Side-chain anchoring

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. 

Table 9 Examples for the Synthesis of Head-to-Tail and Side-Chain-to-Tail Cyclic Peptides Using the Side-Chain Anchor Method 109 340 347352-i7 wm-i9R t071...

Side-chain anchoring of protected Asp or Glu to the Phacm resin 5 can take place with both low yields and substantial levels of epimerization at the a-carbon. The best route to overcome these problems is to use the corresponding cesium or zinc salts in conjunction with bromomethylbenzyl resins,or through a Mitsunobu reaction using triphenylphosphine and DEAD.[i 2]... 

Besides the methods described above for the side-chain anchoring of Ser and Thr, the 3,4-dihydro-2//-pyran-2-functionalized-resin and handle 331 23,124] Table 3) allows the preparation of peptide alcohols by treatment with TEA in the presence of scavengers. Furthermore, the alkylation of Fmoc amino alcohols with a diphenyldiazomethane polymeric resin 34 gives rise to a benzhydryl ether, which can be cleaved with TFA/CH2CI2 (2 98) to give protected peptide alcohols. 

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. 

In side-chain anchoring the amino acid side-chain is linked to the solid support and the C- and N-termini are orthogonally protected. Once chain elongation is finished, deprotection of both ends and subsequent cyclization and cleavage delivers the final cyclized product. Numerous amino acids have been used for side-chain anchoring, including Asx/Glx [155-161], Lys/Orn [158, 162], Ser/Thr [159, 163], Tyr [159, 163, 164], His [165, 166] and Cys [167, 168], on the usual supports and linkers for peptide synthesis (Figure 18.12). 

Figure 18.12 Linkers and resins for the synthesis of cyclic peptides by a side-chain anchoring approach.

One possible reason for the activity of R-ABA at a slow site, but not at the fast type, is that there is interference with receptor essential volume for the fast type, but not for the slow. This is shown in Milborrow s model [18] (Fig. 5), which has the side-chain equatorially oriented. With the side-chain anchored, inversion of configuration causes the 7 -methyl and the 6 -methyls to be on opposite sides, as shown. The axial methyl of R-ABA interferes in the fast site but not the slow, which is postulated as being more accommodating. Because it is now known that PA has significant physiological activity... 

A much wider generalization of the side-chain anchoring principle was reported by Jensen et al. [31]. The growing peptide is linked to the resin through a backbone amide nitrogen using an appropriate handle called a backbone amide linker (BAL) (Scheme 2C). This approach is compatible... 

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)-... 

B. Side-chain anchoring (cyclization/cleavage strategy)... 

Figure 13.8 Proposed reaction mechanism for DNA polymerase catalysis. The polymerase active site contains three carhoxylate residues and probably a lysine. The three carboxylate side chains anchor a pair of divalent metal ions (e.g. Mg ). In the proposed mechanism, two carboxy-lates coordinate directly to the two Mg, one of which promotes the deprotonation of the 3 -OH of the primer. An in-hne attack of the a-phosphorus atom of dNTP forms a bipyramidal pentaco-ordinated oxyphosphorane transition state with the in-coming and departing atoms at apical positions. The possible involvement of a third Mg coordinated to P- and y-phosphates is also shown...

A thiol handle can, in principle, be introduced through an auxiliary group [123] or by direct attachment to a side-chain. While auxiliaries can be anchored either to the backbone or to a side-chain, each approach involves inherent limitations (Fig. 2). When an auxiliary is attached to the backbone, the subsequent coupling to this residue is typically slow, which limits its utility to less hindered junctions. Nevertheless, successful examples have been reported by Kent [124, 125], Botti [126], Dawson [127], Danishefsky [128], and others [123, 129]. Use of a side-chain auxiliary circumvents the above difficulty but requires an appropriate side-chain anchoring site. This method has been successfully demonstrated by Wong et al. with carbohydrate-based auxiliaries at the side-chains of Ser or Thr [130, 131] and Brik et al. with cyclohexane or cyclopentane-based auxiliaries on the side-chains of Asp, Glu, Ser, or Thr [132,133],... 

A -diisopropylcarbodiimide (DIPCDI) as coupling agents. Key aspects of on-resin NCL include Fmoc/tBu chemistry, side-chain anchoring, allyl protection of the penultimate residue to allow introduction of the C-terminal thioester later in the synthetic sequence, anew derivative, Trt-Cys(Xan)-OH, which facilitates selective... 

Ficht S, Payne RJ, Guy RT, Wong C-H (2008) Solid-phase synthesis of peptide and glycopeptide thioesters through side-chain-anchoring strategies. Chem Em J 14 3620-3629... 

The more mobile are the SO3 groups about the side-chain anchoring points, the higher the mobility, but the weaker are the previous two effects. 

Figure2. Side-chain anchoring strategy for solid-phase synthesis of peptide acids with C-terminal cysteine.

The two phases are not clearly observed simultaniously. Thus there is an analogy to the previously discussed polymerization of diacetylene monomers. However, there is no evidence for stereoregularity in these polymers and thus backbone participation in these solid solutions. In fact, no polymer stereoregularity was observed in the analogous bulk polymerization of crystalline vinyl stearate (13). Thus while the side chains anchor the polymerization, the backbone apparently does not crystallize. 

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. 

Another strategy for C-terminal modification and cyclization is side-chain anchoring. Here, the first amino acid is anchored through the side-chain fimctional group. This could be Asp/Asn, Glu/Gln, or indeed most other trifimctional amino acids. 

Wang P, Miranda LP (2005) Fmoc-protein synthesis preparation of peptide thioesters using a side-chain anchoring strategy. Int J Pept Res Ther 11 117-123... 

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