Split-mix method

The major impetus for the development of solid phase synthesis centers around applications in combinatorial chemistry. The notion that new drug leads and catalysts can be discovered in a high tiuoughput fashion has been demonstrated many times over as is evidenced from the number of publications that have arisen (see references at the end of this chapter). A number of )proaches to combinatorial chemistry exist. These include the split-mix method, serial techniques and parallel methods to generate libraries of compounds. The advances in combinatorial chemistry are also accompani by sophisticated methods in deconvolution and identification of compounds from libraries. In a number of cases, innovative hardware and software has been developed tor these purposes. 

The development glycopeptide libraries obtained by the split-mix method is severely hampered by the lack of concurrent development of a general, facile separation and characterization technology. Some headway has been made with chemical coding of the libraries, but very few direct methods of analysis exist. One promising method that could be applied to the direct characterization of both types of libraries is mass spectrometry. More specifically, post-source-decay matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (PSD-MALDI-TOF-MS) and CID-FAB/MS/MS have been used to characterize glycopeptides.53-55... 

While parallel synthesis of arrays of glycopeptides is readily achieved by implementation of the building-block approach (Scheme 14.1, Strategy 2),101 glycopeptide library synthesis in a combinatorial manner via the split-mix method has yet to prove routine. The difficulty lies in the structural analysis of the vast number of compounds generated in picomolar quantities on a single bead. Whereas peptides on... 

The split-mix method realizes the combinatorial distribution rule by mixing the products after each reaction step, then distributing the mixture into equal portions. 

The split-mix method was developed for preparing peptide libraries. The method is based on Merrifield s solid phase procedure, published in 1963 [8], Each coupling cycle of the solid phase synthesis is replaced by the following simple operations ... 

Peptides are not the only potential drug candidates. In most cases, other kinds of small organic molecules are preferred, because of their reduced susceptibility to enzymatic degradation. The split-mix method is fully applicable in the synthesis of organic libraries. Both sequential type and cyclic libraries can easily be prepared if the reaction conditions for solid phase are well developed. It has to be emphasized, however, that the advantages of the split-mix method can be fully exploited only in the case of multi-step synthetic procedures. For realization of the one-pot procedures suggested by Ugi [10], for example, the parallel procedures are better-suited. 

As already mentioned, components of libraries produced by the original split-mix method are discrete compounds. If the libraries are cleaved from the solid support, however, mixtures are formed. The products of the liquid phase synthesis are always mixtures. At the beginnings, finding an active component in a mixture of thousands, or millions of structurally related compounds seemed to be a task like finding a needle in a haystack. Later on, however, reliable methods have been developed to solve this problem. All these methods are based on preparation and screening of properly designed partial libraries. 

The principle of the iteration method was first described by Furka in an unpublished, notarized document [17]. Experimental realization was first demonstrated in deconvolution of a multi-component peptide library prepared by Geysen and his colleagues [18]. Application to libraries prepared by the split-mix method was published in 1991 [19],... 

There were successful efforts to modify the split-mix method, in order to eliminate the disadvantages while preserving the high efficiency. 

Following solid-phase elforts from Kahne s group. Boons et al. [17] reported a small glycoside library that was synthesized using a two-directional split-mix method. As shown in Scheme 14.7,... 

Nine compounds were synthesized via the split-mix method. The compounds were characterized by using GC-MS, HR-MS and by H- and °C NMR, and the isolated yields ranged from 7 % to 27 %. 

Fig. 20.7. Solid-phase synthesis of pyrrole amides by the split-mix method a. acetoacetylation with dike-tene b. separation of the resin into 14 aliquots, enaminone formation with 14 different primary amines ...

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