Solid-phase peptide synthesis coupling protected amino acids

The first version of solid-phase peptide synthesis (SPPS) to be developed used the /-Boc group as the amino-protecting group. It can be cleaved with relatively mild acidic treatment, and TFA is usually used. The original coupling reagent was dicyclohexylcar-... 

The development of chiral peptide-based metal catalysts has also been studied. The group of Gilbertson has synthesized several phosphine-modified amino adds and incorporated two of them into short peptide sequences.[45J,71 They demonstrated the formation of several metal complexes, in particular Rh complexes, and reported their structure as well as their ability to catalyze enantioselectively certain hydrogenation reactions.[481 While the enantioselectivities observed are modest so far, optimization through combinatorial synthesis will probably lead to useful catalysts. The synthesis of the sulfide protected form of both Fmoc- and Boc-dicyclohexylphosphinoserine 49 and -diphenylphosphinoserine 50 has been reported, in addition to diphenylphosphino-L-proline 51 (Scheme 14).[49 To show their compatibility with solid-phase peptide synthesis, they were incorporated into hydrophobic peptides, such as dodecapeptide 53, using the standard Fmoc protocol (Scheme 15).[451 For better results, the phosphine-modified amino acid 50 was coupled as a Fmoc-protected dipeptide 56, rather than the usual Fmoc derivative 52.[471 As an illustrative example, the synthesis of diphe-nylphosphinoserine 52 is depicted in Scheme 16J45 ... 

Due to the suppression of racemization and the ability to couple sterically hindered substrates, this methodology has been utilized in solid-phase peptide synthesis. In particular, 9-fluorenyl-methoxycarbonyl-protected amino acid fluorides have been used with this protocol.110 1,3... 

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... 

Peptide synthesis Polypeptides can be chemically synthesized by covalently linking amino acids to the end of a growing polypeptide chain. In solid phase peptide synthesis the growing polypeptide chain is covalently anchored at its C-terminus to an insoluble support such as polystyrene beads. The next amino acid in the sequence has to react with the free a-amino group on the tethered peptide, but it has a free a-amino group itself which will also react. To overcome this problem the free amino acid has its a-amino group chemically protected (blocked) so that it does not react with other molecules. Once the new amino acid is coupled, its now N-terminal a-amino group is deprotected (deblocked) so that the next... 

Figure 5-14. The Boc strategy for solid phase peptide synthesis. Synthesis proceeds from the C- to the N-terminus. Initially, one amino add (here alanine) protected on its amino group by a Boc group, is coupled to the inert resin using dicyclohexylcarbodiimide (DCCI). The Boc protecting group is cleaved off by treatment with acid. On neutralisation, the next amino acid...

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) ... 

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