Cyclization linear peptides

Many medicinally useful peptides have cyclic structures. Cyclization may result if the amino acids at the two termini of a linear peptide link up to form another peptide bond. Alternatively, ring formation can very often be the resnlt of ester or amide linkages that utilize side-chain functionalities (CO2H, NH2, OH) in the constituent amino acids. 

Many natural products are constrained by macrocyclic motifs, which are often essenhal for natural products to possess the desired biological properties. In the biosynthesis of macrocyclic NRPs and PKs, linear peptides or PKs are often mac-rocyclized by a TE domain located at the C-terminal of multi-modular synthases. For example, in the biosynthesis of the antibiotic tyrocidine A (Tyc A), a linear enzyme-bound decapephde, which is transferred from the last carrier protein (or thiolahon) domain of the Tyc A synthase, is cyclized by an intramolecular Sn2 reachon between the N-terminal amine nucleophile and the C-terminal ester, which is covalently linked to serine residual in the TE domain prior to macro-cyclization (Scheme 7.9) ([35] and references therein). 

In addition to the most common methods for cyclization of linear peptides (vide supra), alternative coupling reagents have been used with varying success such as BOP-Cl, 140-142 norborn-5-ene-2,3-dicarboximido diphenyl phosphate (NDPP),119-143-144 pentafluorophenyl diphenylphosphinate (FDPP),1145-148 diethyl phosphorocyanidate (DEPC), 138-149 or T3P.197-1501... 

Several methods have been developed for the incorporation of thioamide bonds at defined positions into linear peptides (for details see Vol. E 22c, Section 10.9.1) 498,499 The resulting linear precursors can be cyclized by standard procedures, although the thioamide bond should not be located in penultimate position, since activation of the carboxy group leads to thia-zolone formation as outlined in Scheme 31.1500-502 The cyclization yield of thioamide-containing peptides is generally rather low. This effect results from the additional local steric restrictions exerted by the thioamide bond, which leads to decreased conformational flexibility 488 ... 

The conformational analysis of cyclic peptides is generally more straightforward than that of a linear peptide with the same number of residues. This is a result of the constraints imposed by cyclization. 

Methoxypiperazine-2,5-diones have been obtained by the formic acid cyclization of the corresponding linear peptides (91T563). The latter were obtained by electrochemical oxidation of normal dipeptides (Scheme 4). The electrolysis was performed in MeOH-lithium perchlorate (0.1 M) containing NaCl at a platinum anode and was found to be totally regiose-lective. 

Lambert and co-workers50 also synthesized a pair of cyclic octapeptides 82 and 83 and studied their propensity to form nanotubular aggregates (Fig. 5). A linear peptide was initially synthesized on SynPhase Crowns with a Rink amide handle by standard Fmoc chemistry. The first residue used was aspartic acid protected as the ct-allyl ester. The support-bound linear peptide was cyclized in a head-to-tail manner by deprotection of... 

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