Synthesis Of Combinatorial Libraries Research Articles

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.

Analytical techniques for small molecule solid phase synthesis.

Although resin-based chemistry offers many practical advantages over conventional solution phase for the synthesis of combinatorial libraries, effective monitoring of reactions conducted on the support remains a challenge. A number of techniques have been developed to enable the analysis of solid phase organic synthesis either by monitoring the resin-bound species directly or by the analysis of small quantities of material cleaved from the support. This review outlines some of the principles of the various techniques for the analysis of intermediates and products obtained from solid-phase chemistry.

From Protein Domains to Drug Candidates — Natural Products as Guiding Principles in the Design and Synthesis of Compound Libraries.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Rapid screening of molecular arrays using imaging TOF-SIMS

We explored the application of imaging time-of-flight secondary ion mass spectrometry (TOF-SIMS) to the high-throughput analysis needed for combinatorial chemistry research. Prototypical examples include the characterization of polymer resins, which are chemically modified as part of a combinatorial library synthesis. We studied sample conditioning for various polymer matrices, linker systems, and analytes attached to the linkers and found that the hydrophilicity of the supporting substrates play a very important role in confining the signals to a localized area. We also developed protocols for the high-throughput purpose that use specially designed substrates to hold a large number of resins (as many as 10,000), which avoids cross-contamination among components. Using this approach, we are able to perform chemical assays on polymer resins at a rate of about 1–10 s −1. This analysis has equivalent chemical specificity and sensitivity to but a speed at least an order of magnitude faster than that of ESI–MS or LC–MS.

Solid-Phase Synthesis of Guanidinium Derivatives from Thiourea and Isothiourea Functionalities

Guanidinium-based compounds are biologically, medicinally, and pharmaceutically vital molecules. Due to their ability to form H-bond interactions, charge pairing, and cation-π interactions, guanidinium groups also perform key roles in supramolecular chemistry. They are found in nature in numerous forms and can be synthesized using different methods. Solid-phase synthesis permits the preparation of synthetically challenging molecules and can be used for the synthesis of combinatorial libraries of lead molecules. A brief survey of methods for the synthesis of guanidiniums from thiourea and isothiourea using different reagents is discussed. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Novel Facile Synthesis of 2,2,4‐Substituted 1,2‐Dihydroquinolines via a Modified Skraup Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Traceless solid-phase synthesis of 2,6,9-trisubstituted purines from resin bound 6-thiopurines

The preparation of 6-chloro-2-iodo-9-tetrahydropyranylpurine ( 2 ), was achieved in three high yield steps from 6-chloropurine. This derivative was then selectively substituted at C-6 by reaction with a benzylthiol to give 3 , a versatile intermediate for the synthesis of 2,6,9-trisubstituted purines. Reaction of 3 in palladium-catalyzed cross-coupling reactions, (including Sonogashira coupling at room temperature), as well as nucleophilic substitutions with amines occurred selectively at C-2. The 6-thiobenzyl substituent was activated through oxidation to the corresponding sulfone and replaced by various benzyl or phenyl amines. This strategy was subsequently adapted to solid support, wherein 23 is connected to Merrifield resin via a 6-thiovaleric ester linker. The presence of the linker, in combination with the use of palladacycle type catalysts improved the yield of palladium(0)-catalyzed Suzuki and Sonogashira cross-coupling reactions. This strategy opens a new route to combinatorial chemistry library synthesis of trisubstituted purines on the solid support.

Solid-phase synthesis of combinatorial libraries based on enatiomerically pure (1 S,2 S,4 R,5 S)-4,5-dihydroxycyclohexan-1,2-dicarboxylic acid scaffolds

The conditions for solid-phase functionalization of the new enantio-pure scaffold 1 to give libraries of general formula 4 have been derived.

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.

From protein domains to drug candidates-natural products as guiding principles in the design and synthesis of compound libraries.

In the continuing effort to find small molecules that alter protein function and ultimately might lead to new drugs, combinatorial chemistry has emerged as a very powerful tool. Contrary to original expectations that large libraries would result in the discovery of many hit and lead structures, it has been recognized that the biological relevance, design, and diversity of the library are more important. As the universe of conceivable compounds is almost infinite, the question arises: where is a biologically validated starting point from which to build a combinatorial library? Nature itself might provide an answer: natural products have been evolved to bind to proteins. Recent results in structural biology and bioinformatics indicate that the number of distinct protein families and folds is fairly limited. Often the same structural domain is used by many proteins in a more or less modified form created by divergent evolution. Recent progress in solid-phase organic synthesis has enabled the synthesis of combinatorial libraries based on the structure of complex natural products. It can be envisioned that natural-product-based combinatorial synthesis may permit hit or lead compounds to be found with enhanced probability and quality.

Probing the phosphopeptide specificities of protein tyrosine phosphatases, SH2 and PTB domains with combinatorial library methods.

Protein tyrosine phosphatases, SH2 and PTB domains are crucial elements for cellular signal transduction and regulation. Much effort has been directed towards elucidating their specificity in the past decade using a variety of approaches. Combinatorial library methods have contributed significantly to the understanding of substrate and ligand specificity of phosphoprotein recognizing domains. This review gives a brief overview of the structural characteristics of protein tyrosine phosphatases, SH2 and PTB domains and their binding to phosphopeptides. The chemical synthesis of peptides containing phosphotyrosine or phosphotyrosine mimics and the various formats of synthesis and deconvolution of combinatorial libraries are explained in detail. Examples are given as how different combinatorial libraries have been used to study the interaction of phosphopeptides with SH2 domains and phosphatases. The intrinsic advantages and difficulties of library synthesis, screening and deconvolution are pointed out. Finally, some experimental results on the substrate specificity of protein tyrosine phosphatase 1B and the SH2 domain of the adaptor protein Grb-2 are summarized and discussed.

Recent developments in oligosaccharide synthesis: tactics, solid-phase synthesis and library synthesis.

Oligosaccharides, commonly found on the cell surfaces, are deeply involved in a variety of important biological functions, yet demanding difficulties synthesizing such structures limit the investigation of their functions. Technologies to chemically synthesize these oligosaccharides have dramatically advanced during the last two decades mainly due to the introduction of good anomeric leaving groups. In addition, tactical analyses have been addressed to enhance the overall efficiency of oligosaccharide synthesis. Based on the advancement of solution-phase chemistry, solid-phase technologies are being investigated in connection with the current trend of combinatorial chemistry and high throughput screening. This review summarizes the necessary solution-phase methodologies, the status of solid-phase synthesis of oligosaccharides, and combinatorial synthesis of oligosaccharide libraries.

Toward the combinatorial synthesis of polyketide libraries: asymmetric aldol reactions with alpha-chiral aldehydes on solid support.

[reaction: see text] The viability of performing stereocontrolled aldol additions with alpha-chiral aldehydes attached by a silyl linker to a hydroxymethylpolystyrene resin is demonstrated for boron and titanium enolates. Subsequent ketone reduction and manipulation on the solid support leads to elaborate stereopentad sequences, as occur in 6-deoxyerythronolide B and discodermolide.

Synthesis and evaluation of poly(oxyethylene glycol) polymer (POP) supports.

Mono- and alpha,omega-bis-styryl-oligo(oxyethylene glycol) ethers have been constructed in an efficient two-step synthesis. From these precursors, poly(oxyethylene glycol) polymer (POP) supports of varying monomer and cross-linker composition have been produced. The swelling properties and mass-solvent uptake of these novel materials have been evaluated in a variety of solvents, demonstrating that POP supports exhibit enhanced solvent compatibilities over the commercial resins TENTA-GEL, ARGO-GEL, and Merrifield's resin. The utility of POP supports in solid-phase organic chemistry has also been demonstrated successfully. It is anticipated that these high-loading polymeric supports will have generic application in the solid-phase synthesis of combinatorial libraries and the in situ screening of these libraries in the aqueous environment of a bioassay.

Combinatorial synthesis and biological evaluation of isoxazole-based libraries as antithrombotic agents

The 3-substituted phenyl-5-isoxazolecarboxaldehydes have been identified as activated aldehydes for the generation of isoxazole-based combinatorial libraries on solid phase through automation. Three highly functionalized isoxazole-based libraries comprising of 32, 96 and 45 compounds each have been synthesized in parallel format using Baylis Hillman reaction, Michael addition, reductive amination and alkylation reactions. With an objective of lead generation all the three libraries were evaluated for their antithrombin activity in vivo.

Synthesis of combinatorial libraries based on terpenoid scaffolds.

Triterpenoid-based scaffolds betulinic acid (1a) and ursolic acid (1b), have been used for the generation of combinatorial libraries in parallel format using solid phase organic synthesis method. These templates have the potential for the synthesis and amplification of triterpenoid-based compounds with one and two-point diversity. This has been demonstrated by the synthesis of two small libraries comprising 18 derivatives each of betulinic acid and ursolic acid with structural diversity at C-3 and C-28 positions. The primary screening of antimalarial activity of these libraries against P. falciparum in vitro led to the identification of four compounds with 5 fold increase in the activity compared to betulinic and ursolic acids.

Parallel synthesis of tri- and tetrasubstituted ureas from carbamoyl imidazolium salts.

A method for producing tri- and tetrasubstituted ureas from carbamoyl imidazolium salts is presented. Carbamoyl imidazolium salts are prepared from the reaction of N,N carbonyldiimidazole (CDI) with secondary amines, followed by alkylation with iodomethane. These stable salts can be stored for extended periods and are effective electrophilic carbamoylation reagents. Primary and secondary amines add to carbamoyl imidazolium salts at room temperature to give tri- and tetrasubstituted ureas in excellent yields. This reaction was used to synthesize ureas using both liquid-liquid extraction and solid-phase extraction (cation exchange) purification techniques. Liquid-liquid extraction affords the product ureas more cleanly than cationic exchange. A series of urea compounds were synthesized using parallel synthesis techniques in high yields and with suitable purity for routine in vitro biological tests. These studies validate the utility of carbamoyl imidazolium salts as useful building blocks for combinatorial library synthesis.

Novel facile synthesis of 2,2,4 substituted 1,2-dihydroquinolines via a modified Skraup reaction

A variety of 2,2,4 substituted 1,2-dihydroquinolines were synthesized from substituted anilines or aminoheterocycles and the corresponding ketones in good yield via the use of lanthanide catalysts and microwave technology. This method can be readily applied to the general synthesis of combinatorial libraries of dihydroquinolines.

N-to-C solid-phase peptide and peptide trifluoromethylketone synthesis using amino acid tert-butyl esters.

Solid-phase peptide synthesis in the N-to-C direction, opposite to the classical C-to-N direction of peptide synthesis, provides the synthetically versatile C-terminal carboxyl group for further modification into C-terminally modified peptide mimetics. These are of general interest as potential bioactive agents, particularly as protease inhibitors. Elaboration of peptide mimetics on the solid-phase would facilitate synthesis of peptide mimetic combinatorial libraries. This report describes an effective strategy for solid-phase inverse peptide synthesis based on readily available amino acid tert-butyl esters. The potential of this approach for peptide mimetic synthesis is demonstrated by the solid-phase synthesis of two peptide trifluoromethylketones.

Introducing Freshmen Students to the Practice of Solid-Phase Synthesis

Background and Rationale for the Experiment Solid-phase chemistry has revolutionized the synthesis of organic compounds, peptides, oligonucleotides, carbohydrates, drugs, and combinatorial libraries (1‐5). Although many types of compounds incorporating a variety of building blocks can be created, all solid-phase syntheses share a common approach. In a typical synthesis, starting material is anchored to a polymeric support and transformed into product by the action of solution-phase reagents. The product is then liberated into solution. The reverse approach has been used to convert solution-phase reactants into products by means of supportimmobilized reagents and catalysts (6 ). Solid-phase organic synthesis is effective because reagents can be used in excess to drive reactions and immobilized products can be purified by repeated washings (7). In addition, syntheses can be automated. By combining these attractive features, multistep syntheses that would be considered unfeasible under homogeneous solutionphase conditions have been realized. The merit and popularity of solid-phase protocols are illustrated by the example of Bruce Merrifield, who received a Nobel Prize for his seminal contribution, and further, by explosive developments in combinatorial chemistry and drug discovery (5, 8‐11). Our goal was to introduce students in the early stages of academic development to the principles and practice of synthesis. Freshmen students attending a “pick-a-project” course were ideal subjects for the study. Several enrollees had expressed a curiosity in the topic of synthetic chemistry, but clearly lacked the practical experience required to carry out a multistep solution synthesis. As solid-phase methods have proven advantageous, popular, relevant, and technically facile, a project focused on solid-phase synthesis showed promise as an instructional vehicle. Peptide synthesis in particular was chosen because its chemistry has been developed to the point where success is virtually guaranteed if protocols are followed faithfully (2, 12‐14). The novelty of presenting peptide chemistry to freshmen students in a tangible, hands-on fashion rather than by using a textbook approach was also a deciding factor (15). Structure, Content, and Pedagogy Students were asked to write a project proposal, present goals, rationale, and methods to a committee, implement the proposal, document results, and conclude the project in report and oral PowerPoint format before peers and faculty. In addition to instructor guidance and support, the students had intranet access to guidelines on preparing proposals, reports, and oral presentations and to mandatory readings on the subjects of synthesis and analysis (2, 12‐18). Basic chromatography, spectrometry, spectroscopy, kinetics, and enzyme function were discussed, and detailed protocols were supplied to facilitate in-lab instruction. Project objectives were realized by adopting a guided, step-by-step, hands-on approach. The students worked and studied collaboratively in order to promote interactive learning. They were introduced to key concepts with the aid of laboratory demonstrations and visual tools and were encouraged to consolidate these concepts as they implemented the project. The completed project was archived on the intranet for the benefit of future enrollees. Synthesis, Analysis, and Application