Peptidomimetic solution phase

Whilst the same researchers are using new scaffolds and non-peptide chemistries to generate other libraries [31], Kung et al. [32] used this deconvolutive technique on a SPSAF (solution-phase simultaneous Addition of Functionalities) generated library, and Davis et al. [33] reported the recursive deconvolution of a peptidomimetic library of potential artificial enzymes. A future application could be in the popular field of libraries from multicomponent reactions [34], either in solution or in solid phase, which are difficult to deconvolute with classical methods due to the mixtures of components reacting at the same time. 

Figure 9.17 SAR from N-capping modifications of 9.21 structures of the solution-phase peptidomimetic discrete library L12 and of hits 9.23-9.25 obtained from its screening.

The field of peptide synthesis is never far removed from the study of natural products, many of which exhibit peptide and peptidomimetic structures. It is fitting that this treatise be concluded with a section on the synthesis of key peptide-based natural products. Section 16 commences with the synthesis of bacitracin)30 a cyclic peptide with antibiotic properties. The synthesis of this target structure is carried out in solution and by solid-phase chemistry. The molecule contains a lactam-bridged cyclic heptapeptide with a pendent tripeptide (Section 16.1.1). An elegant route to the synthesis of the thiazoline building block is included. 

Several natural products, for example siderophores, contain the N-hydroxy amide Y[CON(OH)] motif [138], Within a peptide backbone, this group increases the stability to enzyme degradation and induces characteristic conformational behavior [139]. In addition to the synthesis in solution of N-hydroxy amide-containing peptides (which is not trivial), a new solid-phase approach has recently been developed [140]. To explore the features of the N-hydroxy amide moiety using automated and combinatorial techniques, a method for the preparation of v /[CON(OH)] peptide ligands for MHC-I molecules has been elaborated [140], The strategy for the parallel preparation of these peptidomimetics on a solid support is illustrated in Scheme 7.9. The key step is the nucleophilic substitution reaction of resin-bound bromocarboxylic acids by O-benzylhydroxylamine, which requires several days. 

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