Macrocycles enniatins

The symmetrical ring enniatin (304) forms a potassium complex (Figure 9.3) whose crystal structure indicates that the cation is contained in the macrocyclic cavity and is coordinated by the six carbonyl oxygen atoms which are orientated such that three lie above and three lie below the main plane of the molecule (Dobler, Dunitz Krajewski, 1969). Apart from those just discussed, it needs to be noted that a range of other structures of antibiotic molecules and their metal complexes have been determined (Hilgenfeld Saenger, 1982). 

The enniatins and beauveracin are cyclic hexadepsipeptides and so are 18-membered macrocycles built up of alternating amino acid and carboxylic acid residues. They exhibit lower selectivity than (137) and consequently are more broad spectrum ionophores. The structure of (138)KI has been solved544 but it was not possible to conclude, with certainty, whether the metal is entrapped in the central cavity, as in related cyclic polyether structures (Figure 14a), or whether it occupi.es a site between two adjacent ligand molecules to give an infinite sandwich (147) as has been found in the RbNCS complex of a synthetic ldlldl isomer of (138).545 Adducts of 1 2 sandwich and 2 3 club sandwich stoichiometry have been proposed for Cs+ complexes of (138),546a and the 1 2 K+ sandwich complex of (138) has been proposed as the species which transports K+ across lipid layers as it shields the metal effectively from solvent interactions.5461 ... 

Although some scattered examples of binding of alkali cations (AC) were known (see [2.13,2.14]) and earlier observations had suggested that polyethers interact with them [2.15], the coordination chemistry of alkali cations developed only in the last 30 years with the discovery of several types of more or less powerful and selective cyclic or acyclic ligands. Three main classes may be distinguished 1) natural macrocycles displaying antibiotic properties such as valinomycin or the enniatins [1.21-1.23] 2) synthetic macrocyclic polyethers, the crown ethers, and their numerous derivatives [1.24,1.25, 2.16, A.l, A.13, A.21], followed by the spherands [2.9, 2.10] 3) synthetic macropolycyclic ligands, the cryptands [1.26, 1.27, 2.17, A.l, A.13], followed by other types such as the cryptospherands [2.9, 2.10]. 

The question of carrier design was first addressed for the transport of inorganic cations. In fact, selective alkali cation transport was one of the initial objectives of our work on cryptates [1.26a, 6.4]. Natural acyclic and macrocyclic ligands (such as monensin, valinomycin, enniatin, nonactin, etc.) were found early on to act as selective ion carriers, ionophores and have been extensively studied, in particular in view of their antibiotic properties [1.21, 6.5]. The discovery of the cation binding properties of crown ethers and of cryptates led to active investigations of the ionophoretic properties of these synthetic compounds [2.3c, 6.1,6.2,6.4-6.13], The first step resides in the ability of these substances to lipophilize cations by complexation and to extract them into an organic or membrane phase [6.14, 6.15]. 

Many antibiotics have turned out to be macrocyclic polypeptides, among which enniatin (65) is a trimer produced by the fungus Fusarium... 

Dobler. M. Dunitz, J.D. Krajewski, J. Structure of the potassium ion complex with enniatin B, a macrocyclic antibiotic with potassium ion transport properties. J. Mol. Biol. 1969, 42. 603-606. 

The number of chemists interested in the problem of ion transport through cellular membranes has increased markedly in recent years, and the tendency to approach the problem from the molecular standpoint has developed to a large degree because of some remarkable observations with model compounds, such as those reported in the November-December, 1968 issue of Federation Proceedings. It has been found that certain macrocyclic antibiotics, such as nonactin, enniatin, and valinomycin,... 

It had been shown by Dunitz and co-workers in 1967 that the structure of the potassium complex of nonactin (la) is as shown in Figure 1. The 32-membered ring can be described as resembling the seam of a tennis ball with the K+ ion at the centre of the ball and the methyl substituents and methylene groups of the furan rings on the outside. More recently, the structure of the K+ complex of another macrocyclic antibiotic with potassium transport properties, enniatin B (2), has been determined. In this case, the carrier-K+ complex is in the form of a charged disc with a lipophilic exterior. The authors point out that both molecules are sufficiently large and impenetrable that any counter-ion or polar molecule in... 

The ion binding strength as evaluated from the Kg values in TABLE IV is comparable to that of beauvericin [12], an eighteen-membered depsipeptide belonging to enniatins, but it is much weaker than that of nonactin [13]. For both of the macrocyclic oligoesters, the Kg values decreased in the order, Cs" > Rb > K+ > Na+ > Li , and Ba " > Ca. ... 

A unique approach to the controlled design of such systems as macrocyclic polylactones, polylactams and related compounds has been developed [1]. The synthesis of these substances, called biomimetic macrocyclic molecules by reason of their resemblance to naturally occuring ionophores (such as valinomycin, nonacdn, enniatin and enterobactin [2-5]), is carried out by a covalent-template method. This description arises from the use of elements forming covalent bonds (tin, silicon, antimony, boron) as matrices. 

The mechanistic problems associated with the transport of cations (especially Na and K+) through membranes have continued to receive attention. The structures of macrocyclic alkali-metal complexes and the thermodynamics of their formation have been reviewed, as has the general question of the selectivity of the carriers towards the metals. The role of hydration energy has been considered and it has been suggested that, at least in the case of the enniatin ionophores, sandwich... 

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