Peptide synthesis, combinatorial strategies

Solid-phase methodology was established in 1963 in pioneering work conducted by Merrifield in the area of peptide synthesis [19]. Interest in this synthetic strategy continues unabated to this day, particularly in connection with the production of new active components for drugs, since the repetitive amide bond formation performed in automated synthesisers lends itself ideally to the construction of extensive substance libraries by combinatorial chemistry [20]. 

The second synthesis strategy commonly used in peptide synthesis and combinatorial chemistry is based on base-labile anchors. The cleavage mechanism is based either on a p-elimination (Fig. 5.6) or a hydrolysis, re-esterification or aminolysis (Fig. 5.7). 

Jacobsen has documented the preparation of a library of peptide-derived chiral thioureas in the context of a combinatorial strategy for the generation of catalysts for asymmetric synthesis [108]. The modular natures of these structures, incorporating amino acids, thioureas, diamines, and salicyl aldehydes, make them particularly well suited for facile catalyst optimization [109], With support from ab initio calculations, an optimal catalyst 151 was identified that displays impressively wide substrate scope together with excellent enantioselectivity in enantioselective Strecker reactions (> 90% ee. Equation 22) [110], For example, asymmetric addition of HCN to imine 150 mediated by 1 mol% of thiourea 151 affords amino nitrile 152 in 97% ee. 

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... 

In Section II.C we will present novel tricyclic xanthene derived amino acid templates, which allow the construction of libraries of cyclic conformationally constrained peptide loop mimetics using the split-and-mix method without having to use tagging and deconvolution strategies. In Section III we will focus on parallel and combinatorial approaches devoted to the synthesis of small molecule, non-peptidic compound collections, which in addition offer the possibility to incorporate structural features derived from protein epitope mapping into conformationally constrained peptide mimetics. 

For many of the prominent inhibitor families (Fig. 3.6.1, Boxes 12 and 13), the available synthetic strategies do not fulfil these requirements. In the synthesis of peptide aldehydes, e.g., the parallel synthesis of variable structures without race-mization is an unsolved problem. The same applies to the synthesis of many peptide isosteres such as the norstatines or the l,3-diamino-2-propanols. Typically, combinatorial variation of the N-terminal and C-terminal positions can be easily attained. The side chain of the isosteric building block itself and its stereochemistry can, however, currently be varied only by a synthetic effort this excludes versatile variation of the central inhibitory element. 

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