Side-chain cyclization

P Rovero, S Pegoraro, F Bonelli, A Triolo. Side reactions in peptide synthesis dehydration of C-terminal aspartylamide peptides during side chain to side chain cyclization. Tetrahedron Lett 34, 2199, 1993. 

Pyroglutamyl peptides are synthetically accessible either by side-chain cyclization of related glutaminyl and glutamyl peptides or by direct acylation of suitably protected peptides with Na-protected or unprotected pyroglutamic acid. 

Due to the relatively high flexibility of cyclic peptides of larger ring size an additional cyclization is sometimes used to constrain their conformation, even by nature, e.g. amanitins and phalloidins. 316 For this purpose primarily side-chain-to-side-chain cyclization is adopted, e.g. Glu/Asp versus Lys or disulfide bridges 1322 alternatively, even the principle of backbone cyclization is applied (see Section 6.8.4)J29>80 323>3241... 

Head-to-Side-Chain and Side-Chain-to-Side-Chain Cyclized Peptides with Boc/Bzl Chemistry General Procedure ... 

H-Thr-TlmGlu-Thr-Ala-Ser-Ala-Arg-Gly-Asp-Leu-Ala-His-Leu-Thr-Thr-Thr-His-Ala-Lys-His-Leu-OH Typical Procedure for Side-Chain-to-Side-Chain Cyclized Peptides with Boc/Bzl Chemistry 1 1 1... 

Among the electrophilic handles proposed for head-to-tail and side-chain-to-tail cyclization of peptides on solid support by intrachain aminolysis with concurrent detachment of the product from the resin in the protected form (see Section 6.8.3.1.3), generally the oxime resin (also called Kaiser resin)1364 365 and a thioester resin[363l are recommended (see Scheme 14). In addition to the classical head-to-tail cyclization,[3431 the oxime resin is used for side-chain cyclizations as well as for the synthesis of multicyclic peptides vide infra). Due to its dual functions, the oxime resin can be employed only with Boc/Bzl chemistry it is not compatible with Fmoc/tBu chemistry where the basic N -deprotection leads to free amino groups and thus to premature cyclization reactions. To avoid this premature cleavage of the... 

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... 

The synthesis of type I bicyclic peptides is the most simple as the two side-chain-to-side-chain cyclizations can be performed successively on the assembled peptide or more appropriately by condensation of the two monocyclic segments preferably in solution. As shown in Scheme 23 (path A), for the synthesis of suitably protected monocyclic peptides, side-chain attachment of Asp or Glu residues to the oxime resin is proposed,[436,43T which leads to the desired cyclization and release of the protected segments as Pac or preferably as A1 es-tersJ396 These are C-terminally deprotected, when required, and then assembled in solution into bi- or polycyclic peptides of type I. 

The synthesis and on-resin cyclization of polycyclic peptides of type I is described in the experimental part of Section 6.8.3.2.3. If side-chain-to-side-chain cyclization is needed the couplings of H-Gly-OFm and Fmoc-Gly-OH should be omitted from that procedure. 

Cysteine is a key amino acid in many proteins, serving as an important catalytic moiety in e.g. cysteine proteases, but most importantly serving as a stabilizer of secondary structures by formation of disulfide bonds. Cysteine side-chain-to-side-chain cyclization is also widely used to stabilize secondary structures important for the bioactivity of peptides.[1121... 

For this discussion, bioactive peptides will be defined as peptides which interact specifically with a target macromolecular acceptor or are derived from domains involved in a critical protein-protein interaction and, therefore, can compete effectively to mimic or disrupt this bimolecular interaction. Once the structure-activity relationship of a bioactive peptide is revealed, one can identify the termini and/or positions in which introduction of a caging group will be disruptive for target recognition. Alternatively, caging the peptide in an inactive conformation can be accomplished by end-to-end or end-to-side-chain cyclization. 

Peptide aldehydes are fairly reactive and usually exist in solution partially as hydrates Xaa[CH(OH)2] (e.g., 3), which are identified using 13C NMR spectroscopy. 3 3" With amino acids containing nucleophilic side chains, cyclized forms predominate (Scheme 2). Argininal analogues such as Z-Leu-Phe-Arg-H have been shown to exist primarily as the carbinol amine 4 with no spectroscopic evidence for an iminium structure. Lysinal derivatives such as Z-Leu-Phe-Lys-H exist both as a cyclic carbinol amine 5 and as an iminium ion 6 as shown by 3H and 13C NMR spectra. The C-terminal ornithinal analogue Z-Leu-Phe-Orn-H exists primarily as the carbinol amine form 7 and the cyclic iminium form 8 as characterized by the 13C NMR spectra. 3,21 In general, the existence of carbinol and iminium cyclized forms does not preclude the existence of the free or hydrated aldehydes under aqueous conditions. 

The cyclic peptide systems in nisin can be considered as side chain-cyclized peptide derivatives. However, they do not contain disulfide bridges, which is the most common... 

The side-chain cyclizations are the basis for conformative rigidity of the molecules and thus for the antibiotic activity of glycopeptide antibiotics. 

Scheme 2-6. The order of the side-chain cyclization reactions performed by three P450-dependent monooxygenases (OxyA/B/C).

The effect of reduced FBP on catalyst deactivation is not related to the reaction temperature as this was similiar for the naphthas with different FBP (Figure 9). Therefore the amount of coke precursors in the heavy end is the important factor. Table II presents the identified C,o aromatics (the heaviest components present in more than just trace concentrations) in the reformate at 102.4 RON. There is a distinct difference between the base naphtha and the FBP 149 °C naphtha with respect to feedstock as well as reformate content of propyl-toluenes and n-butylbenzene, which both can form bicyclic aromatics through direct side-chain cyclization. 

The essential condensation domain mentioned above can, in some cases, not only condensate but also catalyze a side-chain cyclization. It is then called cyclization (Cy) domain. The cyclization is initiated by a nucleophilic attack of the side-chain heteroatom on the carbonyl group of the amide bond formed by... 

Cyclization is one of the earliest techniques applied to design peptidomimetics. Cyclic peptides are more stable to amide bond hydrolysis and allow less conformational flexibility consequently, the resulting analogs are anticipated to be more selective and less toxic. Methods for restricting conformations include peptide backbone cyclization, disulfide bond formation, side-chain cyclization, and metal ion chelation. 

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