Macrocyclic cyclic peptide

The examples summarized in Table 5 and in Sect. 5 of this review illustrate the applicability of RCM to the preparation of various macrocyclic perfume ingredients [30], pheromones [30], antibiotics [31-35], crown ethers [36], cyclic peptides [37],catenanes [38] and capped calixarenes [39]. 

DR. MARGERUM Right. The macrocyclic complex first adds a proton following which trien reacts to form a mixed complex. The latter species then reacts with solvent to become further protonated before trien replaces the cyclic peptide. 

The properties of natural macrocycles, the cyclodextrins, has stimulated interest in the preparation of synthetic macrocycles. Three basic types have been made macrocyclic amines, cyclophanes, and cyclic peptides. Hersh-field and Bender (33) prepared a bicyclic amine with hydroxamate sub-... 

Other examples of Ugi reactions combined with RCM have been described in the literature. Hebach and Kazmaier reported the synthesis of conformationally fixed cyclic peptides [70] and Beck and Domling synthesized biaryl-containing natural product-like macrocycles using this method [41]. The same group also reported combination of Passerini and Horner-Wadsworth-Emmons reactions to obtain butenolides [67] and another variation for the combinatorial synthesis of thiazoles [69]. 

This review will focus on the use of MCR approaches to cyclic peptides, cyclic peptidomimetics, or cyclic pseudopeptides, including small or medium-sized heterocycles as mimics of peptide motifs and macrocycles with amino acid or peptide moieties. 

Chiral macrocyclic amino-ethers have been prepared recently (69). Ligands of type E are obtained by attaching a chain (or two chains, one at each Z center to the type D macrocycles (81). The synthesis of macro-cyclic peptides will not be discussed here. 

The important difference between linear and cyclic peptides is the reduced conformational flexibility imposed by the cyclization. 14,151 Cyclic peptides have, therefore, been under intense investigation with respect to their conformational preferences 30,31 and their different turn motifs, e.g. reverse turns. 32 35 To differentiate between the structural influences of the numerous sequence elements the following special concepts have been described 161 (1) Global constraints are structural characteristics that restrict the whole molecule, e.g. the macrocyclic structure of the peptide framework and (2) local constraints comprise a large number of structure-inducing building blocks, such as proline, D-amino acids, and turn mimetics. 

Analogs of cyclic peptides have been prepared using a variety of spacers and reaction conditions to achieve the macrocyclization. These include olefin metathesis (Section 5.2.3), nucleophilic substitution (Sections 8.2 and 7.2.3), and the Heck reaction [82]. 

Approaches to artificial ion channels have, for instance, made use of macrocyclic units [6.72,6.74] (see also below), of peptide [8.183-8.185] and cyclic peptide [8.186] components, of non-peptidic polymers [8.187] and of various amphiphilic molecules [6.11, 8.188, 8.189]. The properties of such molecules incorporated in bilayer membranes may be studied by techniques such as ion conductance [6.69], patch-clamp [8.190] or NMR [8.191, 8.192] measurements. However, the nature of the superstructure formed and the mechanism of ion passage (carrier, channel, pore, defect) are difficult to determine and often remain a matter of conjecture. 

Several potent inhibitors of fibrinogen binding to gpIIb/IIIa are now known, and some have proven to be effective antithrombotic agents. These inhibitors tend either to be small cyclic peptide mimetics, in which the conformation of an RGD sequence is constrained by macrocyclization, or they are non-peptidic molecules containing functional group mimetics of the Arg and Asp side chains, held in the correct geometry for interaction with the receptor. Examples of both classes are shown in... 

While cyclic peptides have proven to be problematic, we beheve that amino acids are ideal candidates for derivatization of our macrocyclic scaffolds. Mary natural and unnatural amino acids with appropriately protected side chains are commercially available or can be readily prepared providing facile access.22 The a-amino- and a-carboxy- groups common to all of these will provide constant sites for attachment to a macrocyclic scaffold core. Side chains varying in aromatic, aliphatic, polar and ionic characters should provide sufficient chemical diversity. Finally, amino acids may be combined in many ways to form short acyclic peptides, allowing access to more diverse chemical properties not found in individual amino acids. 

Two important examples of cyclic peptides will be highlighted in which amino acid sequences of larger proteins have been successfully used as part of macrocyclic peptide structures to mimic in an almost pars pro toto approach important properties of the parent protein. 

Scheme 5 Synthesis of cyclic peptide mimics via a free-radical mediated macrocyclization...

JHC129>. In the solid state the cyclic peptide based on dipeptidyl imidazole 26 organizes to a rigid molecule in which all lone pairs of the imidazole nitrogens and the hydrogens of the secondary amides point toward the center of the macrocycle. The valine side-chains all lie on the same face of the molecule and adopt axial positions. The imidazole moieties form a cone-like structure <2002TL6335>. 

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