C-terminal carboxy group

Due to the vast numbers and rapidity of novel developments in solid-phase synthesis over the past ten years, a number of reports currently found in the literature deal with solid-phase syntheses of lanthionine peptides. There are at least two different approaches to synthesize lanthionine peptides in which the sulfide bond links amino acid halves that are not direct neighbors within the peptide chain (Scheme 10). One obvious approach, method A, is based on the coupling of a preformed, orthogonally protected lanthionine monomer to the N-terminus of a peptide oxime resin. 48 This is then followed by acid-catalyzed cyclization and simultaneous release from the resin during amide bond formation with the C-terminal carboxy group via the peptide cyclization method on oxime resin (see Section 6.73.2.2). The alternative approach is lanthionine formation after peptide synthesis from amino acid derivatives, such as serine and cysteine (method B). 

The antibiotic viscosin from Pseudomonas viscosa (Scheme 8) is a cyclo-depsipeptide acyl-ated at the N-terminus with D-3-hydroxydecanoic add.[103 112] The C-terminal carboxy group is esterified with the hydroxy group of the Thr3 residue. The synthesis of this natural product presents the problem of an ester ring closure and was performed in two steps with initial solid-phase synthesis of the Thr3-0-branched linear intermediate followed by ring closure with formation of the amide bond.1 131... 

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. 

The choice of protecting groups and of the type of resin-anchor required for synthesis of cyclic peptides on solid supports not only depends upon the particular amino add sequence of the target molecule, but decisively upon the mode of cyclization, particularly whether the C-terminal carboxy group should act as bridgehead or not. Correspondingly, the synthetic routes can be subdivided into two main classes either based on the attachment of the C-terminus to the solid support by suitable anchors or where side-chain functionalities are exploited for this purpose. 

Scheme 17 General Strategies for Peptide Cyclizations On Resin Involving the C-Terminal Carboxy Group...

To obtain free peptides having C-terminal carboxy groups from Boc/Bzl syntheses, the peptide-resin is cleaved with anhydrous strong ( hard ) acid. Liquid anhydrous HF is the cleanest and most used reagent for this purpose. 

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