Macrocyclization of peptides

Because thioether formation is a rapid, irreversible reaction, it has been widely used for the macrocyclization of peptides or peptoids on supports (Entries 1-4, Table 8.5 [62]). For this purpose, either S-protected cysteine or S-protected co-aminomercap-tans are linked to a support and then elongated by standard solid-phase peptide/pep-toid chemistry. When a suitable length has been reached, the terminal amine is acy-... 

In all above examples, macrocyclization of peptidic amino acids by Ugi reaction is the expected transformation, while cyclodimerization is considered to be undesired. Against this notion, Wessjohann and coworkers designed a tethered amino acid having such a backbone that head-to-tail cyclization was impossible because of the conformational constraint [81]. Thus, a twofold Ugi reaction of C-3 amino... 

The orthogonality of allyl-based protection toward Boc and Fmoc groups also allows its use for the side-chain protection of hnear and branched peptides as well as for glycopeptides. It also enables specific deprotection at preselected side-chain groups for macrocyclization of peptides. 

Fig. 8 The head-to-tail macrocyclization of peptides through a traceless Staudinger ligation...

Hackenberger and Kleineweischede reported a traceless Staudinger ligation for the head-to-tail macrocyclization of peptides without a deprotection step (Fig. 8) [63]. In this strategy, a phosphine tethered to a thioester at the C-terminus of a peptide reacts intramolecularly with an azide at the N-terminus to form the cyclic peptide. 

The intermolecular Mizoroki-Heck reaction in macrocyclization of peptides was demonstrated by Byk et al. [207]. The reactions were done out in milligram scale with 15-25% yield. The Pd/C-catalysed Mizoroki-Heck reaction of aryl halides and butyl acrylate performed in an excellent manner. The catalyst could be reused five times without loss of activity [208]. Yields up to 90% could be achieved using bromoarenes and a catalyst loading of 1.5 mol% in a few minutes reaction time. 

Akaji and Kiso demonstrated another interesting example of a Heck cyclization toward the macrocyclization of peptides. The cyclization reaction was faciUtated by the pseudo-high dilution conditions afforded by the sohd support to reduce dimer or ohgomer formation. An iodobenzylamine was coupled to Fmoc-Asp(OfBu)-OH, which was then deprotected and immobilized on a sohd support. Standard Fmoc-based peptide synthesis was then performed and the peptide was capped with an acrylic acid monomer. The Heck macrocyclization was then performed on both the sohd support and in solution phase. Interestingly, based on the HPLC analysis of the reaction mixture, the cychzation on the solid support was generally completed within 2 h (affording a 30% overall yield), while the corresponding solution-phase reaction required approximately 8 h (the yield of the solution-based reaction was not reported). 

Figure 10.11 Macrocyclization of peptides by click chemistry between propargylic acid residues and an azide- functionalized amino acid...

Eunctionalized supramolecular systems based on monolayers of bioactive compounds (macrocyclic ionophoric peptides, crown ethers, nucleoside derivatives) 98MI12. 

The macrocyclization of a peptide was carried out by nucleophihc substitution on a fluorobenzene by the sulfide group of the terminal cysteine of a pentapeptide [164]. The peptide 261 was prepared by standard SPPS and was cyclized under microwave irradiation at 50 °C for 10 min in DMF (Scheme 96). The yields of 262, after cleavage with TFA, were remarkably high for a macrocyclic peptide (70%) and also the resulting HPLC purity was very high. 

Kohli, R.M., Burke, M.D., Tao, J. and Walsh, C.T. (2003) Chemoenzymatic route to macrocyclic hybrid peptide/ polyketide-like molecules. Journal of the American Chemical Society, 125, 7160-7161. 

Macrocyclization of esters of allylglycine with diols has been successfully used to prepare derivatives of 2,7-diaminosuberic acid [861,864]. The latter are surrogates of cystine, and therefore of interest for the preparation of peptide mimetics. For unknown reasons protected allylglycine derivatives can not be directly dimerized by self metathesis [864]. However, catechol [864], ethylene glycol [861], and 1,2- or 1,3-di(hydroxymethyl)benzene derivatives [860] of allylglycine are suitable templates for the formal self metathesis of this amino acid via RCM. 

Interest is mounting in this state, promoted once again by its possible implication in biological systems. Galactose oxidase, for example, is a copper enzyme which catalyses the oxidation of galactose to the corresponding aldehyde. The tervalent oxidation state may be prepared from Cu(II) by chemical, anodic and radical oxidation. Cu(III) complexes of peptides and macrocycles have been most studied, particularly from a mechanistic viewpoint. The oxidation of I" by Cu(III)-deprotonated peptide complexes and by imine-oxime complexes have a similar rate law... 

The energetics of peptide-porphyrin interactions and peptide ligand-metal binding have also been observed in another self-assembly system constructed by Huffman et al. (125). Using monomeric helices binding to iron(III) coproporphyrin I, a fourfold symmetric tetracarboxylate porphyrin, these authors demonstrate a correlation between the hydropho-bicity of the peptide and the affinity for heme as well as the reduction potential of the encapsulated ferric ion, as shown in Fig. 12. These data clearly demonstrate that heme macrocycle-peptide hydrophobic interactions are important for both the stability of ferric heme proteins and the resultant electrochemistry. 

Figure 1.11 Covalent capture of peptide macrocycle dimer (Ghadiri).

The synthesis of a small library of very large (up to 60-membered) steroid/ peptide hybrid macrocycles has been achieved using double and fourfold Ugi reactions. This type of compound has not previously been described in literature. Neither have multicomponent reactions been used so far to form directly macrocycles of this size. In fact, synthetic macrocycles of this size with this structural complexity are very rare. 

This review will focus on the use of MCR approaches to cyclic peptides, cyclic peptidomimetics, or cyclic pseudopeptides, including small or medium-sized heterocycles as mimics of peptide motifs and macrocycles with amino acid or peptide moieties. 

Straightforward, versatile, and generates libraries of macrocyclic pseudo peptides with unprecedent functional and skeletal diversity. For example, natural product-inspired biaryl ether-cyclopeptoid macrocycles were obtained by this methodology [98, 99]. 

Scheme 13 Solid-Phase Peptide Synthesis of an Enkephalin Analogue by Macrocyclization of Cysteine and Dehydroalaninel271...

Approaches to artificial ion channels have, for instance, made use of macrocyclic units [6.72,6.74] (see also below), of peptide [8.183-8.185] and cyclic peptide [8.186] components, of non-peptidic polymers [8.187] and of various amphiphilic molecules [6.11, 8.188, 8.189]. The properties of such molecules incorporated in bilayer membranes may be studied by techniques such as ion conductance [6.69], patch-clamp [8.190] or NMR [8.191, 8.192] measurements. However, the nature of the superstructure formed and the mechanism of ion passage (carrier, channel, pore, defect) are difficult to determine and often remain a matter of conjecture. 

In view of the importance of chiral resolution and the efficiency of liquid chromatographic methods, attempts are made to explain the art of chiral resolution by means of liquid chromatography. This book consists of an introduction followed by Chapters 2 to 8, which discuss resolution chiral stationary phases based on polysaccharides, cyclodextrins, macrocyclic glyco-peptide antibiotics, Pirkle types, proteins, ligand exchangers, and crown ethers. The applications of other miscellaneous types of CSP are covered in Chapter 9. However, the use of chiral mobile phase additives in the separation of enantiomers is discussed in Chapter 10. 

Marshall and coworkers proposed the utilization of metal complexes of chiral azacrowns (MACs) as a strategy to influence the conformation of these macrocycles and to fix the chiral side chains in orientations comparable with those of peptidic p-tums [18-20]. For example, the MAC complex 3 was proposed to serve as... 

Flexible peptides can be conformationally restricted by a variety of methods other than macrocyclization of the peptide. For example, Marshall et al. introduced a-methyl amino acid substituents into peptides as a way to decrease the conformational space available to the resulting peptide (42) these types of approaches led to his "Active Analog" approach for determining bioactive conformations of flexible molecules (43). Some other traditional... 

A mechanistically related and mild fragmentation is that of 2-trimethylsilylethyl esters (Tmse esters). The Tmse residue is a selectively cleavable carboxy-protecting group (see Volume 6, Chapter 3.2) Examples are known for the synthesis, via these esters, of peptides, macrolides such as curvularin and macrocyclic trichothecenes like verrucinol (Scheme 54). °... 

An enzyme has been isolated from the FK520 producer which is believed to be the key one responsible for inserting pipecolic acid into the macrocycle [114]. It is reported to be dimeric and activates pipecohc acid and several structural analogues in an ATP-dependent reaction to give an enzyme-bound amino-acyl adenylate. There is evidence that this then reacts to form a thioester linkage to the enzyme. This mechanism of activation is the same as that found in the non-ribosomal biosynthesis of peptide natural products such as gramicidin [112]. 

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