Solution-phase parallel synthesis of a 1140-member ureidothiophene carboxylic acid library

A 1140-library of thiophene ureidoacids was synthesized by the reaction of a set of 60 primary or secondary amines with a number of 19 thieno[3,2-d]- or thieno[2,3-d][1,3]oxazine-2,4-diones. All compounds were obtained by a simple solution-phase combinatorial strategy on a 200-400-mg scale with over 70% yields and purities over 80%. Sixty library members chosen at random were successfully characterized by standard 1H NMR, HPLC/MS, and IR studies. Analgesic, antalgic, and antiinflammatory potential were investigated. The 1140-member ureidothiophene carboxylic acid library will be used in high-throughput screening assays.     

Solution-phase parallel synthesis of a library of delta(2)-pyrazolines

A parallel synthesis of a library (80 members) of 2-pyrazolines in solution phase is described. The 2-pyrazoline core was accessed through the [3 + 2] cycloaddition of nitrilimines with enoyl oxazolidinones. The cycloaddition provided two regioisomers, the major product being the C regioisomer. The oxazolidinone moiety was further reduced to the primary alcohol, producing another library of 5-hydroxymethyl-2-pyrazolines. The Lipinski profiles and calculated ADME properties of the compounds are also reported.     

Solution-phase parallel synthesis of carbamates using polymer-bound N-hydroxysuccinimide

[formula: see text] A convenient method for the synthesis of carbamates using polymer-supported N-hydroxysuccinimide is described. Various carbamates were synthesized in highly pure form without the need for chromatographic purification. This new "catch and release"-type solid-phase synthesis should be useful for combinatorial synthesis of various carbamates.     

Solution-phase parallel synthesis of an N-alkylated dihydropteridinone library from fluorous amino acids

Parallel synthesis of an N-alkylated dihydropteridinone library has been accomplished in five steps starting from two displacement reactions of 4,6-dichloro-5-nitropyrimidine, first with fluorous amino acids, then with secondary amines. The hydrogenation of the nitro group followed by microwave-assisted cyclization gave the dihydropteridinones. Further diversification was achieved by the reaction of dihydropteridinones with benzyl halides to afford mono-N-alkylated products. All the reaction intermediates and final products were purified by SPE or precipitation without the need to perform chromatography.     

Solution-phase parallel synthesis of spirohydantoins

Spirohydantoins are considered privileged structures, making them attractive for the preparation of compound libraries with the potential for diverse biological activity. However, very few modifications of this scaffold have been reported to date. The spirohydantoin template was elaborated into a library of 168 compounds through a two-step solution-phase parallel synthesis starting from various N-substituted piperidinones. The Strecker reaction was employed to generate alpha-amino nitriles from aniline and TMSCN (or KCN). Subsequent reaction of the anilido nitrogen with a diverse set of isocyanates, followed by refluxing under acidic conditions, afforded the title library in high yield and purity.     

Solution-phase library synthesis of furanoses

The solution-phase synthesis of amido-, urea-, and aminofuranoses was achieved. Alkylated furanose aldehydes were treated with primary amines in the presence of sodium triacetoxyborohydride to give secondary amines. Subsequent acylation with acid chlorides and isocyanates afforded amidofuranoses and ureafuranoses, respectively. Second, reductive amination of furanose aldehydes with secondary amines yielded tertiary amines. The resulting acetonides were treated with alcohols in the presence of acid to yield mixed acetals. In the library syntheses, functionalized scavenger resins were used in the purification of intermediates and products.     

Solution-phase parallel synthesis of substituted benzimidazoles

A solution-phase parallel synthesis of o-phenylenediamines is described. These intermediates were then subsequently converted to benzimidazole scaffolds (three-point diversity) in excellent purities and yields. High-throughput purification of this multistep synthetic sequence was accomplished using polymer-bound scavengers and reagents and liquid-liquid extraction protocols.     

Solution-phase synthesis of a tricyclic pyrrole-2-carboxamide discovery library applying a stetter-Paal-Knorr reaction sequence

The solution-phase synthesis of a discovery library of 178 tricyclic pyrrole-2-carboxamides was accomplished in nine steps and seven purifications starting with three benzoyl-protected amino acid methyl esters. Further diversity was introduced by two glyoxaldehydes and 41 primary amines. The combination of Pauson-Khand, Stetter, and microwave-assisted Paal-Knorr reactions was applied as a key sequence. The discovery library was designed with the help of QikProp 2.1, and physicochemical data are presented for all pyrroles. Library members were synthesized and purified in parallel and analyzed by LC/MS. Selected compounds were fully characterized.     

Solution-phase parallel synthesis of an isoflavone library for the discovery of novel antigiardial agents

Combinatorial chemistry has become a dramatically useful tool for the development of new medicinal agents. In the search to discover a novel and effective lead for the treatment of giardiasis, solution-phase synthesis of a library of isoflavone derivatives has been accomplished. Of the products screened, several compounds such as P(A1,B1) and P(A1,B11) exhibited potent antigiardial activity. The details of synthesis, in vitro antigiardial assay, and preliminary structure-activity relationships of these compounds are described.     

Solution-phase parallel synthesis of highly diverse spiroisoxazolinohydantoins

Practical and efficient solution-phase parallel synthesis of spiroisoxazolinohydantoins under mild conditions has been developed. This spiroisoxazolinohydantoin skeleton possesses three diversity points. The key intermediate, exo-methylenehydantoin bearing two positions of diversification, is prepared via a one-pot synthetic route from N-substituted methyl ester serine. Employing various alkyl halides, isocyanates, and oximes, this chemistry is applied in the generation of an 18-member demonstration library with high yield, high purity and excellent regioselectivity.     

Solution-phase parallel synthesis of carbamates as gamma-secretase inhibitors

A novel methodology for parallel liquid-phase synthesis of carbamates suitable for the preparation of sterically hindered molecules is disclosed. The alcohols are converted to 4-nitrophenylcarbonates, followed by the reaction with amines. Side product 4-nitrophenol and the unreacted excess amines are scavenged by appropriately chosen cleanup resins, selected among Amberlyst A26 (hydroxide form) and macroporous sulfonic acid (MP-TsOH) or polystyrene isocyanate (PS-NCO) and polystyrene benzaldehyde (PS-PhCHO) resins. As a part of a medicinal chemistry program directed toward finding gamma-secretase inhibitors as prospective drug candidates for Alzheimer's disease, a 6 x 24 library of carbamates was prepared. Out of 144 library members, 133 had a purity for the targeted compound of 80% or better. The prepared compounds were assessed in the gamma-secretase inhibition assay and demonstrated activity with IC 50 values in the range from 1 microM to 5 nM, with the activity of 7 compounds being better than 10 nM.     

Solution-phase parallel synthesis of a 1,2,7-trialkyl-1H-imidazo[4,5-g]quinoxalin-6-ol library scaffold

This paper describes solution-phase parallel synthesis of a library with a novel 1,2,7-trialky-1H-imidazo[4,5-g]quinoxalin-6-ol scaffold and three points of diversity. The library is prepared using 1,5-difluoro-2,4-dinitrobenzene as the starting material and commercially available chemicals as the building blocks. A new, inexpensive, and practical apparatus for parallel filtration is also described.     

Solution-phase parallel synthesis of hexahydro-1H-isoindolone libraries via tactical combination of Cu-catalyzed three-component coupling and Diels-Alder reactions

Parallel solution-phase synthesis of combinatorial libraries of hexahydro-1 H-isoindolones exploiting a novel "tactical combination" of Cu-catalyzed three-component coupling and Diels-Alder reactions was accomplished. Three distinct libraries consisting of 24 members (library I), 60 members (library II), and 32 members (library III) were constructed. Variation of three substituents on the isoindolone scaffold in library I was exclusively achieved by the choice of the building blocks. In the syntheses of libraries II and III, sublibraries of isoindolone scaffolds were prepared initially in a one-pot/two-step process and were further diversified via Pd-catalyzed Suzuki cross-coupling reaction with boronic acids at two different diversification points. The Lipinski profiles and calculated ADME properties of the compounds are also reported.     

Direct synthesis of functional azaxanthones by using a domino three-component reaction

NH aldimines, generated in situ from the corresponding aldehydes by reaction with ammonium acetate, serve as nitrogen nucleophiles in reactions with 3-(1-alkynyl)chromones and 3-cyanochromones that generate functionalized azaxanthones. These processes take place under mild conditions that do not require dry solvents. The products of the reactions described represent new chemical entities. We believe that the newly developed cascade process will serve as a potent method for the synthesis of N-heterocycles and in diversity-oriented synthesis.     

Solution-phase parallel synthesis of S-DABO analogues

A simple and straightforward methodology for the parallel, solution-phase synthesis of a new series of S-DABO derivatives 1 and 2, bearing aromatic substituents at the C2 and C6 positions, has been developed. Starting from potassium ethyl malonates 3, thiouracil intermediates 5 were prepared through parallel synthesis and isolated as pure products by simple extraction with ethyl acetate. Selective S-benzylation of 5 was achieved in few minutes under microwave irradiation to give the title compounds 1, which were oxidized in parallel to the corresponding sulfones 2. Some of the new compounds 1 showed potent inhibitory activity against HIV-1 RT.     

Ugi four-center three-component reaction for the parallel solid-phase synthesis of N-substituted thiomopholinones

Starting with resin-bound bifunctional 2-(2-aminoethylthio)acetic, an efficient synthesis of a variety of N-cycloakyl thiomopholinones is described utilizing the Ugi four-center three-component reaction (U-4C-3CR).     

Solution-phase parallel synthesis of diverse 1,5-benzodiazepin-2-ones

A practical and efficient parallel method has been developed for the synthesis of 1,5-benzodiazepin-2-ones with a large variety of substituents at the 3-, 4-, 5-, 7-, and 8-positions using 1,5-difluoro-2,4-dinitrobenzene as the starting material. All the reactions involved here are highly effective in giving the desired products under mild conditions.