Synthesis of Cyclic Peptides

The present author has synthesized a number of cyclic peptides containing imino acid residues such as Cyclo-(Sar2), Cyclo-(Sar-Gly), Cyclo-(Sar4), Cyclo-(Sar6), Cyclo-(Sar-Sar-Gly)2, Cyclo-(Pro-Sar-Gly)2, and Cyclo-(Sar-Gly-Gly)2. For example, the syntheses (20) of CyclO Sar-Sar-Gly)2 and Cyclo- Pro-Sar-Gly)2 are illustrated in Fig. 1. Throughout this artide, amino adds are referred to the L-enantiomer unless 

In Fig. 2 two C atoms of two L-amino acid residues are placed at tire corner of the /3-turn. These bulky residues tend to occupy the comer of the p-tum. A peptide bond placed at the turn is neady perpendicular to the plane of the sheet. The peptide oxygen projects downward in Fig. 2 a and upward in Fig. 2b. These two types of conformation are possible for the l-l sequence, and their mirror images can accommodate the D-D quence. R 2 Fig. 2a and R/4.1 in Fig. 2b take an equatorial position and thus interfere least with the adjacent peptide oxygen. On the other hand, in Fig. 2a and R,vi-2 in Fig. 2b tsjce an axial position and thus are involved in the more crowded portion of the / tum. If glycine is the (i-f l)-th residue of Fig. 

2 a (G - L sequence) or is the (i+2)-th residue of Fig. 2b (l - G sequence), the p-turn is conformationally stable. Their mirror images can accommodate D G and G D sequences, respectively. If the D-amino acid residues are replaced by the (i+l)-th residue of Fig. 2 a and the (i+2)-th residue of Fig. 2 b, all the bulky substituents take an equatorial position, which makes the conformation stable. This consideraticxi implies that the p-turn of Fig. 2a-type accommodates the D L. sequence and that of Fig. 2b-type the L D sequence, which are minor images of eadi other. 

As will be dealt with subsequently, Cyclo-(Sar4) has been proved to assume a centroi mmetric conformation, as riiown in Fig. 3, in whidi the sequence of peptide 

Comprehensive investigations have been carried out with synthetic Qrdic dipeptides and cyclic hexapeptides because they are sjynthesized more easily than others. Under suitable reaction conditions, cydic peptides with the requisite number of amino acid residues and a known sequence can be nthesized without racemiza-tion. A review article for the nthesis of cydic peptides has been publidied recently (32). 

In order for cyclic peptides to be useful models for biopolymers, they diould be synthesized in a good yield. In the synthesis of cyclic peptides the requisite kinds of a-amino acids are at first condensed into linear peptides having a known sequence, and then the linear peptides are cyclized or ( do-dimerized to give cyclic peptides. Any kind of naturally occurring a-amino acid can be used as the component of cyclic peptide. The present author was interested in cyclic peptides containing N-substituted amino acid (imino acid) for the following reasons  

There are many kinds of naturally occurring, biologically active cyclic peptides and depsipeptides containing imino acid residues (S). 

Cyclic peptides containing imino add residues are usually soluble in nonpolar organic solvents. 

Cis as well as trans peptide bonds occur in cyclic peptides containing imino add residues (9-11). 

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FIGURE 5.23 Synthesis of cyclic peptides by head-to-tail cyclization of resin-bound peptides using Boc/Bzl chemistry59 and Fmoc/tBu chemistry.60 The carboxy-terminal protectors are orthogonal to the other protectors. The nature of the linker determines the nature of the product. Both chemistries are compatible with the two types of linkers. All = allyl. 

P Rovero, L Quartara, G Fabbri. Synthesis of cyclic peptides on solid support. Tetrahedron Lett 23, 2639, 1991. 

Horton, D.A., Bourne, G.T., and Smythe, M.L. Exploring privileged stmctures the combinatorial synthesis of cyclic peptides./. Comput.-Aided Mol. Des. 2002, 36,415-430. 

Horton DA, Bourne GT, Smythe ML (2002) Exploring privileged structures the combinatorial synthesis of cyclic peptides. Mol Divers 5(4) 289-304... 

Several reviews are available that contain additional information on the synthesis of cyclic peptides.170-721... 

Protection Schemes for the On-Resin Synthesis of Cyclic Peptides... 

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. 

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