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Peptide-bridged Dicatechol Ligands for Stabilization of Linear Compared with Loop-type Peptide Conformations

Although it is important to control the configuration at selected amino acids, the real challenge is structural fixing of small peptidic domains. Thus, to investigate the effect of metal coordination on the microstructure of small peptides, the dipeptide- and tripeptide-bridged ligands 2-H4 and 3-H4 (Figure 1.3.9) were prepared by use of a standard peptide-coupling procedure [22].

Valine is an amino acid with a bulky isopropyl substituent. This leads in oligo-valins to repulsion of the isopropyl groups and the preference of a ^-sheet-type structure in which the substituents at the peptide are separated as far as possible

Fig. 1.3.9. Val-Val- and Val-Val-Val-bridged dicatechol ligands 2-H4 and 3-H4.

The Val-Val-bridged ligand 2-H4 has a spacer which, because of steric constraints, prefers the stretched ''sheet type'' structure. This forces the metal binding sites to be located far away from each other. On coordination to titanium(IV) ions this leads to the formation of a triple-stranded helicate-type complex [23Ti2]4~ (initially as a mixture of up to eight different regio- and stereoisomers). One dominating thermodynamically favored isomer is formed when a solution of the complex is left for several days at room temperature. NMR spectroscopy shows that the main isomer has C3-symmetry and, therefore, the three ligand strands must all be orientated in the same direction with the three N-termini binding to one metal and the C-termini to the other (Figure 1.3.10). The ligand strands are thus forced to adopt a stretched conformation, probably leading to a ¿-sheet type microstructure at each ligand [23].

Ligand 3 has more flexibility than ligand 2, because of the third amino acid and the additional flexibility at the further a-bonds. In a coordination study with titanium(IV) ions and base, 3 did not lead to one specific triple-stranded dinuclear complex [33Ti2]4~ but to a mixture which also contains a single-bridged species. In the latter two metal centers are connected by one ligand 3 whereas the two remaining ligands 3 bind with both binding sites to the same metal. In contrast to the studies with ligand 2, an unspecific mixture of structurally diverse coordination compounds is formed. It would, however, be of some interest to obtain selectively loop-type structures as found in the single bridged isomer of [33Ti2]4~ [23].

This can be achieved by using the cis molybdenum(VI)dioxo ion instead of titanium(IV). In this ion two corners of the octahedron at the molybdenum are already blocked by oxygen atoms and only two catechol units can be bound to the metal. Thus, reaction of ligand 3-H4 with MoO2(acac)2 in the presence of potassium carbonate leads to a mononuclear macrocyclic complex [3MoO2]2~ in which a loop-type conformation is stabilized at the peptide (Scheme 1.3.3) [23]. (Similar

1.3.4 Approaches Used to Stabilize Bioactive Conformations at Peptides by Metal Coordination I 41

Scheme 1.3.3. Stabilization of a loop-type structure at a tripeptide by coordination of ligand 3 to the MoO22+ fragment.

experiments with ligand 2-H4 and molybdenum(VI)dioxo do not lead to defined complexes. In this case the spacer seems to be sterically too hindered to enable formation of a short-turn structure.)

These coordination studies with titanium(IV) or molybdenum(VI)dioxo and oligo-valine bridged dicatechol ligands show that the preferred conformation of geometrically constrained ligands with bulky amino acids as building blocks can control the specificity of complex formation. With titanium(IV) either the selective formation of one triple-stranded complex (ligand 2) or the unspecific formation of mixtures of valence isomers (ligand 3) can be observed. On the other hand, cis-MoO2, which can bind both catechol units of one ligand strand 3 can be used to obtain macrocyclic complexes with a loop-type peptide front. Here the metal complex fragment acts as a clip and stabilizes the peptidic loop-type microstructure

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