Side-chain protecting groups

Peptide Synthesis and Self-Assembly Table 1 Common side-chain protecting groups... 

The polymer-bound p-nitrobenzophenone oxime (71d) has been found to be a suitable support for stepwise peptide synthesis. Protected peptides can be assembled on 70d by coupling and deprotection steps similar to those employed in the usual Merrifield solid-phase procedures (Scheme 39). Cleavage of peptides from 71d can be accomplished with hydrazine and amino acid esters under mild conditions, which do not affect benzyl ester side-chain protecting groups. 

Table 2 Side-Chain Protecting Groups Suitable for the Boc/Bzl/Pac Strategy...

A third modality is based on the use of orthogonal protection during SPPS synthesis to achieve selective removal of a specific side-chain protecting group, followed by selective modification with an activated benzophenone moiety. At the conclusion of the side-chain modification, which is carried out on the resin-bound peptide, stepwise elongation of the peptide chain is resumed.11571 Table 5 provides a current summary of reported biologically active peptides substituted with a benzophenone moiety and includes some synthetic details about their preparation. 

Boc-group removal usually requires treatment of the resin-bound carbamate with 50% TFA in DCM for 0.5 h (Section 10.1.10.1). Under these conditions, neither cleavage of the peptide from the support nor hydrolysis of side-chain protective groups... 

Before cleavage with HF, those side-chain protective groups that will not be cleaved by HF must be removed (e.g. /V-formyl groups from tryptophan, A-dinitro-phenyl groups from histidine). The A-terminal Boc group is also usually removed before treatment with HF, to minimize the risk of alkylation of electron-rich function-... 

The conditions used for final cleavage of the peptide from the support depend on the type of support and linker chosen. Because side-chain protective groups must also be removed, the use of scavengers is required during cleavage to avoid alkylation of the peptide. 

Table 16.1. Recommended side-chain protective groups for solid-phase peptide synthesis [18].

After completion of a coupling reaction, and before another amino acid can be added to the /V-terminus, it is necessary to remove the protecting group. This must be done by selective reactions that do not destroy the peptide bonds or side-chain protecting groups. This part of peptide synthesis is discussed in Section 23-13, and some reactions useful for removal of the AT-terminal protecting groups are summarized in Table 25-2. 

The combination of very mild coupling and deprotection protocols provides the flexibility needed in order to incorporate a variety of side-chain-protecting groups, cleavable by acid (Boc), base (Fmoc), Pd(II) (Aloc)J43 or nucleophiles (Dde)J441 Linear precursors of such templates with four orthogonally protected lysine residues are generally obtained in yields around 80% and cyclization proceeds quickly at high dilution almost quantitatively. 

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