Solid-phase peptide synthesis amino acid side chain protecting groups

Figure 8.1 Process of solid-phase peptide synthesis. In the process, X = linker which is later incorporated into the polymer matrix Y = temporary protecting group R s = amino acid side chains protected with semipermanent protecting gronps if necessary. Carbodiimide is used as the coupling reagent...

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. 

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. 

All peptides were prepared by solid-phase peptide synthesis on a peptide synthesizer. [1171 Various protection groups were used for the terminal positions and side-chain functionalities of the amino acids. The coupling mixture consisted of HBTU/HOBt/amino acid/NMM. Deprotection of the desired side chains with piperidine in NMP, followed by cyclization with HBTU/HOBt/NMM in HFIP/NMP, led to the formation of lactam bridges on the resin. 

Solid-phase peptide synthesis is based on the sequential addition of protected amino acids onto an insoluble support. Addition proceeds from carboxy terminus to amino terminus. The first amino acid is attached to a solid support by a linker and, if necessary, side-chain amino acid function is protected throughout chain assembly. The carboxy group of the in-coming, acylating amino acid is activated for coupling while its amino group is protected temporarily for each coupling step and then deprotected for the next cycle. The... 

In solid phase peptide synthesis, polypeptides are chemically synthesized by addition of free amino acids to a tethered peptide. To prevent unwanted reactions, the a-amino group and reactive side chain groups of the free amino acids are chemically protected or blocked, and then deprotected or deblocked once the amino acid is attached to the growing polypeptide chain. 

The linear precursor of, for example, 34 [51] was obtained by solid-phase peptide synthesis performed on an SASRIN -resin applying the Fmoc/ Bu strategy. This allowed the preparation of a protected peptide with both free amino and carboxylic acid termini, which were head-to-tail cyclized using diphenylphosphorylazide, leading to the protected cyclic peptide. Removal of side chain protecting groups afforded 34. 

Matsuo et al. (57) also have prepared this peptide via solid-phase peptide synthesis. The protected decapeptide resin ester (V -Boc-Gln-His-Trp-Ser(OBzl)-Tyr(OBzl)-Gly-Leu-Arg (N02)-Pro-Gly-resin ester) that corresponds to the amino acid sequence of LH-RH/FSH-RH was synthesized using V -Boc chemistry by the method described by Stewart and Young (38), which starts with V -Boc-Gly-resin ester (1.0 g 0.35 mmole). The side-chain protections were as follows Ser and Tyr were protected by Bn groups. Gin by a Np group, Arg by a... 

Several syntheses of the peptide have been reported by solution methods (74-76). After the introduction of solid-phase peptide synthesis, Marshall and Merrifield conducted the first study of the synthesis of the peptide by using the new technique (77). A -Boc chemistry was used, and Merrifield resin was selected as the solid support. The side chain protections were as follows His, Arg, and Asp were protected by Bn groups Arg by a NO2 group. The Phe was esterified onto the resin in ethanol with the presence of 1 equivalent of triethylamine. The symmetric anhydride method was used for the coupling of the amino acids, and DCC was the coupling reagent. The following cycle of reactions was used to introduce each new residue (Table 7) ... 

Another means of overcoming the sterically very demanding coupling reactions is to reduce the bulkiness of the residues, inherent to the presence of both the C"ra-disubstitu-tion, and the urethane protecting group. This has been demonstrated by the use of a-azi-do acids in which the azide is the precursor of the amino function [113]. These monomers can be activated as acid chlorides, and their preparation is also compatible with the presence of the side chain protecting group used in Fmoc-based peptide synthesis. This approach has been exploited in the solid-phase synthesis of a-aminoisobutyric acid (Aib)-rich peptides [114]. 

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