Split and combine

Scheme 79. The split and combine method of preparing a combinatorial small molecule library...

A further improvement of this approach, to create increased molecular diversity, was applied to the synthesis of a soluble peptidomimetic combinatorial library of about 60 000 compounds [22]. This library generated using the split and combine method is based on a dipeptide scaffold, which incorporates 50 different L-, D- and unnatural amino acids,... 

To demonstrate the potential of this method, a model library of isoxazolidines on Rink amide resin was synthesized by the split-and-combine method [25] (Scheme 16.1). The polymer-bound library obtained consists of a total of 18 compounds. If one considers the different building blocks of the synthesis, a nitro group or the carboxamidomethyl residue is found in 50 % each of the compounds, a cyano, N,N-dimethylamino, or trifluoromethyl group in 33 % each and a succinimide, N-methylsuccinimide, or sulfone group in 33 % each. 

Scheme 16.1 Solid-phase synthesis of isoxazolidines according to the split-and-combine method, (a) Distribution of the resin into two equal portions, coupling of bromocarboxylic acids with N,N -diisopropyl-carbodiimide (D1C), combination of the resin, substitution with hydroxylamine. (b) Distribution of the resin into three equal portions, condensation with three different aromatic aldehydes to the corresponding nitrones, combination of the resin, (c) Distribution of the resin into three equal portions, cyclo-addition with three different dipolarophiles to isoxazolidines, combination of the resin.

When applied together with a LC-MS analysis, IR mapping allows a statistical investigation and thus a rapid quality control of the library synthesized by the split-and-combine method. The decisive advantage of this technique is that 1R analysis, in contrast to mass spectrometry, can be carried out without destruction of the sample, and with spatial resolution. 

Using the split-mixed or the split and combine technology developed by Furka et al.3 361 Lam et and Houghten et al. the problems of different reaction rates can be elegantly avoided as depicted schematically in Figure 1.833. 

As with other applications of combinatorial chemistry, libraries of catalyst candidates are mainly generated either by parallel synthesis (Scheme 3, middle) (6) or by the split-and-combine approach (Scheme 4) (7). Parallel (in many instances automated) synthesis has the advantage that the identity of the synthesis products (e.g., ligands) is known, and that existing methods of solution-phase synthesis (and analysis) can be applied with only little modification. 

Figure 8.7 Schematic representation of split-and-pool combinatorial nucleotide synthesis. An example of split-and-pool (split-and-combine) synthesis of trideoxyribonucleotides complementary to codons by the sohd phase phosphoramidite nucleotide synthesis is illustrated. Each cycle in the synthesis includes spht (equal molar spUt), react (deprotection, coupling with 4 protected nucleotides and oxidation) and combine steps. After 3 cycles of 4 reactions (corresponding to couphng reactions with 4 nucleotides per cycle), the final combined library consists of a mixture all 64 trinucleotides...

In the split-pool procedure, also known as the portioning-mixing method, the solid support is first divided into as many equal portions as the number of amino acids in the peptide s sequence [74,75,83], Each portion is coupled individually to only one amino acid. All portions of the resin are mixed, and the entire process of splitting and combining is repeated until all amino acids have been combined. An exorbitantly large number of derivatives can be synthesized at a time. 

Platinum has a myriad of practical uses, especially in the field of electrochemistry where it is used as a catalyst and as a reference electrode. In particular, platinum is the most active known pure metal for the oxygen reduction reaction (ORR) in which O2 is split and combined with protons to form H2O. This is an important step in low-temperature fuel cells (polymer electrolyte fuel cells, direct methanol fuel cells, etc.) as it often is what limits the total fuel cell efficiency. Furthermore, platinum is rather expensive with the materials cost of its use in fuel cells being roughly half of the total fuel cell cost. Consequently, a great deal of effort is made in order to optimize its use. 

This can have important implications with regard to their positive conveying efficiency and the nature of mixing between the screws. Trapezoidal-shaped screws are generally more effective in both these respects. Furthermore, with these designs, controlled material stream splitting and combination can occur across the intermeshing zone [37]. 

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