Parallel and split-mixed synthesis

A major problem associated with the synthesis of mixtures is that not all the reaction partners will couple with the same reaction rate and this will give rise to a non-equimolar distribution of the products. This problem could be solved more or less efficiently in the field of peptide and oligonucleotide chemistry by adjusting the concentrations of the amino acid- and nucleic acid components according to their respective reaction rates. In the field of combinatorial synthesis of small molecules this problem is much more severe. 

The split-mixed methodology is ideal for linear stategies like the synthesis of polypeptide libraries where the economisation of reaction steps gains importance. Large libraries can be synthesised, every bead containing only one single compound. Tagging or deconvolution are usually required in order to determine the stmcture of active compounds. 

The substances can be either tested on bead or after cleavage depending on the availatnlity of biological tests. 

The methodology is limited, however, to relatively little material available on a single bead. Furthermore, resynthesis of the interesting members of the library in greater amounts will be necessary. 

In Chapters 1.8.1-1.8.3 we discussed the fundamental strategies of parallel and combinatorial synthesis. Whether reactions should be performed in solution or on solid supports or whether the compounds are obtained as singles or as mixtures from parallel or split-mixed synthesis, depends largely on the complexity of the underlying chemistry and the way compounds are identified and screened. The resulting structural diversity, however, is only determined by the way the molecules were assembled and the types of building blocks employed. 

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Various sulhir-containing odorants, such as 2-thioalcanes, 3-acetylthio-2-alkyl aikanals, and trialklylated 1,3,5-dithiazines were prepared by conventional, parallel, and split-mix synthesis approaches. 2-Heptanethiol, newly identified in bell peppers, and 3-acetylthio-2-methylpentanal showed relatively low odor thresholds of 10 and 5 pg/kg water, respectively. Several odorants were found to develop interesting notes, which are compatible with both savory and sweet flavors. 

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