Protection schemes orthogonal

The general strategy is based on selective deprotection and oxidation of pairwise cysteine residues, as specified by the orthogonal protection scheme selected for this purpose. Since multiple disulfide bonds are formed step-by-step, reaction conditions are required that prevent breaking or scrambling of the disulfide bonds already formed. Therefore, throughout the synthesis, exposure to thiols or alkaline conditions as well as lengthy reaction times that may cause disulfide disproportionation must be avoided. 

In the case of bi- or tricyclic peptides more than three levels of orthogonality in the protecting schemes is required (see Section 6.8.3.2.5). 

The majority of cyclic peptides synthesized on solid support are cyclized in the head-to-side-chain or side-chain-to-side-chain mode. For this purpose the amino acids involved in cyclization must be side-chain protected in a manner that allows for an additional level of orthogonal deprotection. Thus, upon assembly of the fully protected linear precursor on-resin, deprotection of the functionalities involved in the lactam ring formation is performed, followed by regio-selective cyclization by amide bond formation, and finally by the resin-cleavage/deprotection step as outlined in Scheme 16. In Table 8, examples of syntheses of such cyclic peptides are listed with the relevant information regarding protection scheme, resin anchor, and mode of cyclization. 

The usefulness of this family of protecting groups has been proved in countless applications, both in the total synthesis of natural products, where protecting group orthogonality is often a critical issue (e.g., in the total synthesis of Calicheamycin [ 15] or Aplysiatoxin [16] Scheme 13.3) or in the light-directed synthesis of oligonucleotides (DNA-chips) [17]. 

For the design of synthetic routes based on protected hydrazides the appropriate choice of the protecting groups for the a-amino, A -hydrazide and side-chain functionalities is of critical importance, although the possibility offered by the azide procedure to apply the strategy of minimum protection significantly facilitates the problem of an orthogonal protection scheme. In Table 1 different examples of such protection schemes are listed. 

Figure 5 Representative triply orthogonal protection scheme for Fmoc-t-butyl strategy.

The first three-dimensional orthogonal protection scheme, fully compatible with the Fmoc/rBu chemistry, was developed independently by Ban-nawarth s and Albericio s groups, combining Fmoc (a-NHaj/allyl a-... 

The techniques in solid-phase organic chemistry complement those from solid-phase peptide assembly. Synthesis is performed on resins using anchoring linkages and orthogonal protection schemes. Molecules are cleaved from the solid support, purified (see Chapter 18), and then analyzed by high-performance liquid chromatography or mass spectrometry (see Chapters 19 and 20). Reactions can be performed in a simple apparatus that... 

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