Peptides side-chain protection

O-Acylated Hmb is stable to acidolysis by TFA giving a useful additional feature to Hmb-containing peptides. Side-chain protection and the V -protection, if it is first replaced with Boc before Hmb O-acetylation, can be removed and backbone protection retained. After deacetylation of Hmb with aqueous hydrazine the peptide can be further purified before removal of the Hmb groups, useful when the product is poorly soluble. This feature is also useful for the purification of large polypeptides as the presence of backbone protection on the side-chain deprotected peptide prevents the formation of relatively stable folded structures that can complicate HPLC purification.1 11... 

Polymer-supported esters are widely used in solid-phase peptide synthesis, and extensive information on this specialized protection is reported annually. Some activated esters that have been used as macrolide precursors and some that have been used in peptide synthesis are also described in this chapter the many activated esters that are used in peptide synthesis are discussed elsewhere. A useful list, with references, of many protected amino acids (e.g., -NH2, COOH, and side-chain-protected compounds) has been compiled/ Some general methods for the preparation of esters are provided at the beginning of this chapter conditions that are unique to a protective group are described with that group/ Some esters that have been used as protective groups are included in Reactivity Chart 6. 

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

AM Felix, MH Jimenez, T Mowles, J Meienhofer. Catalytic hydrogenolysis in liquid ammonia. Cleavage of V -benzyloxycarbonyl groups from cysteine-containing peptides with terf-butyl side chain protection. Int J Pept Prot Res 11, 329, 1978. 

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. 

The mild acidolytic cleavage procedure noted above is used to deprotect various side chain protected peptides synthesized in solution or on chlorotrityl-resin with tyrosine O-sulfate synthons as listed in Table 4. The overall yields are significantly superior to those obtained by postsynthetic sulfation of the purified peptides, since they are typical for synthetic peptides after the final deprotection and purification step. The additional main advantage of this approach derives from a facile analytical characterization, since sulfonated byproducts at the tyrosine and tryptophan level, as well as oxidation of the methionine residues resulting from postsynthetic sulfation of tyrosine peptides are avoided. 

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 synthesis of type I bicyclic peptides is the most simple as the two side-chain-to-side-chain cyclizations can be performed successively on the assembled peptide or more appropriately by condensation of the two monocyclic segments preferably in solution. As shown in Scheme 23 (path A), for the synthesis of suitably protected monocyclic peptides, side-chain attachment of Asp or Glu residues to the oxime resin is proposed,[436,43T which leads to the desired cyclization and release of the protected segments as Pac or preferably as A1 es-tersJ396 These are C-terminally deprotected, when required, and then assembled in solution into bi- or polycyclic peptides of type I. 

Thiazolidine-4-carboxylic acid containing peptides exhibit an enhanced polar character when compared with most of the side-chain protected cysteine peptides. 139 The anomalously low nucleophilicity of its imino group (pATa = 6.24) in comparison to that of proline (pXa = 10.60) is due to the resonance stabilization of its unprotonated form 187188 This supposed resonance stabilization is supported by the X-ray crystal structure of 4-thiaproline.1 88 ... 

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