Split-pool method for synthesis of solid-state material combinatorial libraries

The synthesis and analysis of inorganic material combinatorial libraries by the split-pool bead method were demonstrated at the proof-of-concept level. Millimeter-size spherical beads of porous gamma-alumina, a commonly used support material for heterogeneous catalysts, were modified with Al(13)O(4)(OH)(24)(H(2)O)(12)(7+) cations in order to promote irreversible adsorption of the anionic fluorescent dyes Cascade Blue, Lucifer Yellow, and Sulforhodamine 101. The compositions of individual beads were easily determined through three split-pool cycles using a conventional fluorescence plate reader. Small split-pool material libraries were made by adsorbing noble metal salts (H(2)PtCl(6), H(2)IrCl(6), and RhCl(3)) into the beads. Analysis of these beads by micro-X-ray fluorescence showed that quantitative adsorption of metal salts without cross-contamination of beads could be achieved at levels (0.3 wt % metal loading) relevant to heterogeneous catalysis. The method offers the potential for synthesis of rather large libraries of inorganic materials through relatively simple benchtop split-pool chemistry.     

Quantified MS analysis applied to combinatorial heterogeneous catalyst libraries

A high-throughput screening system for secondary catalyst libraries has been developed by incorporation of an 80-pass reactor and a quantified multistream mass spectrometer screening (MSMSS) technique. With a low-melting alloy as the heating medium, a uniform reaction temperature could be obtained in the multistream reactor (maximum temperature differences are less than 1 K at 673 K). Quantification of the results was realized by combination of a gas chromatogram with the MSMSS, which could provide the product selectivities of each catalyst in a heterogeneous catalyst library. Because the catalyst loading of each reaction tube is comparable to that of the conventional microreaction system and because the parallel reactions could be operated under identical conditions (homogeneous temperature, same pressure and WHSV), the reaction results of a promising catalyst selected from the library could be reasonably applied to the further scale-up of the system. The aldol condensation of acetone, with obvious differences in the product distribution over different kind of catalysts, was selected as a model reaction to validate the screening system.     

Efficient solid-phase synthesis of peptide-based phosphine ligands: towards combinatorial libraries of selective transition metal catalysts

A new methodology for the solid-phase synthesis of peptide-based phosphine ligands has been developed. Solid supported peptide scaffolds possessing either primary or secondary amines were synthesised using commercially available Fmoc-protected amino acids and readily available Fmoc-protected amino aldehydes for reductive alkylation, in standard solid-phase peptide synthesis (SPPS). Phosphine moieties were introduced by phosphinomethylation of the free amines as the final solid-phase synthetic step, immediately prior to complexation with palladium(II), thus avoiding tedious protection/deprotection of the phosphine moieties during the synthesis of the ligands. The extensive use of commercial building blocks and standard SPPS makes this methodology well suited for the generation of solid-phase combinatorial libraries of novel ligands. Furthermore, it is possible to generate several different phosphine ligand libraries for every peptide scaffold library synthesised, by functionalising the scaffold libraries with different phosphine moieties. The synthesised ligands were characterised on solid support by conventional (31)P NMR spectroscopy and, cleaved from the support, as their phosphine oxides by HPLC, (1)H NMR, (31)P NMR and high resolution ESMS. Palladium(II) allyl complexes were generated from the resin bound ligands and to demonstrate their catalytic properties, palladium catalysed asymmetric allylic substitution reactions were performed. Good yields and moderate enantioselectivity was obtained for the selected combination of catalysts and substrate, but most importantly the concept of this new methodology was proven. Screening of ligand libraries should afford more selective catalysts.     

Template-directed approach to solid-phase combinatorial synthesis of furan-based libraries

A novel furan based scaffold 5-hydroxymethylfurfural has been identified for the generation of combinatorial libraries using template directed approach on solid phase. This scaffold has been utilized to afford furan-based bi-heterocyclic structures with extensive chemical diversity using cycloaddition, multicomponent and cyclization reactions.     

Flow fine synthesis with heterogeneous catalysts

In the past few decades, organic reactions under flow conditions have attracted increasing attention. Flow reactions have a number of advantages over batch reactions in terms of environmental compatibility, efficiency, and safety. In particular, flow reactions with heterogeneous catalysts that yield desired products without significant levels of by-product formation can enable purification processes to be avoided. This feature can allow flow reactions to be assembled in a multi-step and continuous manner for the synthesis of complex molecules. These new techniques have opened up new approaches to the synthesis of fine chemicals and are expected to play a prominent role in future chemical manufacturing processes. In this context, this review aims to summarize recent developments in continuous-flow reactions with heterogeneous catalysts for synthesis of fine chemicals.     

Solid-phase extraction for combinatorial libraries

Solid-phase extraction (SPE) has during the last three years emerged as a convenient method for the purification of compound libraries prepared by solution synthesis. The widespread use of SPE in combinatorial chemistry can be explained by straightforward SPE method development facilitated by the availability of numerous commercial SPE resins. High-speed automated SPE is readily accomplished by taking advantage of commercial laboratory robot systems. The present review summarizes and discusses advancements made in the use of different SPE resins and molecule tagging techniques for optimization of ion-exchange, reversed-phase, normal-phase and fluorous-phase SPE in combinatorial chemistry.     

Partial alloc-deprotection approach for ladder synthesis of "one-bead one-compound" combinatorial libraries

The topologically segregated bilayer-bead concept has been applied to encoded "one-bead one-compound"(OBOC) combinatorial libraries to avoid the interference of coding tags with biological screening. In this paper, we report on the development of a novel partial Alloc-deprotection (PAD) approach and the use of this approach to establish a new ladder-synthesis method for OBOC combinatorial libraries to further exploit the concept. In the PAD approach, Alloc-protected beads are partially deprotected, sequentially layer by layer, starting from the outer layer toward the bead interior. The degree of deprotection (or thickness of each layer) is controlled by the time of exposure to the deprotecting agent, palladium. By repetitive use of the PAD approach, a small portion of Alloc-protected N termini in the bead interior is liberated in each synthetic cycle for generation of an additional ladder member such that each library bead will carry a full-length library compound on the bead surface and a series of truncated ladder members in the bead interior. For the libraries containing isobaric residues, a simple encoding strategy is introduced in the ladder-synthesis method so that the isobaric residues can be differentiated by the coding tags. One advantage of this encoding strategy is that the coding tags are confined together with the truncated ladder members in the bead interior, thus maintaining the arrangement that only the library compounds are displayed on the bead surface. The PAD approach of forming multiple concentric functional layers inside a bead is simple, reliable, and may have other applications in addition to OBOC combinatorial library bead encoding, such as the development of novel optically encoded beads for multiplex immunodiagnostics or even information recording.     

Recent advances in heterogeneous catalysts for the synthesis of imidazole derivatives

Among the bioactive heterocyclic frameworks, nitrogen containing multisubstituted imidazoles are versatile building blocks of many naturally occurring products. Imidazoles possess wide range of biological properties including anticancer, anti-inflammatory, antimicrobial, and antihypertensive activities with potential applications in other sectors. Multicomponent reactions in combination with heterogeneous catalysts and nanocomposites have contributed significantly to organic synthesis in general and imidazoles, in particular with high functional group tolerance. Owing to their tunable properties, lower operational cost, thermal stability, recyclability, and easily separation from products, heterogeneous catalysts and nanocomposites are integral part of numerous pharmaceutical, agrochemical, and industrial processes. There has been increased focus on the development of green and sustainable catalytic procedures for the building of novel and biologically potent imidazole conjugates. This article emphasizes the recent advances in recyclable catalysts and protocols, and their merits for the synthesis of diverse multisubstituted imidazole conjugates by one-pot reaction approach and the catalyst and reactant interactions.     

Multiobjective optimization of combinatorial libraries

Combinatorial chemistry and high-throughput screening have caused a fundamental shift in the way chemists contemplate experiments. Designing a combinatorial library is a controversial art that involves a heterogeneous mix of chemistry, mathematics, economics, experience, and intuition. Although there seems to be little agreement as to what constitutes an ideal library, one thing is certain: only one property or measure seldom defines the quality of the design. In most real-world applications, a good experiment requires the simultaneous optimization of several, often conflicting, design objectives, some of which may be vague and uncertain. In this paper, we discuss a class of algorithms for subset selection rooted in the principles of multiobjective optimization. Our approach is to employ an objective function that encodes all of the desired selection criteria, and then use a simulated annealing or evolutionary approach to identify the optimal (or a nearly optimal) subset from among the vast number of possibilities. Many design criteria can be accommodated, including diversity, similarity to known actives, predicted activity and/or selectivity determined by quantitative structure-activity relationship (QSAR) models or receptor binding models, enforcement of certain property distributions, reagent cost and availability, and many others. The method is robust, convergent, and extensible, offers the user full control over the relative significance of the various objectives in the final design, and permits the simultaneous selection of compounds from multiple libraries in full- or sparse-array format.     

A general method for designing combinatorial peptide libraries decodable by amino acid analysis

Herein we describe an algorithm for designing combinatorial peptide libraries for split-and-mix synthesis on solid support that are decodable by amino acid analysis (AAA) of the beads. AAA is a standard service analysis available in most biochemical laboratories, and it allows one to control the quality of the peptide on each bead, an important feature that is missing from most library decoding protocols. In the algorithm, each AA is assigned to two variable positions in the sequence grouped in a "unique pair". This arrangement limits sequence design because both the number of unique pairs U (setting the maximum number of variable AA) and the maximum number S of different AA per variable position depend on the peptide length N (U=N(N-1)/2), S=N-1). The method is therefore only suitable for focused libraries. An application example is shown for the selection of peptides with N-terminal proline or hydroxyproline catalyzing an aldol reaction from a combinatorial library of 65536 octapeptides. A simple enumeration program is available to help design combinatorial libraries decodable by amino acid analysis. The method applies to linear and cyclic peptides, can be used for nonnatural building blocks, including beta-amino acids, and should help to explore the vast chemistry of linear and cyclic peptide for catalysis and bioactivity.     

Software for automating analysis of encoded combinatorial libraries

This paper describes the applications which are used to automate the analysis of encoded combinatorial libraries. Commercial packages from MDL, Oracle and Agilent are linked with application software written in C/C++, in Microsoft Access and in ChemStation macro language. Encoding correspondence lists for each of up to three synthetic steps are conveniently associated with building block lists using the first application, CodeGen. The second application Decode allows the user to identify the individual beads picked onto a 96-well plate and the pool number for each bead. The decoding chromatography data for each well is then loaded into the program. The chromatography data is used to identify the tags used in the synthesis. Along with the building block information from ISIS/Host, the building block used in each step of the synthesis can be identified. A third routine, Code-to-Structure, takes the coded library building blocks and creates the connection table in ISIS for each structure found by the decode program. For quality control of encoded library synthesis, the decoded structures on a set of beads is compared to the LC/UV/MS data for the ligand cleaved from the same bead. CAPTURE, a GlaxoSmithKline proprietary application, is used to display and analyze the decoded structures and associated mass spectral data. This application uses simple isotopic composition and electrospray ionization rule sets to predict mass spectra and judge the concordance of a structure- mass spectrum data set. An ancillary program, EIC, is used to extract predicted single ion chromatograms from the full scan LC/MS data.     

2D and 3D spatially addressed arrays for high-throughput automated synthesis of combinatorial libraries

One of the key elements in the drug discovery process is the use of automation to synthesize libraries of compounds for biological screening. The "split-and-mix" approaches in combinatorial chemistry have been recognized as extremely powerful techniques to access large numbers of compounds, while requiring only few reaction steps. However, the need for effective encoding/deconvolution strategies and demands for larger amounts of compounds have somewhat limited the use of these techniques in the pharmaceutical industry. In this paper, we describe a concept of directed sort and combine synthesis with spatially arranged arrays of macroscopic supports. Such a concept attempts to balance the number of reaction steps, the confidence in compound identity, and the quantity of synthesized compounds. Using three-dimensional arrays of frames each containing a two-dimensional array of macroscopic solid supports, we have conceptualized and developed a modular semiautomated system with a capacity of up to 100 000 compounds per batch. Modularity of this system enables flexibility either to produce large diverse combinatorial libraries or to synthesize more focused smaller libraries, both as single compounds in 12-15 micromol quantities. This method using sortable and spatially addressed arrays is exemplified by the synthesis of a 15 360 compound library.     

Device for preparing combinatorial libraries in powder metallurgy

This paper describes a powder-metering, -mixing, and -dispensing mechanism that can be used as a method for producing large numbers of samples for metallurgical evaluation or electrical or mechanical testing from multicomponent metal and cermet powder systems. It is designed to make use of the same commercial powders that are used in powder metallurgy and, therefore, to produce samples that are faithful to the microstructure of finished products. The particle assemblies produced by the device could be consolidated by die pressing, isostatic pressing, laser sintering, or direct melting. The powder metering valve provides both on/off and flow rate control of dry powders in open capillaries using acoustic vibration. The valve is simple and involves no relative movement, avoiding seizure with fine powders. An orchestra of such valves can be arranged on a building platform to prepare multicomponent combinatorial libraries. As with many combinatorial devices, identification and evaluation of sources of mixing error as a function of sample size is mandatory. Such an analysis is presented.     

Plasma chemical synthesis and activation of heterogeneous catalysts gas treatment

Bulk and supported catalysts that are active in the CO oxidation reaction were obtained by the reaction of a low-temperature plasma with various catalyst materials Treating oxide catalysts with an HF discharge plasma results in an increase of their activity.Institute of General and Inorganic Chemistry, Ukrainian Academy of Sciences, Kiev. Translated from Teoreticheskaya in Eksperimental'naya Khimiya, Vol. 27, No. 6, pp. 641–646, November–December, 1991. Original article submitted August 27, 1991.     

Solid-phase synthesis of a peptide-based P,S-ligand system designed for generation of combinatorial catalyst libraries

An efficient methodology for the solid-phase synthesis of diverse combinatorial peptide-based P,S-ligand libraries based on a modular approach was developed. Chiral thioethers were introduced into a series of peptide scaffolds using commercially available Fmoc-protected cysteine derivatives, and secondary amines were incorporated into the peptide backbones by reductive alkylation using readily available Fmoc-protected amino aldehydes. Phosphinylation of the secondary amines of the scaffolds, applying two different reagents, yielded two different types of ligands. Subsequent complexation with palladium afforded six- or seven-membered chelates, respectively. The selectivity, in an asymmetric allylic substitution reaction, of the two different types of chelates, derived from the same peptide scaffold, was complementary in all cases studied, affording the product as opposite stereoisomers with up to 60% ee. These results hold great promise for the identification of highly selective catalysts upon screening of larger P,S-based catalyst libraries.     

High-throughput selection for heterogeneous catalysts

A catalyst library of 80 samples with different mass ratios of rare earth elements, cobalt (Co), cerium (Ce), and indium (In), was prepared by impregnation of a fresh HZSM-5 zeolite support. A high-throughput detection setup, based on UV absorption spectroscopy, was developed for heterogeneous catalyst selection. The catalytic properties of the library were tested in the selective catalytic reduction of NO by methane at 673 K. Among the Co/Ce series, the catalyst with Co/Ce = 2:1 and Co/H-ZSM5 = 2.5% has shown remarkable efficiency (up to 78%). In the Ce/In series, the reactivity of the catalyst with the support composition of Ce/In = 1:1 and Ce/H-ZSM5 = 2.0% was < or = 88%. Our initial experiments definitely indicated that this simple and inexpensive multichannel setup can be applied for the selection of other heterogeneous catalysts. According to the variation of the UV light intensity, resulting from the absorption of the reactant or product, it was possible to monitor the relative quantity of reactants or products during a catalytic reaction.     

PEG based resins for protease drug discovery synthesis, screening and analysis of combinatorial on-bead libraries

This review will cover the entire hit identification process performed with biocompatible, aqueous solvated, poly[ethylene glycol] (PEG) based resins - from synthesis, through screening, to analysis. The different types of resins (including their preparation) will be discussed and compared individually. Examples of one-bead-one-compound substrate libraries will be presented, as will one-bead-two-compounds libraries used for the discovery of enzyme inhibitors. The review includes a section covering organic and bio-organic reactions performed on all-PEG resins and discusses on-bead screening of the libraries with biomolecules. Finally, analysis of compounds on single beads, either via investigation by on-bead NMR or by ladder-coding of the combinatorial compound is covered. In general, the review will focus on chemistry, libraries, synthesis, screening, and analysis, using all-PEG based resins.     

New synthesis method for nickel phosphide hydrotreating catalysts

Nickel phosphide particles on silica and alumina support were prepared from metal or metal oxide particles by treatment with phosphine and hydrogen at moderate temperature, resulting in small particle sizes equivalent to that of the precursor particle size.     

Toward dynamic combinatorial libraries of cryptands

The first examples of dynamic combinatorial libraries of cryptands, created using the chemistry of imines is presented. Experiments, in which two trialdehydes compete for one triamine in a small library, show the full reversibility of cryptand formation, since the library composition is the same irrespective of the sequence of introducing the building blocks to the mixture.     

Computational screening of combinatorial catalyst libraries

A catalyst design methodology, utilizing combinatorial synthesis in parallel with chemometric analysis, is presented, which considers the 3D steric and electrostatic properties of substituents about a constant core structure.