Synthesis split-and-pool

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 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. 

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. 

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. 

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. 

In the laboratory we have several automatic and semiautomatic robotic apparatus including the IRORI Nanokan optical encoding system for split- and pool-synthesis (34) and synthesizers from Advanced ChemTech and the MiniBlock from Mettler, Toledo, OFI. 

Approximately 100 mg of resin was distributed to each of the reaetion bloek wells (of an ACT block or a Bohdan block) by pipetting a slurry of the resin in DMF/DCM (3 1) or as dry resin into each IRORI kan. The peptides were then assembled by the combinatorial chemistry apparatus suited for parallel or split-and pool-synthesis (34) using in situ neutralization/HBTU activation protocols for BOC chemistry. The resin was initially washed with DCM and the BOC protecting group removed by washing twice with a 40% solution of TFA in DCM. 

Automated Synthesis of Linear Peptides Using Split- and Pool-Synthesis (34)... 

Returning to the hypothetical split and pool synthesis (Fig. 2), the chemist would next split the equimolar mixture of three products into another three identical pools. Reaction of each of these pools separately with three different... 

Iterative deconvolution works best when a single compound of the mixture is much more active than all others. Conversely, deconvolution is difficult when all members of a library have similar activity—as is often the case in the later stages of a drug discovery process. Because of the difficulties associated with mixture deconvolution, split-and-pool synthesis is best suited to the early lead discovery phase of the drug discovery process. Later stages, requiring direct comparison of one compound against another, are best served by other methods described below. 

Figure 3 Chemically encoded split-and-pool synthesis.

Figure 11.2 Principle of split-and-pool synthesis of catalysts.

Split-and-pool synthesis A method of synthesizing a diverse library of compounds. 

Iterative Deconvolution. The first iterative library was composed of 400 separate hexapeptide mixtures, in which the first two positions from the amino terminus contained single individual amino acids. Out of the 20 proteinogenic amino acids, 400 dipeptides were formed (AA, AC, and so on through YW, YY). The remaining four positions were mixtures of 19 amino acids (cysteine was excluded), so that each mixture was composed of 19" or 130,321 individual peptides. Thus, a total of400 x 130,321 (52,128,400) hexapeptides were synthesized. This library was prepared using the T-bag method in combination with split-and-pool synthesis. ... 

Chemical History of the Resin Formulations. The most straightforward solution to track the chemical history during split-and-pool synthesis is labeling paper disks," T-bags, wafers, or capsules with an alphanumeric code... 

R. Shukla, Y. Sasaki, V. Krchnak, B. D. Smith, Identification of synthetic phosphatidylserine (PS) translocases from a combinatorial library prepared by directed split-and-pool synthesis. J. Comb. Chem. 2004, 6, 703-709. 

Since only little information on inorganic split-and-pool synthesis is available in the literature [36-38], and since this method is not simply a parallelization or automatization of known synthetic approaches, this concept is discussed here in detail. 

One crucial feature of the split-and-pool synthesis as known in medicinal chemistry is the attachment of the desired compounds to a carrier particle or their confinement within a container. Both the carrier or the container are typically tagged so that the sequence of steps they have undergone can be backtracked and thus the nature of the compound attached to the carrier or present in the container can be established after a subsequent screening. The most often used combinatorial principle in organic synthesis is nowadays the concept of one bead one compound [39-41], If this could be transferred to the world of materials science, a powerful synthetic methodology would become available. 

Figure 12.5 Principle of the split-and-pool synthesis for the example of three steps with three different reactions in each step. This results in 3 different compounds after the first step, 9 different compounds after the second step, and 27 different compounds after the final step. For each of the three reaction vessels in the final step, deconvolution of 9 different compounds is necessary, since the last reagent added is known for the final step...

From a chemical point of view, inorganic solid carrier -materials are far from being inert toward catalytic reactions (apart from selected 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-and-pool synthesis. 

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