid hydrazides or beta-aminoketones, respectively. A total of 275 3-thio-1,2,4-triazoles and 283 2-thioimidazoles were synthesized out of the attempted 288 in each case. Most the yields were between 45% and 98%, and all the compounds synthesized were purified to >85% purity. Variations in yields revealed no definitive trends and were mainly attributed to bulky alkylating agents used and the plate well location of the reaction mixtures.     

Combinatorial synthesis of 3,5-dimethylene substituted 1,2,4-triazoles

Combinatorial cyclizations of imidates and hydrazides with methylene linked R groups, generated from the corresponding nitriles and carboxylic acids, respectively, provided a large library of 3,5-dimethylene substituted 1,2,4-trizoles. [formula: see text].     

A convenient synthesis of 3,5-disubstituted-1,2,4-triazoles

The condensation of an acyl hydrazide and an amidine to afford an acylamidrazone, followed by thermal cyclization, provides a convenient method for preparing 3,5-disubstituted-1,2,4-triazoles in high yields.     

Plate-to-plate fluorous solid-phase extraction for solution-phase parallel synthesis

A commercially available Argonaut VacMaster-96 plate-to-plate solid-phase extraction (SPE) station equipped with 24 FluoroFlash cartridges is employed for parallel purification of fluorous reaction mixtures. Each cartridge charged with 3 g of fluorous silica gel has the capability to produce up to 100 mg of purified small molecules. The 24-well receiving plate has a standard footprint that can be directly concentrated in a Genevac vacuum centrifuge. Important issues such as sample loading, product cross-contamination, cartridge reuse, and reproducibility are investigated. The SPE system has been demonstrated in the purification of three small libraries that were produced involving amine scavenging reactions with fluorous isatoic anhydride, amide coupling reactions with 2-chloro-4,6-bis[(perfluorohexyl)propyloxy]-1,3,5-triazine (fluorous CDMT), and amide coupling reactions with a newly developed fluorous Mukaiyama condensation reagent.     

Iron carbonyl-mediated parallel solution-phase synthesis of cyclohexadienoic acid amides

Iron carbonyl-stabilized cations have been employed to develop methodology for carbon-carbon and carbon-heteroatom formation suitable for the preparation of combinatorial libraries. Different nucleophiles were added to tricarbonyl(cyclohexa-1,3-dienylcarboxylic acid 4-nitro-phenyl ester)iron hexafluorophosphate. Aminolysis, followed by decomplexation, yielded substituted cyclohexadienyl amides of high purity. Carbon, oxygen, and sulfur nucleophiles gave good results, while amine nucleophiles gave products of somewhat lower purity.     

Efficient and regiospecific one-pot synthesis of substituted 1,2,4-triazoles

An efficient one-pot, three-component synthesis of substituted 1,2,4-triazoles has been developed, utilizing a wide range of substituted primary amines and acyl hydrazides.     

Facile peptide thioester synthesis via solution-phase tosylamide preparation

Preparation of peptide thioester is essential for native chemical ligation and block condensation. Our novel methodology involves conversion of the carboxylic acid of a peptide into a thioester using p-toluenesulfonyl isocyanate, followed by alkylation, then thiol substitution. Our methodology can also be used for the preparation of glycopeptide thioesters. Furthermore, it is possible to carry out the reaction as a sequential peptide chemical ligation.     

Solid-phase and solution-phase parallel synthesis of tetrahydro-isoquinolines via Pictet-Spengler reaction

An efficient parallel synthesis of 6,7-dimethoxytetrahydroisoquinolines is reported. The key reaction step is 3,4-dimethoxyphenethylimines reacting with acid chlorides to form an N-acyliminium ion intermediate, which undergoes Pictet-Spengler condensation to give the desired products in >80% yield. Both solution-phase and solid-phase synthesis of 6,7-dimethoxytetrahydroisoquinolines are described.     

Microwave-assisted synthesis of macroheterocyclic compounds using 1-alkyl-1,2,4-triazoles

Russian Chemical Bulletin - Microwave-assisted synthesis of new representatives of triazole-containing macroheterocycles bearing 1-alkyl-1,2,4-triazole moieties was described. The developed...     

Polymer-supported 1,3-oxazolium-5-olates: synthesis of 1,2,4-triazoles

A traceless synthesis of 3,5-disubstituted 1,2,4-triazoles has been developed on polymeric supports. The synthetic process utilizes immobilized mesoionic 1,3-oxazolium-5-olates (munchnones) as key intermediates in the 1,3-dipolar cycloaddition reaction. The initial step in the synthesis involves reductive alkylation of phenylglycine methyl esters with Ameba resin. The resulting immobilized amino acid esters were subsequently acylated with a variety of carboxylic acid chlorides and subjected to hydrolysis with 15% KOH to yield the polymer-bound carboxylic acids. Finally, the cycloaddition between diethyl diazocarboxylate or 4-phenyl-4H-1,2,4-triazoline-3,5-dione and the polymer-bound munchnones generated from the corresponding carboxylic acids afforded the polymer-bound 3,5-disubstituted 1,2,4-triazoles. Cleavage from the polymeric support using trifluoroacetic acid gave the desired 3,5-disubstituted 1,2,4-triazoles with excellent yield and high purity.     

Chlorotrimethylsilane-promoted synthesis of 1,2,4-triazolopyrimidines from 3,5-diamino-1,2,4-triazoles and pentane-2,4-diones

An efficient synthesis of 2-amino-1-R-[1,2,4]triazolo[1,5-a]- pyrimidinium or 3-amino-2-R-[1,2,4]triazolo[4,3-a]pyrimidi- nium chloride derivatives by heterocyclization of 3,5-diamino- 1-R-1,2,4-triazoles (R = Alk or Ar) with pentane-2,4-diones was developed. The process is promoted by chlorotrimethyl- silane which plays the dual role of carbonyl-activating agent and water scavenger.     

Synthesis of 1,2,4-triazoles and 1,2,4-oxadiazoles

Monothiodiacylamines reacted regiosepecifically with hydrazines and hydroxylamine to give substituted 1,2,4-triazoles and 1,2,4-oxadiazoles in excellent yields.