Split synthetic strategy

Sathish M, Viswanathan B, Viwanath RP (2006) Alternate synthetic strategy for the preparation of CdS nanoparticles and its exploitation for water splitting. Int J Hydrogen Energy 31 891-898... 

The synthetic strategy employed during the combinatorial syntheses can be used to assist in determining these pooling strategies. In random incorporation syntheses, a single bead could contain millions of different molecular species. In mix and split syntheses (also called pool and divide syntheses or one bead-one compound syntheses) only one compound is attached to any given solid-phase synthetic bead. 

The split and mix approach forms the basis of all solid support-based combinatorial synthetic strategies. 

FIGURE 8.2 The generic representation of split-mix-recombine synthetic strategy with three unique monomers (A, B, and C) at each synthetic step. The final outcome for this example is the synthesis of all possible combinations, 27 unique compounds after three synthetic rounds. 

Apart from that, the synthetic pathways differ. Nicolaou derives the dioxabicyclo[3.2.1]-octane skeleton from the ketone 5, which can be split into the two building blocks 6 and 7 by cleavage of the C1-C7 bond. The synthetic strategy of Evans regards the ketone 8 as the... 

The ERETIC method may be most useful for split-and-pool syntheses where it is undesirable to further complicate the NMR spectrum of complex mixtures by adding a standard. In both split-and-pool and parallel synthetic strategies, micro- to nanoscale reactions generate small amounts of product. For example, solution-phase libraries can be generated in 96-well microtitre... 

One-Bead-One-Compound Concept. The split-and-pool synthetic strategy is undoubtedly the most efficient method to prepare large numbers (millions) of compounds. A critical feature of the split-and-pool method is the fact that any bead at any time can be present only in one reaction vessel and therefore reacting with only one amino acid (in more general terms, with one building block). This means that there is only one chemical entity on each bead (excluding side products). The consequence of this is that any bead picked from a mixture of millions of beads contains only one compound. This is the basic premise of the OBOC concept. The distribution of beads is driven by statistics and multiple beads can contain the same compound if the number of compounds is substantially lower than the number of beads. 

The synthetic strategy used for Ae preparation of star-shaped polyesters with linear star arms (structures 7 and can also be applied to Ae synthesis of star-shaped polyesters with hyperbranched star arms. For this purpose silylated 3,5-bisacetoxybenzoic acid was polycondensed with the di-, tri- or tetrafunctional phenolacetates 3, 6 or 14. In all cases both viscosity and GPC measurements confirmed that the molecular weights varied with the feed ratio monomer/"star-center". In the case of structure 15 NMR spectroscopy also allowed the determination of the DP which also paralleled Ae feed ratio (Figure 7). The results obtained fi om hyperbranched polyesters of structure 15 are summarized in Table 5 (19). Unfortunately, the "star-center" 6 turned out to be unfavorable for NMR spectroscopic determination, because all its NMR signals were obscured of DP s by the signals of the 3-Hybe units and acetate endgroups. In the case of "star-center" 14 the tert.butyl groups was split of as isobutylene in the course of the polycondensation (20). 

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. 

All the spectroscopic approaches applied for structural characterization of mixtures derive from methods originally developed for screening libraries for their biological activities. They include diffusion-ordered spectroscopy [15-18], relaxation-edited spectroscopy [19], isotope-filtered affinity NMR [20] and SAR-by-NMR [21]. These applications will be discussed in the last part of this chapter. As usually most of the components show very similar molecular weight, their spectroscopic parameters, such as relaxation rates or selfdiffusion coefficients, are not very different and application of these methodologies for chemical characterization is not straightforward. An exception is diffusion-edited spectroscopy, which can be a feasible way to analyze the structure of compounds within a mixture without the need of prior separation. This was the case for the analysis of a mixture of five esters (propyl acetate, butyl acetate, ethyl butyrate, isopropyl butyrate and butyl levulinate) [18]. By the combined use of diffusion-edited NMR and 2-D NMR methods such as Total Correlation Spectroscopy (TOCSY), it was possible to elucidate the structure of the components of this mixture. This strategy was called diffusion encoded spectroscopy DECODES. Another example of combination between diffusion-edited spectroscopy and traditional 2-D NMR experiment is the DOSY-NOESY experiment [22]. The use of these experiments have proven to be useful in the identification of compounds from small split and mix synthetic pools. 

Diversity Sciences developed a library synthesis strategy that combines the simplicity of parallel synthesis and the power of resin-mixing techniques. The general format is four 96-well plates that give rise to 384 synthetic wells, as shown in Figure 8.9. The layout of the synthesis blocks enables 16 unique monomers in monomer position A (across rows) and 24 unique monomers in monomer position B (down the columns). All of the 384 wells are preloaded with off-the-shelf resin where each well has a unique binary code embedded in the analytical construct. The first two points of diversity (monomer A and monomer B) is added in all possible combinations by parallel synthesis. Each spatial location has a unique binary-mass code that encodes for a particular combination of monomer A and monomer B. For example, binary code number 8 represents monomer Al and monomer B8. After the addition of monomer B, the resin from all 384 wells is mixed together and split into 96 identical pools, to which monomer C is added. The third monomer, monomer C, is spatially encoded, since the 96 pools are not mixed after the last step and screened as pools. Upon decoding, the identification of the binary code reveals the combination of monomer A and monomer B on each bead. 

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