Split-pooling

For example (a) A Strategy for Macro-cyclic Ring Closure and Functionalization Aimed toward Split-Pool Syntheses, D. Lee, J.K. Sello, S.L. Schreiber, J. Am. Chem. Soc. 1999, 121, 10648-10649 ... 

Exploring the leucine-proline binding pocket of the Src SH3 domain using structure-based, split-pool synthesis and affinity-based selection. /. Am. Chem. Soc. 1998, 120, 30-36. 

The isorniinchnone cyclization/isocyanate cycloreversion process for substituted furan synthesis has been well studied, as exemplified by the conversion of 104 to 106 (Scheme 19.19). In a solid-phase adaptation of this transformation, two groups independently utilized this reaction to estabhsh a traceless self-cleaving method for the synthesis of substituted furans [176, 177]. Further investigation of the thermal requirements of this cycloreversion led to its application in the split-pool synthesis of a small library of amides [178]. 

Oikawa M, Ikoma M, Sasaki M (2005) Parallel synthesis of tandem Ugi/Diels-Alder reaction products on a soluble polymer support directed toward split-pool realization of a small molecule library. Tetrahedron Lett 46 415-418... 

The HDAC inhibitors TSA and TPX (Fig. 2) have been utilized as structural leads in the early stages of the quest for new and more selective small molecule inhibitors of the HDAC enzyme family. In order to investigate the function of the individual HDAC members, Schreiber et al. synthesized a library of 7200 potential HDAC inhibitors based on the structural features of TSA and TPX [93]. The members of this library were prepared on solid support by means of split pool methods. The key characteristics of these compounds consist of a dioxane-containing capping region and a zinc binding motive, connected via an aliphatic chain. Three different zinc binders, i.e., carboxylic acid, o-aminoanilide and hydroxamic acid were used. 

A variety of unfunctionalized secondary alcohols, including saturated and unsaturated carbinols, are resolved by catalyst 25 with moderate to high selectivi-ties (fcrei=4 to >50, see Scheme 5) [25]. Octapeptide 25 was discovered by screening a split-pool library of peptide catalyst candidates for acylation of 1-phe-nylethanol (3), using a reactivity-based fluorescence screen [26], followed by structure optimization with directed libraries. While substrates with increased steric bulk about the alcohol are resolved with highest selectivities, even 2-butanol is resolved with modest selectivity (fcrei=4). Peptide-based catalysts have also been applied to the resolution of tertiary alcohols, a relatively unexplored area of nonenzymatic asymmetric acylation catalysis [27-29], By using a fluores-... 

The synthetic approach of inorganic materials via the Split Pool methodology is closely connected to the question of synthesizing materials on or within physical entities that will contain the library member throughout the synthetic process. If physical entities are employed as carriers that show sufficient chemical inertness towards the screening process, a separation of the final library compound may... 

Generally, solution-based approaches for the generation of inorganic split and pool libraries have substantial advantages over approaches where solid phases are introduced as chemical sources during the different synthetic steps. Solution chemistry offers, potentially, a wide range of synthetic opportunities that can be exploited not only for the purpose of parallel synthesis but also for synthetic steps for Split Pool library creation. 

Fig. 2.19 Pathway for obtaining carrier -free inorganic solids via a solution/precipitation based Split. Pool methodology.

From a chemical point of view it has of course to be mentioned that these inorganic carrier materials are far from inert towards catalytic reactions (apart from select exceptions) and will in many cases become an active component as such via the synthetic pathway followed. This is also an important differentiation with regard to the traditional organic Split Pool synthesis. 

For optical analysis via imaging of the final Split Pool-library an AX 70 microscope was used (Olympus). The apparatus was equipped with an automated xyz-table and autofocus-control. The software package analysis 3.0 (SIS) was used for hardware control and analysis means. Pictures were taken in the multi-imaging alignment mode at a magnification of five. 

To verify the success of the different deposition steps, in combination with the Split Pool methodology X-ray fluorescence was chosen as an analysis tool. Elemental analysis was performed by X-ray fluorescence analysis on an Eagle II pProbe (Roentgenanalytik) with Rh-Ka radiation. An essential feature is the small diameter of the measurement spot The X-ray beam is focused by a multi-capillary system to a 50 pm spot on the sample surface. XRF analysis of the 8x12 catalyst library selection (Fig. 2.20) was routinely accomplished automatically by an elemental mapping at a pattern of 512x400 points, equally distributed over the rectangular library field, each point (50 pm diameter) was measured for 300 ms. 

Fig. 2.21 Routine workflow for Split. Pool combinatorial synthesis and testing and archiving.

Klein, J., Zech, T., Newsam, J. M., Schunk, S. A., Application of a novel split pool principle for the fully combinatorial synthesis of functional inorganic materials, Appl. Catal. A 2003, 254, 121-131. 

Solid-phase synthesis techniques applied either in a parallel fashion in automated synthesis or in split-pool-synthesis enable the rapid production of compound libraries containing thousands of members. But the original expectation that new hits will be discovered solely by the creation of a large quantity of library members was not fulfilled. Some of the libraries contained hardly any hit, because the underlying structures therein were not biologically relevant. Thus an old question returned Where in the almost indefinite space of thinkable chemical compounds are the structures which are of biological relevance [2] ... 

Split/pool solid-phase libraries and solution-phase pools... 

Mixture analysis methods are of little value for interesting sized libraries. Single-bead analysis methods are being developed which can be used to assure the quality of larger solid-phase split pool libraries. 

The extension of the application of combinatorial chemistry from lead discovery to lead optimization has resulted in a gradual shift from split-pool protocol-based libraries generating mixtures of compounds to the parallel synthesis of discrete analogs (see Fig. 5). The emphasis in the latter case is not on the size of the libraries but rather on the yield, purity,... 

Lewis K, Fitch W, Maclean D, Characterization of split/pool combinatorial libraries, Proc. 45th ASMS. Conf, p. 1265, 1997. 

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