Synthesis of Cyclic Peptides on Solid Supports

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. 

AR Mitchell, SBH Kent, M Englehard, RB Merrifield. A new synthetic route to tert-butoxycarbony lam i noacyl-4-(oxymcthyl)phenacetamidomethyl-rcsin, an improved support for solid-phase peptide synthesis. J Org Chem 43, 2845, 1978. 

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

A Trzeciak, W Bannwarth. Synthesis of head-to-tail cyclic peptides on solid support by FMOC chemistry. Tetrahedron Lett 33, 4557, 1992. 

M-L Valero, E Giralt, D Andreu. A comparitive study of cyclization strategies applied to the synthesis of head-to-tail cyclic analogs of a viral epitope. J Pept Res 53, 56, 1999. 

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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. 

Rovl991 Rovero, R, Quartara, L. and Fabbri, G., Synthesis of Cyclic Peptides on Solid Support, Tetrahedron Lett., 32 (1991) 2639-2642. 

Synthesis of Homodetic Cyclic Peptides on Solid Support... 

Allyl (Al) esters are suitable for the temporary protection of carboxy groups in peptide and glycopeptide synthesisP " and also in the synthesis of cyclic peptides.In the latter case these esters allow, for example, on-resin head-to-taU cyclizations of peptides that are attached via the side chains of aspartic acid and glutannic acid residues to the solid support.t 1 The application of aUylic protecting groups in peptide synthesis has been comprehensively reviewed by Guibe.f ... 

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. 

For the synthesis of dihydrothiazole-containing cyclic peptides alternative synthetic routes are presently available.1514570 In one of these approaches suitably protected 2-(aminoal-kyl)dihydrothiazole-4-carboxylic acids are prepared and then used as building units for the assembly of the target peptides by standard synthesis on solid supports 519 539 561 571 572 or more frequently in solution, 539571 followed by cyclization again by standard protocols. 552 564 However, great care has to be taken in all these synthetic steps because of the facile race-mization at both chiral centers of the dihydrothiazole building blocks (see Scheme... 

Fig. 4. The extent to which cyclic peptide synthetic strategies may be accomplished on solid support. Note that the catechol safety-catch linker requires the inversion of the order of synthesis where the protecting groups are removed followed by cyciization.

Diethoxyphosphoryloxy-l,2,3-benzotri-azin-4(3Hj-one (DEPBT), an effective coupling agent for the synthesis of linear and cyclic peptides, both in solution and on solid support. Beside its remarkable resistance to racemization in peptide bond formation, it is not necessary to protect the... 

A different approach toward cyclic peptides has been presented by Leatherbarrow and coworkers, employing ring-dosing metathesis (RCM) on a solid support [50], The authors reported on the synthesis of conformationally strained cyclic peptides of the Bowman-Birk inhibitor type, which are naturally occurring serine protease... 

The oxidation-reduction method, developed initially by Mukaiyama et al. [133] and related to the previously described organophosphorus methods, has permitted a variety of important solid-phase applications. The mechanism of the activation is complex and involves the oxidation of the triaryl/ alkyl-phosphine to the oxide as well as reduction of the disulfide to the mercapto derivative. However, different active species, such as 81 (Fig. 11), the 2-pyridyl thioester, or even the symmetrical anhydride, have been postulated to form. For the intermediate 81, the peptide bond formation may proceed through a (cyclic transition state. The method has been used for conventional stepwise synthesis [134], acylation of the first protected amino acid to a hydroxymethyl resin, and to achieve segment condensation on a solid support in the opposite direction (N C) [135,136]. Lastly, it has been used for efficient grafting of a polyethylene glycol (molecular weight 2000) derivative to an aminomethyl resin to prepare PEG-PS resins [137]. 

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