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.     

Modular,parallel synthesis of an illudinoid combinatorial library

[structure: see text] A library of 49 illudinoids was prepared via a three-step synthesis using a parallel synthesizer and solid-phase extractive purification. Products could be rapidly prepared for initial biological testing against three cancer cell lines, which revealed library members that inhibit nonsmall cell lung cancer. The activities of the library members are not easily correlated with structure, meaning the empirical approach used here is essential for such nonintuitive discoveries.     

Solution phase synthesis of a diverse library of highly substituted isoxazoles

The iodocyclization of O-methyloximes of 2-alkyn-1-ones affords 4-iodoisoxazoles, which undergo various palladium-catalyzed reactions to yield 3,4,5-trisubstituted isoxazoles. The palladium-catalyzed processes have been adapted to parallel synthesis utilizing commercially available boronic acid, acetylene, styrene, and amine sublibraries. Accordingly, a diverse 51-member library of 3,4,5-trisubstituted isoxazoles has been generated.     

Combinatorial liquid-phase synthesis of structurally diverse benzimidazole libraries

An expedient liquid-phase synthesis for construction of the diverse benzimidazole libraries is described. Nucleophilic aryl substitution of poly(ethylene glycol)-supported 4-fluoro-3-nitrobenzoic acid 3 with several primary amines under basic conditions, followed by Zn/NH(4)Cl mediated nitro group reduction, gave the PEG bound diamines 5. Subsequent cyclization of immobilized o-phenylenediamine 5 using thiocarbonyldiimidazole (TCD) or thiophosgene in dichloromethane furnished benzimidazole-2-thiones 6. Treatment of 6 with alkyl halides and benzylic halides in the presence of triethylamine provided 1-substituted-2-alkylthio-5-carbamoylbenzimidazoles on the support. The desired products 8 were severed from the PEG under mild conditions in high yield and high purity.     

Design and synthesis of a diverse morpholine template library

Efficient and general procedures have been developed for the solution-phase preparation of substituted morpholine derivatives, and a library has been produced around generic structure 1. This library was designed with proprietary modeling software for use as a general screening library. The 30 R1 reagents were phenols, and the 275 R2 reagents were taken from five different reagent classes, giving a variety of product classes in the final library of 8250 potential products. All of the library members were generated from a common intermediate, mesylate (5), which was synthesized efficiently, in bulk, in three steps from N-benzylethanolamine (2). High-throughput chemistry using robotics was carried out to produce the 7907 library members, which were individually characterized by reversed-phase LC/MS analysis.     

Microwave-assisted parallel synthesis of a 14-helical beta-peptide library

To facilitate the preparation of beta-peptide libraries in parallel, we have adapted reaction conditions for the solid-phase synthesis of 14-helical beta-peptides for use in a multimode microwave reactor. The low temperature/pressure requirements of microwave-assisted beta-peptide synthesis were found to be compatible with multiwell filter plates composed of polypropylene. Microwave heating of the 96-well plate was sufficiently homogeneous to allow the rapid preparation of a beta-peptide library in acceptable purity.     

Soluble polymer-supported convergent parallel library synthesis

Soluble polymer-supported convergent synthesis has for the first time been successfully exploited for parallel library synthesis; sub-libraries of tripeptide iodoarenes and arylboronic acids reacted smoothly in a multipolymer PdII-catalyzed Suzuki coupling reaction to generate a library of bisaryl-linked hexapeptides.     

Modular synthesis of ChiraClick ligands: a library of P-chirogenic phosphines

A library of novel and diverse P-chirogenic phosphine ligands containing a triazole moiety (ChiraClick ligands) were prepared in high yield in a modular fashion that allows for variation of both the phosphine and the triazole structure, as well as giving access to the two enantiomers of the ligand.     

Little artifices of huge libraries: Secrets of parallel liquid-phase synthesis

Key aspects of differences between liquid-phase parallel synthesis and preparation of a single compound at a time are reviewed. Specific technique and equipment is required to make in the parallel manner such processes as heating (involving MW ovens and flow microreactors), extraction, filtration, and chromatography. Rich illustrations may be useful in educational courses on medicinal and combinatorial chemistry.

     

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 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.     

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.     

Modular synthesis and preliminary biological evaluation of stereochemically diverse 1,3-dioxanes

Modular synthesis and substrate stereocontrol were combined to furnish 18,000 diverse 1,3-dioxanes whose distribution in chemical space rivals that of a reference set of over 2,000 bioactive small molecules. Library quality was assessed at key synthetic stages, culminating in a detailed postsynthesis analysis of purity, yield, and structural characterizability, and the resynthesis of library subsets that did not meet quality standards. The importance of this analysis-resynthesis process is highlighted by the discovery of new biological probes through organismal and protein binding assays, and by determination of the building block and stereochemical basis for their bioactivity. This evaluation of a portion of the 1,3-dioxane library suggests that many additional probes for chemical genetics will be identified as the entire library becomes biologically annotated.     

The parallel synthesis of a disaccharide library using a solid phase, peptide-templated strategy

A novel strategy for the synthesis of oligosaccharides, involving the use of a solid phase peptide template, has been successfully applied to the construction of a twelve member disaccharide library.     

Microwave-assisted parallel synthesis of a 4,6-diamino-2,2-dimethyl-1,2-dihydro-1-phenyl-s-triazine library

Microwave-assisted parallel synthesis of a library of 20 phenyl dihydrotriazines was successfully achieved and compared to an identical library generated by conventional parallel synthesis. Microwave synthesis dramatically decreased reaction times from an average of 22 h to 35 min, and compounds generated using microwave irradiation were purer. Isolated yields of all the compounds were comparable when the two methods were used.     

Combinatorial liquid-phase synthesis of

A new method for the synthesis of [1,4]oxazepin-7-ones from readily available aldehydes and alpha-amino alcohols was developed using the Baylis-Hillman reaction as the key step. To determine the scope and limitations of the method, a mixture library was synthesized from six aldehydes and six alpha-amino alcohols on the soluble polymer support poly(ethylene glycol) 5000 monomethyl ether (MeOPEG) via split synthesis and analyzed by GC-EIMS. Those oxazepines that were formed predominantly were resynthesized in a parallel synthesis and fully characterized. Thus, we have shown that split synthesis on MeOPEG can be an efficient method to rapidly screen the substrate spectrum of a newly developed reaction sequence.     

Discovery of a new efficient chiral ligand for copper-catalyzed enantioselective Michael additions by high-throughput screening of a parallel library

A combinatorial library of 125 chiral Schiff base ligands 5 was synthesized with the use of solution-phase parallel synthesis and solid-phase extraction (SPE) techniques to scavenge excess reagents and reaction by-products and avoid chromatography. The synthetic methodology coupled five N-Boc-protected beta-amino sulfonyl chlorides 1a-e with five different amines 2f-j to give 25 N-Boc sulfonamides 3, which were in turn deprotected and coupled with five salicylaldehydes 4p-t to give 125 ligands 5 in good yields and of sufficient purity to be used in ligand-catalyzed reactions. These ligands were tested in the copper-catalyzed conjugate addition of dialkyl zinc to cyclic and acyclic enones. A multisubstrate high-throughput screening of the library was performed with an equimolar mixture of 2-cyclohexenone and 2-cycloheptenone (9 and 10, respectively, 0.2 mmol total), with 5.5 mol% ligand 5 (0.011 mmol) and 5 mol% Cu(OTf)2 (OTf= OSO2CF3) (0.010 mmol) in 1:1 toluene/ hexane at - 20 degrees C. From the screening of the library, 5bhr was identified as the best ligand, which yielded 3-ethylcyclohexanone (12) and 3-ethylcycloheptanone (13) in 82% and 81% ee, respectively, and complete conversions. Under optimized conditions (2.75 mol% 5bhr, 2.5 mol% copper(i) triflate, toluene as reaction solvent), improved results were obtained for 12 (90% ee, 93% yield) and for 13 (91% ee, 95% yield). Selected ligands 5 were also tested in the addition of Me2Zn to 2-cyclohexenone (9, ee up to 79%), of Et2Zn to 2-cyclopentenone (11, ee up to 80%) and to acyclic enones 16 and 17 (ee up to 50%).     

Solution-phase parallel synthesis of a pyridinium pyrazol-3-olate inner salt library using a three-component reaction

We present here the discovery of a novel, versatile, multicomponent reaction leading to various 4-[4-(pyridinium-1-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-2H-pyrazol-3-olate inner salts. The structure of the unusual zwitterionic inner salts was elucidated, and the scope of the novel reaction was investigated. After rapid optimization, the reaction was adapted to parallel synthesis, and an 800-membered compound library was produced.     

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.