Solid-phase peptide synthesis polymer-bound amino acid

Once the first amino acid is bound to the polymer, additional amino acids can be added sequentially. The steps of the solid phase peptide synthesis technique are illustrated in the accompanying scheme. In the last step, HF cleaves the polypeptide chain from the polymer. 

Unlike reagents bound to crosslinked polymeric supports, soluble macromolecules are able to interact with reactive groups attached to insoluble polymers. This fact was demonstrated by Frank and Hagenmaier, who developed an alternating liquid-solid phase peptide synthesis procedure. Amino acids attached to crosslinked polystyrene via a carbamate linker were condensed with a peptide ester of polyethyleneglycol monostearylether (Scheme 1.6.12). 

Fig. 16. Sdiematk presentation of peptide synthesis by inverse solid phase method based DO the use of polymer-bound amino acid active esters (coupling reagent) and polymer-bound piperazine (deprotecting reagent)...

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. 

An important feature of Merrifield s method of sequential synthesis on the polymer support is that the synthesis goes unchecked. Unless the coupling reaction proceeds to completion in every step, the final product obtained after cleavage is bound to be contaminated with peptides differing from the desire sequence by one or more amino acid residues. Thus, because of the multiple uncertainties associated with solid-phase synthesis, it is highly desirable to have rapid analytical control of the two major synthetic operations, i.e., coupling and deprotection, in order to achieve unambiguous synthesis of the desired peptide. 

Attention should be given to the similarity between solid phase technology and the biological synthesis of proteins. In both cases, an amino acid is attached via the carboxylate function to a large macromolecular surface upon which the sequential addition of other amino acids and peptide bond formation occurs. In one case, the polymer, like the tRNA molecule at the peptidyl site, is the leaving group, while in the other case, the polymer, like the tRNA molecule at the aminoacyl site, remains bound to the chain after formation... 

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