Head-to-tail cyclic peptides

M-L Valero, E.Giralt, D Andreu. Optimized Asp/Glu side chain anchoring in synthesis of head-to-tail cyclic peptides by Boc/OFm/benzyl chemistry on solid phase, in R Ramage, R Epton, eds. Peptides 1996. Proceedings of the 24th European Peptide Symposium, Mayflower, Kingswinford, 1998, pp 857-858. 

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

Z.2 Synthesis of Head-to-Tail Cyclic Peptides of Varying Ring Sizes... 

In addition to sequential and chemical diversity, cyclic peptide libraries offer the possibility of conformational diversity where all components of the library differ from each other in their conformation, despite the identical connectivity. In this context two complementary approaches have been proposed, i.e. spatial screening based on head-to-tail cyclic peptides and cycloscan where the rest of the modes of cyclization are exploited. 

More recent advances in the synthesis of head-to-tail cyclic peptides combine solid-phase peptide synthesis with solid-phase cyclization reactions whilst the peptide is still attached to the resin. 25 Such methods have obvious merits as they reduce manipulation of the peptides in solution. The method typically requires a suitable side-chain functional group... 

Fig. 2. Methods for the cyclization of head-to-tail cyclic peptides. Method A, solution cyclization. Method B, cyclization via side chain or backbone attachment. Method C, cyclization via cleavage through an active ester.

Besides C-terminal and side-chain attachment of the first amino acid derivative onto the solid support, there is a third possibility, which involves attachment of a backbone amide nitrogen to an appropriate handle/support, as shown in Scheme This strategy represents a novel and general concept for the solid-phase preparation of peptides having a variety of C-terminal functionalities, including peptide alcohols, A,A-dialkylamides, esters, thioesters, aldehydes, and head-to-tail cyclic peptides. 

To obtain head-to-tail cyclic peptides on the solid-phase, the N- and C-termini must be free and not linked to the resin. Two strategies are commonly used (i) a side-chain anchoring approach and (ii) a backbone amide linker. 

The first reported solid-phase synthesis of head-to-tail cyclic peptides was based on the intramolecular aminolysis of resin-bound o-nitrophenyl esters. The cyclization proceeds concurrently to cleave the peptide from the resin, after deprotection and neutralization of the AT-terminal residue (Scheme 2A). Accordingly, Fridkin et al. [3] reported the preparation of several simple, unhindered cyclopeptides, such as cyc/o(Ala-Gly-Ala-Ala). Similarly, Flanigan and Marshall [4] obtained activation of the resin-bound peptide ester, after elongation of the peptide chain, by oxidation of the 4-(methyl-thio)phenyl (MTP) linker to a sulfonyl ester. Subsquent deblocking of the A-terminal residue and intramolecular condensation yielded the desired cyclic peptide. However, this method was found not to be suitable for the synthesis of longer and more hindered cyclic peptides [5]. 

Scheme 2 General strategies for the synthesis of head-to-tail cyclic peptides.

The same method can be used for the construction of Asn- or Gin-containing head-to-tail cyclic peptides, using a benzhydrylamine instead of a benzyl alcohol linker, as shown by Tromelin et al. [19]. The synthesis of an 18-mer head-to-tail cyclic peptide designed to mimic a loop involved in the curaremimetic action of a snake toxin protein, cycto(Asn-Tyr-Lys-Lys-Val-Trp-Arg-Asp-His-Arg-Gly-Thr-Ile-Ile-Glu-Arg-Gly-Pro), was prepared. 

Scheme 5 Synthesis of head-to-tail cyclic peptides according to Trzeciak and Bannwarth [25] and Kates et al. [26].

The versatility of the side-chain anchoring approach in the synthesis of head-to-tail cyclic peptides is shown by a synthesis of cyclic phos-phorylated glycopeptides. In order to obtain a constrained peptidic inhibitor of mannose 6-phosphate receptor (MPR), Franzyk et al. [40] synthesized three cyclic hexapeptides a-glycosylated with two phosphorylated o (l->2)-... 

Protection of the carboxyl of Asp/Glu by 2,4-dimethoxybenzyl (Dmb) esters provides an approach for head-to-tail cyclic peptide formation (ffi). The Dmb ester can be removed selectively by 1% v/v TFA in DCM in the presence of tBu- and sulphonyl-based side-chain protection within minutes. However, the technique is limited as these conditions are sufficient to remove the side-chain trityl protection of Cys and His residues. Minor incidental loss of rBu during this procedure has also been reported (83). 

Alsl994 Alsina, J., Rabanal, F, Giralt, E. and Albericio, F., Solid-Phase Synthesis of Head-to-Tail Cyclic Peptides via Lysine Side-Chain Anchoring, Tetrahedron Lett., 35 (1994) 9633-9636. 

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