Solid phase peptide synthesis restrictions

Since most aaAAs are hydrophobic in nature, peptides rich in aaAAs are generally restricted to study in organic solvents due to their low solubility in aqueous media. There have been very few examples of side-chain functionalized aaAAs that would allow for the synthesis of highly water-soluble peptides rich in aaAA content.3 This is primarily due to difficulty of synthesis, since side-chain functionalized derivatives must be orthogonally protected to allow for incorporation into solid-phase peptide synthesis. The harsh conditions, under which standard methods of aaAA synthesis are performed, make this a difficult task. 

In contrast to Fmoc-Lys(biotin)-OH, Fmoc-Glu(biotinyl-PEG)-OH has excellent solubility in DMF and other solvents used in solid phase peptide synthesis. The PEG-spacer restricts hindrance between the peptide and avidin, leading to better biotin binding. 

This volume, like others in the Practical Approach Series, is intended to be primarily a practical guide to the subject, and as such, no attempt has been made by contributing authors to provide comprehensive reviews of the literature. As the title suggests, this work is devoted entirely to the Fmoc/tBu approach of solid phase peptide synthesis. This is not intended as any slight on the Merrifield technique it was felt best to restrict the scope of this volume, in view of the limited space available, the number of similar works covering the Merrifield technique already in print, and the numerous innovations made in the Fmoc/fBu method over the last decade. 

Inspired by the success of solid-phase peptide and oligonucleotide syntheses, in the early 1970s several research groups attempted to develop methods for solid-supported oligosaccharide synthesis.53 However, since the early methods for glycosidic bond formation were rather restricted, the success of these solid-phase strategies was limited and only simple di-and trisaccharides could be obtained. 

The functional group tolerance of the ruthenium-based metathesis catalysts has had a tremendous impact on solid-phase organic synthesis. The efficacy of the reaction in solution generally translates directly to solid-phase transformation and its potential has been harnessed in a number of library syntheses, solid-phase syntheses of natural products, or diversity-oriented syntheses. It enables the use of chemically robust alkenes as linkers which can be cleaved by RCM or CM. It, of course, provides new manifolds of diversification in diversity-oriented synthesis as has been elegantly shown in landmark examples by Schreiber and Nelson. Another metathesis application of paramount importance is in peptide chemistry where solid-phase synthesis is omnipresent. The ability to stabilize secondary structures in short peptide motifs and replace pharmacologically unsuitable disulfide bonds or simply restrict the conformation of a peptidic library has already been successfully implemented in a number of important examples. The orthogonality of the metathesis reaction to peptide chemistry provides a really powerful tool in this regard. 

A major advancement in the Fmoc-based solid-phase synthesis of Tyr(P)-peptides was realized with the Fmoc-Tyr[PO(OR1)2]-OH derivatives 7 (R1 = Bzl, tBu, Mdpse) [Mdpse = 2-(methyldiphenylsilyl)ethyl] in which the acid-labile phosphate esters offered simple cleavage by TFA treatment. While the initial difficult synthesis of derivatives 7 restricted general synthetic usage, the subsequent commercial availability of these derivatives and their compatibility with solid-phase synthesis has provided a simple and efficient procedure for the routine synthesis of large complex Tyr(P)-peptides. 

The peptides (17)-(22) were prepared by the usual solid-phase method of peptide synthesis utilizing different resins. The structures of D-Phe (22a) and its conformationally restricted phenylalanine analogue D-Tic (tetrahy-droisoquinoline-3-carboxyIic acid, 22b) positioned at the A-terminal position of the somatostatin analogues are shown. 

Until 1992, combinatorial libraries were almost entirely restricted to peptides and oligonucleotides, but peptides are not ideal as drugs because they have poor oral bioavail-ablity and a short half-life, so the pharmaceutical industry needed more useful libraries. Chiron experimented with N-substituted glycine peptoids (Figure 2), where the side chains are attached to the amide nitrogen,but the real breakthrough in what is usually called small-molecule chemistry came when Bunin and Ellman reported the solid-phase synthesis of a 1,4-benzodiazepine library (Figure 3). Very soon afterwards DeWitt et al. reported a similar synthesis of benzodiazepines... 

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