Split-and-pool

Combinatorial approaches have been applied to this chemistry. In a method amenable to split and pool, PAL, or Rink resin, 89 is modified with an acetoacetate to generate the solid supported aminocrotonate 90. Either a two- or three-component Hantzsch protocol is followed to produce 91. Treatment with TFA carries out the cleavage from the resin and the cyclization to dihydropyridine 92. 

In related work a library of 1,458 peptide ligands and various metal salts was tested in hydrolysis reactions of (p-nitrophenyl)phosphates.35 An active substructure composed of polymer-bound histidine in combination with Eu3+ was identified by further dissecting the original hit structure. It needs to be pointed out that catalytically active polymer beads can also be tested for catalytic activity using IR-thermography. In a seminal paper this was demonstrated using 7,000 encoded polymer beads prepared by split-and-pool methods, specifically in the metal-free acylation of alcohols.36... 

For this library, we chose to use three types of isocyanates (neutral, electron rich, and electron deficient) to demonstrate the broad utility of the urea-formation reactions. Employing the above strategy and using the split-and-pool approach, we synthesized a 27-membered urea library with purities ranging from 95 to 99%. All the compounds prepared were characterized by 1FI NMR and mass spectroscopy. Acetonitrile can also be used as a substitute for DCM, but lower yields and product purities are generally observed. Attempts to use other protic solvents, such as isopropyl and ethyl alcohol, were unsuccessful. The best results were achieved when a chlorinated solvent (DCM) was used. The structure identity of all products was confirmed by 1FI NMR and MS spectroscopy. Expected molecular ions (M + Na+) were observed for all the products, and in all cases as the base peak. The compounds and yields are listed in Appendix 3.1. 

Figure 11.12 Illustration of a sequence of split and pool steps for the generation of single bodies containing either different organic molecules or inorganic materials.

Solid-phase organic syntheses typically use large excesses of reagents to drive reactions to completion so that, ideally, products liberated from resins should not require purification. Optimization of conditions is a critical part of solid-phase syntheses. Transfer of organic reactions in solution to a solid matrix is not a trivial undertaking, and lack of analytical methods accentuates this problem. Libraries prepared without adequate refinement of conditions tend to be of poor quality. For libraries so large that all the constituents cannot be fully characterized, well-optimized reaction conditions are absolutely essential. Techniques like split and pool, 2 for instance, can only be applied successfully after thorough optimization. 

Directed Sorting Split-and-Pool Combinatorial Synthesis... 

The concept of reducing the number of reaction vessels and exponentially increasing the number of synthesized compounds was brought to a next level of simplicity by the split-and-pool method of Furka et al.5 The split-and-pool method was independently applied by Lam et al.6 in a one-bead-one-compound concept for the combinatorial synthesis of large compound arrays (libraries) and by Houghten et al.7 for the iterative libraries. Now several millions peptides could be synthesized in a few days. In Furka s method the resin beads receiving the same amino acid were contained in one reaction vessel—identical to Frank s method—however, the beads were pooled and then split randomly before each combinatorial step. Thus the method is referred to as the random split-and-pool method to differentiate it from Frank s method in which each solid-phase particle was directed into a particular reaction vessel (the directed split-and-pool method). 

The key differences are as follows. In the directed split-and-pool method... 

The principal differences between those two methods are reflected in their applications. The random spht-and-pool method is suited for the synthesis of smaller quantities of large sizable libraries (i.e., million compounds), whereas the directed split-and-pool technique is suited for the synthesis of larger quantities of smaller compound collections (i.e., several hundred to several thousand compounds). In this chapter, a simple technique for directed spht-and-pool technique is described. 

An alternative method for tracking the chemical history is encoding by spatial address. The identity of each entity is defined by its spatial address. A one-dimensional directed split-and-pool procedure, referred to as necklace coding, has been developed for synthesis carried out on SynPhase Crowns and Lanterns.13 Individual supports are strung on a Teflon thread and the position of a particle on the thread (necklace) encoded the previous chemical history (Fig. 1). A similar concept was later reported by Furka and co-workers14,15 Two-and three-dimensional encoding of the directed split-and-pool synthesis platform has been patented by Selectide Corp.16... 

The third challenge was to integrate and/or automate the handling of individual particles between combinatorial steps. During the early years of directed split-and-pool methodology the entire process was done... 

The algorithm described above is for a three-step combinatorial synthesis. However, the method is not limited to only three-step combinatorial libraries the solid-phase support can be derivatized before the directed split-and-pool synthesis on the Encore synthesizer. The necklace coding can also be a very useful tool during the chemistry development process. 

Combinatorial chemistry has moved from specially centralized laboratories, often equipped with multimillion-dollar robots, onto the bench of individual medicinal chemists. This change in direction requires the availability of personal chemistry tools that are simple to operate, easy to arrange in the laboratory, and reasonably priced. Such instruments are now available for the effective synthesis of combinatorial libraries. The Encore synthesizer represents a simple and efficient personal chemistry tool that allows the execution of directed split-and-pool combinatorial synthesis. The current version of the Encore synthesizer is designed for solid-phase synthesis on SynPhase Lanterns however, it can be modified for synthesis on alternative solid supports such as resin plugs from Polymer Laboratories (e.g., StratoSpheres Plugs). 

The split-and-pool synthesis not only simplifies the complexity of the combinatorial synthetic process, but also offers additional important benefits. To undertake a full range of solid-phase chemical reactions, elaborate reaction conditions are needed for some chemical transformations. These include, but are not limited to, low temperature and inert atmosphere conditions. Parallel synthesis of a thousand compounds requires handling of a thousand reaction vessels. The timely addition of sensitive reagents (e.g., butyl lithium) at low temperature (—78°) under inert atmosphere during parallel synthesis is not a trivial task. It can be done if sophisticated automated synthesizer equipment is designed to handle and tolerate such reaction conditions. Such a synthesis can alternatively be performed easily in a manual fashion using a split-and-pool method that requires only a limited number of reaction vessels. Examples from Nicolaou s17 and Schrei-ber s18,19 laboratories have shown that the split-and-pool method is the methodology of choice for the synthesis of complex and diversity-oriented combinatorial libraries. 

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. 

When performing a synthetic combinatorial chemistry experiment, several basically different strategies may be followed to create a library of compounds. The most commonly used are mixelsplU (or split and pool) synthesis [1] masking strategies [15, 16] and parallel synthesis. In this chapter, the attention is focussed on the application of parallel synthesis to catalysis in the liquid phase. 

Although our main research interest has been in the field of heterogeneous catalysis, we have performed several proof of concept studies showing that FTIR imaging is flexible enough to be applied to the study of resin-supported combinatorial libraries, of the type commonly employed in split-and-pool syntheses. It was shown that the... 

Being in a way the link between pellet-type reactors and well-type reactors, Klein et al. presented a multiple-bead reactor [74] in combination with a split and pool synthesis. The reactor shown in Figure 3.43 consists of pellet-type catalyst carriers, so-called beads, which are positioned in square containers. 

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