Side-chain protection

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. 

Specifically, the carboxylates of N -Fmoc-protected (and side chain-protected) N-substituted glycines were activated and then coupled to the secondary amino... 

In the Fmoc protection approach, the acid-labile ferf-butyl groups are often used for side-chain protection. The base-labile Fmoc groups can be easily removed during a synthesis using piperidine (Fig. 4). The final global deprotection together with cleavage from the polymeric support is achieved with TFA. 

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

A methyl substituent on the a carbon of the phenylethylamine side chain protects against deamination by MAO the prolonged action of amphetamine and related... 

A Loffet, HX Zhang. Allyl-based groups for side-chain protection of amino-acids. Int J Pept Prot Res 42, 346, 1993. 

C-D Chang, M Waki, M Ahmad, J Meienhofer, EO Lundell, JD Haug. Preparation and properties of N -9-fluorenylmethoxycarbonyl amino acids bearing tert. -butyl side chain protection. Int J Pept Prot Res 15, 59, 1980. 

LA Carpino, H Shroff, SA Triolo, EME Mansour, H Wenschuh, F Albericio. The 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl group (Pbf) as arginine side chain protectant. Tetrahedron Lett 34, 7829, 1993. 

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. 

Opinions differ as to which support, which anchoring bond, which side-chain protection, which a-amine protecting groups, and which activation reagent is best. Most of the changes in chemistry have certain advantages, but also certain disadvantages. Choices will depend on individual laboratories and especially on the problem at hand. 

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

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... 

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