A Combinatorial Library Approach to Artificial Receptor Design

Goodman, Murray; Jubian, Vrej; Linton, Brian R.; Hamilton, Andrew D.

doi:10.1021/ja00151a039

Cited by 90 publications

(31 citation statements)

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“…As the first level of dynamic library, we chose to use two tridentate ligands assembling on a transition metal of octahedral coordination geometry (Scheme 1). The diversity of compounds (Scheme 1, 2) in this case can be generated by using ligands with varying substituents, similar to the static libraries reported by the Hamilton group (28). If excess of the ligands is present in the system, their exchange in the metal coordination sphere will result in the interconversion of all possible combinations, thereby forming a dynamic library (3, Scheme 1).…”

Section: Resultsmentioning

confidence: 68%

Double-level “orthogonal” dynamic combinatorial libraries on transition metal template

Goral

Nelen²,

Елисеев³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

148

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Dynamic combinatorial libraries are mixtures of compounds that exist in a dynamic equilibrium and can be driven to compositional self adaptation via selective binding of a specific assembly of certain components to a molecular target. We present here an extension of this initial concept to dynamic libraries that consists of two levels, the first formed by the coordination of terpyridine-based ligands to the transition metal template, and the second, by the imine formation with the aldehyde substituents on the terpyridine moieties. Dialdehyde 7 has been synthesized, converted into a variety of ligands, oxime ethers L 11-L33 and acyl hydrazones L44-L77, and subsequently into corresponding cobalt complexes. A typical complex, Co(L 22)2 2؉ is shown to engage in rapid exchange with a competing ligand L11 and with another complex, Co(L22) 2 2؉ in 30% acetonitrile͞water at pH 7.0 and 25°C. The exchange in the corresponding Co(III) complexes is shown to be much slower. Imine exchange in the acyl hydrazone complexes (L 44-L77) is strongly controlled by pH and temperature. The two types of exchange, ligand and imine, can thus be used as independent equilibrium processes controlled by different types of external intervention, i.e., via oxidation͞reduction of the metal template and͞or change in the pH͞temperature of the medium. The resulting double-level dynamic libraries are therefore named orthogonal, in similarity with the orthogonal protecting groups in organic synthesis. Sample libraries of this type have been synthesized and showed the complete expected set of components in electrospray ionization MS. R apid development of combinatorial chemistry and highthroughput experimentation in basic and applied research (1-4) generates increasing demand in new approaches that simplify and expedite synthesis and screening of diverse arrays of compounds and materials. Dynamic combinatorial chemistry (5-11) has attracted increasing interest over recent years as a new approach that combines in one system the library generation and screening processes. The dynamic libraries are designed as mixtures of components that can reversibly interconvert in a dynamic equilibrium that is driven by molecular recognition of a specific molecular target toward that assembly or a subset of components that form the library constituent best bound to the target.One of the key issues in designing dynamic libraries is the choice of the reversible chemical reaction that can interconvert the library components. A number of such reactions have been tested, which include transacylation (12-15), imine exchange (16-20), isomerization (21-23), thiol-disulfide exchange (24, 25), and ligand exchange in coordination complexes (17,18,26).A logical development of dynamic combinatorial chemistry would aim toward the combination of two or more reversible processes within one library. To extend the comparison with ''static'' chemical libraries, such multilevel organization in the dynamic library would be similar to advancing from a static library of components having ...

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Section: Resultsmentioning

confidence: 68%

Double-level “orthogonal” dynamic combinatorial libraries on transition metal template

Goral

Nelen²,

Елисеев³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

148

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“…10 mol % peptide-based ligand 10 mol % Ti(OiPr) 4 2 equiv TMSCN Scheme 5. Peptidic Schiff bases may be screened for identification of an effective chiral ligand for catalytic enantioselective addition of TMSCN to meso epoxides.…”

Section: Discussionmentioning

confidence: 99%

“…Combinatorial and related strategies have indeed been utilized recently in investigations involving materials science, [2] molecular recognition, [3,4] polymer chemistry, [5] and asymmetric catalysis. [6] This article is a brief overview of the recently developed diversity-based approaches in the screening and identification of effective metal-based catalysts for enantioselective synthesis.…”

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confidence: 99%

High-Throughput Strategies for the Discovery of Catalysts

Shimizu,

Snapper,

Hoveyda

1998

Chem. Eur. J.

155

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IntroductionThe major application of combinatorial chemistry remains the search for biologically active molecules.[1] Diversity-based strategies, however, might be effective in the identification of compounds that have attractive properties. Combinatorial and related strategies have indeed been utilized recently in investigations involving materials science, [2] molecular recognition, [3,4] polymer chemistry, [5] and asymmetric catalysis. [6] This article is a brief overview of the recently developed diversity-based approaches in the screening and identification of effective metal-based catalysts for enantioselective synthesis. In a few instances, it is likely that the more traditional design and screening approaches, often based on a priori mechanistic bias, would have been less successful, at least within the same time span. The searches for therapeutic agents and asymmetric catalysts share a number of facets. Traditionally, both fields have relied on iterative approaches wherein a single compound is designed, synthesized, and tested (Scheme 1). The cycle is repeated until a compound is obtained with the desired levels of enantioselectivity or activity. In contrast, as illustrated in Scheme 1, a high-throughput strategy enables one to generate and test simultaneously considerably larger numbers of candidates, potentially reducing the entire search cycle to one or two iterations. Design Synthesis Testing Design Synthesis Testing ClassicalHigh Throughput Scheme 1. The diversity-based approach can provide a wealth of data on reactivity and selectivity in an efficient manner.Combinatorial chemistry brings together rational design and high-throughput evaluation; it is rooted in empirical observations and logical deduction. Structure ± selectivity observations remain the basis for propagating molecular features from one generation of catalysts to the next. Such strategies therefore permit more initial guesses and a greater allowance for failure. Combinatorial chemistry is particularly well-suited to optimizing novel and previously unexamined reactions for which little mechanistic data is available. Such strategies can be viewed as the chemists attempt to address the notion that mechanistic subtleties that often differentiate the selectivity and reactivity of one substrate or catalyst from another may not be generalized. Such a broad-based approach relieves the chemist of the risk of following a relatively narrow path selected on the basis of fickle mechanistic parameters. It is perhaps fair to state that the development of almost all successful asymmetric catalysts has benefited, at some point, from serendipitous observations. Combinatorial chemistry integrates this aspect of catalyst discovery into the overall search process, increasing the rate at which advantageous mutations can occur. Nevertheless, a combinatorial approach can significantly promote the mechanistic studies of new asymmetric processes, as it can put forth a large structure ± selectivity database from which mechanistic paradigms can be generated. Hi...

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“…described one of the fi rst examples of a combinatorial approach to synthetic receptors using reversible coordination around a metal ion [20] . In the same year Harding et al .…”

Section: Early DCL Smentioning

confidence: 99%

“…In the same year Harding et al . described the guest -induced amplifi cation of a metallo -macrocycle 4 and metallo - [2]catenane 5 from a mixture (Scheme 1.4 ) [20,21] . Although not described as such, these examples employed the basic principles of DCC -template -stabilized selection of effective synthetic receptors from among an equilibrating library of potential receptors.…”

Section: Early DCL Smentioning

confidence: 99%