Natural macrocycles

Polymer-supported synthesis of natural macrocyclic lactones and other 0-heterocycles 99AG(E)1903. 

S-2.2.2 Neutral Carrier Electrodes hi addition to charged liquid ion exchangers, liquid-membrane electrodes often rely on the use of complex-forming neutral carriers. Much effort has been devoted to the isolation or synthesis of compounds containing cavities of molecular dimensions. Such use of chemical recognition principles has made an enormous impact upon widespread acceptance of ISEs. The resulting neutral carriers can be natural macrocyclic molecules or synthetic crown... 

Many other cyclic and noncyclic organic carriers with remarkable ion selectivities have been used successfiilly as active hosts of various liquid membrane electrodes. These include the 14-crown-4-ether for lithium (30) 16-crown-5 derivatives for sodium bis-benzo-18-crown-6 ether for cesium the ionophore ETH 1001 [(R,R)-AA -bisd l-ethoxycarbonyl)undecyl-A,yVl-4,5-tctramcthyl-3,6-dioxaoctancdiamide] for calcium the natural macrocyclics nonactin and monensin for ammonia and sodium (31), respectively the ionophore ETH 1117 for magnesium calixarene derivatives for sodium (32) and macrocyclic thioethers for mercury and silver (33). 

Scheme 81 ROCM performed on epoC (237c), an unstrained natural macrocycle synthesis of epoC analogs with modified side chain [171]...

A very large number of synthetic, as well as many natural, macrocycles have now been studied in considerable depth. A major thrust of many of these studies has been to investigate the unusual properties frequently associated with cyclic ligand complexes. In particular, the investigation of spectral, electrochemical, structural, kinetic, and thermodynamic aspects of macrocyclic complex formation have all received considerable attention. 

Synthetic macrocycles - Natural macrocycles Bioinorganic chemistry ... 

In this chapter, representatives of the natural macrocycles are presented and selected model studies are also described. Emphasis will be given in the following discussion to a few of the better understood areas involving natural macrocyclic systems. Initially, the nature and function of the cyclic antibiotic category of macrocycles are discussed. Subsequently, aspects of the roles of the natural N4-donor systems are presented. 

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-... 

Cyclohexadecen-l-one can be added to perfume compositions as a substitute for the natural macrocyclic ketone musks. 

Natural macrocycles displaying antibiotic propenies are also very efficient in the recognition of alkali metal ions. For instance, valinomycin (5 in Fig, 3) gives a strong and selective complex in which a K+ ion is included in the macrocyclic cavity in octahedral environment of six carbonyl oxygens (Fig. 4). 

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]. 

Sirolimus (Rapamycin, Rapamune ), a natural macrocyclic lactone, is a potent immunosuppressive agent. It was developed by Wyeth-Ayerst Laboratories (Philadelphia, Pennsylvania, U.S.A.) and approved by the Food and Drug Administration for the prophylaxis of renal transplant rejection in 1999 (28,29). Sirolimus has its roots in Easter Island, where an actinomycete streptomyces hygroscopicus was found that produced a novel macrolide antibiotic with potent antibiotic, potent antifungal, immunosuppressive, and antimitotic activities. 

Rapamycin (Rapamune, Wyeth-Ayerst Laboratories) is a natural macrocyclic lactone with a potent immunosuppressive and antiproliferative effect that was approved by the Food and Drug Administration for the prophylaxis against renal transplant rejection,... 

Natural macrocycles concerned with complexing of Na+ and K+ and their transport through the hydrophobic lipid bilayer of cell membranes have been noted (see Fig. 3-3). 

A close relationship has existed between the field of bioinorganic chemistry and that of macrocyclic or macropolycyclic chemistry for the last 20 years. In part, this is due to direct overlap relating to the existence of the natural macrocyclic antibiotics and porphyrins. However, a long and fruitful association also exists in a third area the use of macrocyclic or cryptate complexes to model metalloprotein active sites or to mimic their chemistry (1-3). 

Cyclization via intramolecular olefination of complex phosphonates remains the most important method of synthesis for complex natural macrocycles. Examples include syntheses of 20-membered macrolide antibiotic, aglycones of venturicidins A and B,108 oleandomycin (a 14-membered macrolide antibiotic), 109 the 19-membered macrocyclic antibiotic, anti-tumour agent (-t-)-hitachimycin,ll0 and the macrocyclic lactones (183).1H Cyclization of the phosphonate (184) under Masamune-Roush conditions has been used to synthesize the 28-membered macrolactam myxovirescin B.112... 

Model synthetic studies directed to producing natural macrocyclic compounds were realized by Gil et al. [49]. As a convenient model, the readily accessible substrate 86 was used. It was made available by phase-transfer catalyzed condensation of commercial 3-(3-p)0 idyl)-l-propanol and l-bromo-4-chlorobutane and, on refluxing in acetonitrile, furnished different products depending on reaction times. In this way, cyclic dimer 87 was obtained as the iodine salt in the presence of potassium iodide, and a mixture of linear or cyclic polymers by prolonged time, as summarized in Fig. (32). Dimers and oligomers were purified chromatographically over alumina by gradient elution with... 

Fig. (32). Model synthetic studies toward natural macrocyclic alkylpyridinium alkaloids...

Syntheses of amines using nitrobenzenesulfonamides (/V-amidcs), in particular, total syntheses of natural macrocyclic polyamines 04CC353. 

Busch, D. H.. K. Farmery, V. Goedken, A. C. Katovic, A. C. Melnyk, C. R. Spevati, and N. Tokel (1971) Chemical Foundations for the Understanding of Natural Macrocyclic Complexes, in Bioinorganic Chemistry—Advances in Chemistry. Vol. 100, American Chemical Society, Washington DC. 

For example, potassium-selective electrodes can be constructed with the natural macrocycle valinomycin as a neutral carrier in diphenyl ether. This membrane has a much... 

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