Segment condensation

J Bodi, H Nishio, T Inui, Y Nishiuchi, T Kimura, S Sakakibara. Segment condensation of sparingly soluble protected peptides in chloroform-phenol mixed solvent, in S Bajusz, F Hudecz, eds. Peptides 1998. Proceedings of the 25th European Peptide Symposium. Akademiai Kiado, Budapest, 1999, pp 198-199. 

Table 1 C-Terminal Amino Acid Residues Acceptable for Segment Condensation Reactions...

Solid-Phase Segment Condensation - The Application of Backbone Protection to Solid-Phase Protein Synthesis... 

Scheme 2 Structure of the Pentacyclic 34-Residue Peptide Antibiotic Nisin and Strategy Used for Segment Condensation 13 ...

Historically, the methods used for ring closure of linear precursor peptides via amide bond formation evolved in parallel to the methods applied in segment condensations from the azide and active ester procedures to the use of coupling reagents such as DCC in the presence of additives, or of the more recently developed phosphonium and uronium/gua-nidinium reagents. In all cases the choice of method is mainly dictated by the epimerization problem when chiral amino acids act as the carboxy component in the cyclization reaction, and by other side reactions. 

Indeed, there were those who described the azide coupling method as racemization-free. [15l However, this viewpoint proved to be overly optimistic. In 1970, Sieber reported that during a synthesis of calcitonin M by the azide method, significant epimerization occurred during two of the segment condensation steps in one of these reactions 40% of the epimerized product was observed. 16 There is a crucial detail in the experimental procedure here. The workers used tert-butyl nitrite to convert a peptide hydrazide into a peptide azide, but did not isolate the azide as was typical for research at that time. Instead, they neutralized the active intermediate in situ with DIPEA and added the amino segment for acylation. This demonstrates another important theme in the control of epimerization, the presence of a tertiary amine in the reaction mixture, even if only as a neutralization equivalent, can result in the formation of epimerized products. Indeed, most observations of racemization during... 

On the other hand, pyrenyl-L-alanine 184 has also been used as a conformational probe in the characterization of an artificial 4-a-helix bundle protein.11,121 The 53-residue peptide 186 incorporating one residue of 184 in each of two different helical segments was synthesized by solid-phase synthesis using a segment condensation strategy and the oxime resin. Boc-pyrenyl-L-alanine 191 was coupled just like any other amino acid by the BOP/HOBt method in DMF. CD and fluorescence studies demonstrated that the two pyrene groups were in close proximity forming an excimer complex, which is possible only when the polypeptide chain folds into a 4-a-helix bundle structure. 

The spontaneous formation of piperazine-2,5-diones occurs mainly during N-deprotection or the acylation step to dipeptide esters (usually unhindered esters such as Me, Et, Bzl, and Pac esters) that contain an TV-alkyl amino acid especially at the C-terminusJ152 In some cases the formation of piperazine-2,5-diones becomes the major reaction product and thus prevents peptide elongation by the [1+2] or [1+3] segment condensation strategy in solution synthesis or elongation of the peptide from the C-terminus in SPPS. Piperazine-2,5-dione formation... 

This tripeptide was a key intermediate in an attempted preparation of c[3-(benzyloxymethyl)-2-nitrobenzoyl-Thr-D-Val-Pro-Sar-(Me)Val-] by the [2+3]-segment condensation strategy peptide and cyclization between Sar and (Me)Val. This side reaction was circumvented by using the dipeptide H-D-Val-Pro-OtBu in a [3+2]-segment condensation strategy. Contrary to its benzyl ester, this dipeptide did not form the piperazine-2,5-dione because of presence of the bulky tert-butyl ester.[165 1661 Cyclization was performed between Pro and Sar. 

Scheme 34 Synthesis of an (Oxomethyleneamino) Peptide by Segment Condensation using a Chloromethyl...

Using a solution segment condensation reaction analogous to that described above it is possible to obtain a maximal 50% yield of a monosubstituted template using one equivalent of peptide nucleophile. The monosubstituted product can be purified away from the unsubstituted and disubstituted templates, and subjected to a second coupling reaction with a different peptide nucleophile affording an unsymmetrical peptidomimetic, albeit in modest yield. 

Helical modes represent a most significant structural motif in biology. The a-helical coiled coil is nature s route for dimerizations.Such molecules can interact with DNA and function as important components of many biological systems (Section 13.2). The synthesis of coiled coils in solution and by segment condensation is described (Sections 13.2.1.1 and... 

Cyclosporin (Section 16.1.3) is an undecapeptide that acts as a potent immunosuppressant. Seven of its eleven residues are N-methylated. Its synthesis in solution was carried out by a series of segment condensations)32,33 The didemnins (Section 16.1.4) are isolated from marine organisms known as tunicates. Their therapeutic potential lies in applications as antitumor, antiviral, and immunosuppressant agents. The didemnin family of natural products contains peptidomimetic residues including A,0-dimethyltyrosine-proline and leucine—2-(hydroxyisovaleryl)propionic acid and (4-hydroxy)-2,5-dimethyl-3-oxo-... 

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