Condensation fragments

The following short descriptions of the steps involved in the synthesis of a tripeptide will demonstrate the complexity of the problem amino acid units. In the later parts of this section we shall describe actual syntheses of well defined oligopeptides by linear elongation reactions and of less well defined polypeptides by 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. 

Another solid phase fragment condensation with CDI and 1-hydroxybenzotriazole in the synthesis of the human insulin B-chain afforded the oligopeptide in 75% yield. The reaction time with the coupling pair CDI/HOBt was shorter than in the case of the DCC/ HOBt system.136 The CDI/HOBt activation method was also applied to the synthesis of a... 

A huge number of transition metal-sulfur clusters have been synthesized,36 most of which have been obtained based on the self-assembly methods. On the other hand, to construct the cluster cores with the desired metal-sulfur compositions and connecting schemes, rational pathways leading to the high-yield syntheses of tailored metal-sulfur clusters have recently been explored. Fragment condensations have been demonstrated to be the powerful methods to obtain such clusters numerously,37 some examples of which are shown below. 

Fe4(p3-S)3(p2-S)3, a 10-atom cluster present in the nitrogenase M center. Fragment condensation was used by the authors of reference 37 to synthesize [MoFe6S6(CO)i6 2 from the fragments Fe2S2(CO)612 and [Mo(CO)4I3] . None of the clusters mentioned so far mimic either the total structure or any function of those present in MoFe-protein. 

Scheme 13.8 Synthesis of a lipoglycopeptide by means of fragment condensation methodology.

Of course, isotope filtering is not restricted to such binary systems, but can also be applied to multicomponent systems such as multiprotein complexes, or one or more ligands bound to proteins or protein complexes. It is also conceivable to construct single molecules from sections with different isotopic labeling in order to selectively observe one part by isotopic filtering. However, in these cases a specific synthetic approach has to be designed to allow for efficient incorporation of the isotope labels into the appropriate parts only (for example, by fragment condensation or inteins see also Chapt. 1) [5]. 

The scheme of cluster condensation or cluster fragment condensation leads eventually to structures observed in bulk metals. Particularly through extensive condensation of tetrahedral and octahedral clusters, arrangements closely related to the hexagonal and cubic close-packed structures can be obtained. Condensation also of icosahedral five-fold symmetrical clusters may be related to crystalline and quasicrystalline metallic structures. 

Temperature-dependent (at 25 °C 907 bp DNA fragments condensate as B-DNA with a contour length of approximately 320 nm, while at 25 °C they condensate as A-DNA with a contour length of approximately 250 nm)... 

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 . ... 

Scheme 5 Total Synthesis of Human Insulin by Selective Formation of Disulfides at Different Stages of a Fragment Condensation Scheme 1... 

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. 

Scheme 21 Synthesis of Human Insulin by the Fragment Condensation Strategy in Solution1184183 ...

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. 

Note that proteins are now synthesized routinely by stepwise assembly or fragment condensation (see Vol. E22a, Section 4.1 ) 67 68 and chances of product contamination with shorter fragments that may have similar retention times under RP-HPLC should be considered 69 Additionally, size-exclusion HPLC was found to be particularly useful in distinguishing linear from cyclic peptides. 

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