Peptide Fragment Condensation

One of the few studies on the application of peptide fragment condensation on soluble polymer supports was published by Narita et al. [39,97-100]. First, they prepared the chloromethyl polystyrene support, not by the usual polymer-analogous chloromethylation reaction but by copolymerization of styrene with chloromethyl styrene in a molar ratio of 1 9 ... 

Having initiated the study because of the serious proMems in fragment condensation on crossUnked polymer supports, they actually found that amino groups were present in the support poly(styrene-co-divinylbenzene) which were sterically inaccessible for peptide fragments such as Boc-(Ala)2-(Leu)3-OH and Boc-(Ala)2-(Leu)3-(Pro)2-(Leu)3-OH. Finally, they emphasized the versatiUty of soluble supports and the Umitations of crossUnked polymer supports for peptide fragment condensation. 

The N-to-C assembly of the peptide chain is unfavorable for the chemical synthesis of peptides on solid supports. This strategy can be dismissed already for the single reason that repeated activation of the carboxyl ends on the growing peptide chain would lead to a much higher percentage of racemization. Several other more practical disadvantages also tend to disfavor this approach, and acid activation on the polymer support is usually only used in one-step fragment condensations (p. 241). 

The gastrointestinal hormone secretin is prepared by fragment condensation. The tetrapeptide L-Thr-L-Phe-L-Thr-L Ser is coupled to the C-terminal nonadecapeptide of the hormone, and the tetrapeptide L-His-L-Ser- 3-benzyl-L-Asp-Gly is coupled to the tricosa-peptide resulting from the first coupling. 

A superspiral consisting of two spirals (coiled coil), known as the leucine zip, is formed in this sequence via dimerisation. The condensation reaction, carried out in the aqueous phase, involves two peptide fragments which contain 15 and 17 amino acid residues respectively. Activation takes place via thioester formation (see Sect. 5.3.1). The ligation to a complete GCN4 matrix gives a new 32 amino acid peptide, which can itself serve as a matrix. The autocatalytic reaction exhibits a parabolic increase in the peptide concentration (caused by product inhibition see Section 6.4). 

El, Ed electrophilic peptide fragments consisting of 17 D- and L-amino acid residues T condensation product formed from E and N TlL, Tdd peptide containing only L- or D-amino acid sequences Tdl peptide containing both amino acid species... 

Simplicity. The simplest building blocks suitable for the given task can be efficiently condensed within themselves or with related building units with complementary functionalities, leading to complex structures, analogous to fragment condensation in peptide synthesis . ... 

It has long been recognized that fragment condensation on a solid phase would be highly desirable. 1,5,6 However, the solid-phase fragment coupling approach has been limited by the notoriously poor solubility properties of fully protected peptides that make them difficult to purify and characterize. 

Route A utilizes Boc/Bzl chemistry for the synthesis of the main peptide with Fmoc/OFm at the side-chain functions where additional chemistry is performed. For synthesis of extended cyclic peptides, the /V "-Fmoc group is removed and the extension is synthesized with Fmoc/ Bzl chemistry, whereas for reverse-extended cyclic peptides, the to-Fm ester is hydrolyzed and the peptide spacer is built up in the N-to-C direction with fluorenylmethyl esters with all the risk of epimerization or more correctly, it is incorporated by fragment condensation. 

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