Homodetic peptides

Blackburn, C., and Kates, S. A. (1997) Solid-phase synthesis of cyclic homodetic peptides. Methods Enzymol. 289,175-198. 

Ghadiri, R.M. Cyclic Homodetic Peptides with Repeating d-l Chirality, Employable for Assembling and Disassembling Molecular Tubes, 96-632444 6613875 (2003). 

Silyl ethers of hydroxy amino acids have been employed in both solid-phase and solution peptide synthesis. Since the TBDMS and TBDPS ether groups are stable to piperidine and other basic reagents, these derivatives of Ser and Thr (Tables 8 and 9) can be used in the Fmoc strategy.Homodetic peptides and depsipeptides have also been synthesized using TBDMS hydroxy protection for phenyllactic acid and hydroxyisovaleric acid, respectively. 

Homodetic peptide, a peptide containing exclusively peptide bonds. 

Peptides in which all of the covalent linkages between the constituent amino acids are peptide bonds are termed homodetic peptides, whereas those that contain peptide bonds together with other covalent linkages between certain amino acid residues are called heterodetic peptides. Examples of these covalent linkages... 

The cycle of a homodetic peptide contains only eupeptide bonds formed from two a-amino acids. The other peptide bonds are known as Isopeptides . 

Cyclic dipeptides, bearing the DKP ring, in which the amide linkages are cis, are known to represent the simplest form of homodetic cyclic peptides. ... 

Cyclic peptides in which the ring consists solely of aminoacid residues with eupeptide links may be called homodetic cyclic peptides. Three representations are possible. Gramicidin S is given as an example. In this decapeptide, all amino acids are l, with the exception of Phe which is d, as is shown by o-Phe or oPhe. 

Homodetic cyclic peptides are classified according to the location of the ring juncture as shown in Scheme 1. The most common mode of cyclization is head-to-tail where ring closure occurs by amide bond between the N-terminal amino group and the C-terminal carboxy group. Additional ring closures involve side-chain functionalities such as head-to-side-chain, side-chain-to-side-chain or side-chain-to-tail cyclizations. Moreover, in backbone cycliza-tions 29 (see Section 6.8.3.2.4) the backbone amides may be linked to a second backbone amide or to side chains as well as to the termini of the peptide. 

In addition to homodetic cyclic peptides, chemical ligation methods have been developed that lead to heterodetic cyclic peptides containing thiazolidine. 158-161 ... 

Synthesis of Homodetic Cyclic Peptides on Solid Support... 

In the following discussion a selection of optimized procedures is presented for the synthesis on solid support of homodetic monocyclic and bicyclic as well as mixed homodetic/ heterodetic bicyclic peptides that contain at least one lactam ring, whereas heterodetic cyclic peptides containing other than amide bonds or peptidomimetics are not discussed here because of their unlimited diversity. 

Both homodetic and heterodetic cyclizations via the peptide termini and/or the sequence-encoded side-chain functionalities limits the variability in ring size and chemistry. In order to enhance the diversity in these terms, the concept of extended and reverse-extended lactam ring (also called branched peptides) was introduced.1415 As shown in Scheme 19, this necessitates an additional spacer consisting of an amino acid residue or of a peptide chain inserted between the two side-chain functionalities involved in cyclization. Depending upon the parallel or antiparallel orientation of the inserted spacer, the resulting constructs are termed extended (branched) and reverse-extended peptides.[415]... 

The bicyclic peptides that have been synthesized with at least one lactam ring correspond to the structures shown in Scheme 22, and examples of such syntheses of homodetic or mixed homodetic/heterodetic structures are listed in Table 12. For bicyclic or polycyclic cystine peptides see Sections 6.1 and 6.2. In the ring structures of types I-III both rings derive from side-chain-to-side-chain cyclizations. In the structures of types IV-VI an cofunctionalized amino acid is employed as bridgehead. This can be linked directly to three... 

Similarly, the mixed homodetic/heterodetic bicyclic structures containing a disulfide bridge are preferably produced as monocyclic compounds that are then typically oxidized in solution adopting standard procedures as described in Section 6.1.1 (Scheme 23, path Bl). If even disulfide formation is performed on resin by the procedures reported in Section 6.1.2, an additional level of selective protection is required for the cysteine thiol functions. The synthetic paths Bl and B2 are also applicable for the synthesis of type II and III bicyclic peptides, independent of whether only lactam bridges are produced or mixtures of lactam/ disulfide bridges. 

Blaha, K. Linear Peptides Synthetic Methods Wade, R. Linear Peptides Synthesis and Structure — Activity Relationships Wieland, T., Birr, C. Homodetic Cyclic Peptides, in Amino Acids, Peptides and Related Compounds, International Review of Science, Vol. 6 (ed. Rydon, H. N.), p. 73, 97, 183, Butterworths, London 1976... 

The oxime resin 5z [255,256], which forms an acid-stable anchor for the carboxyl group of amino acids, has been used for some time for the synthesis of C-terminal modified peptides and homodetic cyclic peptides. The key step in lactam formation is intramolecular nucleophilic attack of the A-terminus at the anchoring group. The resin also reacts with isocyanates and the products undergo nucleophilic attack by amines resulting in the release of ureas [257], Resin-bound Boc-tryptophan has been used in the acid-catalyzed Pictet-Spengler synthesis with final products cleaved as primary amides by... 

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