Synthetic macrocycles crown ethers

Following the development of effective synthetic routes to macrocyclic crown ethers as exemplified in eq. 9 for the synthesis of [l8]crown-6 IS), extensive studies were initiated on the factors affecting their complexing ability. The success of this work... 

Our own approach to the combination of crown ether and dihydropyridine chemistry has involved constructing the dihydropyridine as an integral portion of the macrocyclic crown ether ring (see 24b, for example). The first synthetic approach involved ring-closure of an alicyclic precursor by means of the Hantzsch 1,4-dihydropyridine synthesis as illustrated for the preparation of (50, eq. 24). Such Hantzsch esters (general type 46) are attractive in that the acid functionalities at the 3,5-positions can be used as handles for attaching the (dihydro)pyridine... 

Pedersen, Cram and Lehn received the Nobel Prize in Chemistry in 1987 for their work on synthetic macrocyclic compounds. In their Nobel lectures, Pedersen (1988) described the discovery of crown ethers, Cram (1988) and Lehn (1988) the further development of work on new synthetic macrocycles and their host-guest properties. 

The condensation reactions described above are unique in yet another sense. The conversion of an amine, a basic residue, to a neutral imide occurs with the simultaneous creation of a carboxylic acid nearby. In one synthetic event, an amine acts as the template and is converted into a structure that is the complement of an amine in size, shape and functionality. In this manner the triacid 15 shows high selectivity toward the parent triamine in binding experiments. Complementarity in binding is self-evident. Cyclodextrins for example, provide a hydrophobic inner surface complementary to structures such as benzenes, adamantanes and ferrocenes having appropriate shapes and sizes 12) (cf. 1). Complementary functionality has been harder to arrange in macrocycles the lone pairs of the oxygens of crown ethers and the 7t-surfaces of the cyclo-phanes are relatively inert13). Catalytically useful functionality such as carboxylic acids and their derivatives are available for the first time within these new molecular clefts. 

Different classifications for the chiral CSPs have been described. They are based on the chemical structure of the chiral selectors and on the chiral recognition mechanism involved. In this chapter we will use a classification based mainly on the chemical structure of the selectors. The selectors are classified in three groups (i) CSPs with low-molecular-weight selectors, such as Pirkle type CSPs, ionic and ligand exchange CSPs, (ii) CSPs with macrocyclic selectors, such as CDs, crown-ethers and macrocyclic antibiotics, and (iii) CSPs with macromolecular selectors, such as polysaccharides, synthetic polymers, molecular imprinted polymers and proteins. These different types of CSPs, frequently used for the analysis of chiral pharmaceuticals, are discussed in more detail later. 

With the gift of hindsight, it is obvious that the majority of synthetic chemists would turn to macrocyclic compounds in the first instance for a ready source of molecular receptors. Indeed, this is exactly what has happened, although the most popular line (that concerned with macrocyclic polyethers) to date was to come on the scene serendipitously at just the right time. To their credit, synthetic chemists grasped the opportunity and wasted no time in developing the chemistiy of the crown ethers. 

A comprehensive review of synthetic macrocycles gave detailed tabulations of preparations, effects of binding sites and thermodynamic data known up to 1973.456 Table 60 gives thermodynamic data for the formation of silver(I) crown ethers in aqueous solution and includes several more recent figures.457,458... 

The field, as we now know it, started with the selective binding of alkali metal cations by natural [1.21-1.23] as well as by synthetic macrocyclic and macropoly-cyclic ligands, the crown ethers [1.24,1.25] and the cryptands [1.26,1.27]. The out-... 

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]. 

The most popular and commonly used chiral stationary phases (CSPs) are polysaccharides, cyclodextrins, macrocyclic glycopeptide antibiotics, Pirkle types, proteins, ligand exchangers, and crown ether based. The art of the chiral resolution on these CSPs has been discussed in detail in Chapters 2-8, respectively. Apart from these CSPs, the chiral resolutions of some racemic compounds have also been reported on other CSPs containing different chiral molecules and polymers. These other types of CSP are based on the use of chiral molecules such as alkaloids, amides, amines, acids, and synthetic polymers. These CSPs have proved to be very useful for the chiral resolutions due to some specific requirements. Moreover, the chiral resolution can be predicted on the CSPs obtained by the molecular imprinted techniques. The chiral resolution on these miscellaneous CSPs using liquid chromatography is discussed in this chapter. 

Pedersen s reports of the compounds he called crown ethers (Pedersen, 1967) began a world wide synthetic effort to prepare novel macrocycles, to define the limits of crown ether structure, and to assess the range of their biological and chemical properties. Among the latter, great effort was expended to define and understand cation complexation by these remarkable molecules. On the biological side, the toxic effects of crown ethers to cell lines and animals were assayed to understand their inherent safety or danger and the... 

A number of other synthetic ion channels have been developed that incorporate crown ethers as critical elements. They cannot all be described and illustrated in this short chapter but it is important to note them. Voyer and coworkers developed channels that use an a-helical backbone to align a series of crowns into a channel that was both functional and biologically active (Voyer and Robataille, 1995 Voyer et al., 1997). Pechulis and coworkers developed a channel in which a central crown used tartaric acid subunits to anchor steroids, which formed the channel s walls (Pechulis et al., 1997). Mendoza and coworkers prepared an active channel based on a calixaiene central unit but that had crown ether headgroups (de Mendoza et al., 1998). Hall and coworkers modified the tris(macrocycle) design originating in our lab to form a redox-switchable crown that was active in bilayers (Hall et al., 1999, 2003). 

The synthesis of macropolycyclic cryptands generally involves stepwise, straightforward pathways (18, 20, 33) based on the successive construction of systems of increasing cyclic order macrocyclic, macrobicyclic, and so on. Newkome has recently reported a satisfactory quaternization-dealkylation procedure, facilitating the synthesis of 8 (34). Unlike the synthetic approaches to simple crown ethers (10,... 

Since the pioneering work of Pedersen (1), Lehn (2), and Cram (3) on synthetic macrocyclic and macropolycyclic host systems such as the crown ethers, cryptands, and spherands, there has been an enormous development of the field of host-guest or supramolecular chemistry. Molecular hosts designed to bind inorganic and organic, charged and neutral guest species via cumulative, noncovalent interactions have all been reported and extensive reviews on this subject have appeared (4-8). 

The earliest recognised examples of synthetic supramolecular structures were the complexes formed from crown ethers and metal cations [19]. Since then numerous macrocycles have been synthesised. Representative examples are the cryptands [20], These differ from crown ethers in that the former contains a tridimensional cavity while the latter are characterised by a hole. Similarly, calix[4]arenes are compounds with a cup -like structure that through lower rim functionalisation gives rise to a hydrophilic and a hydrophobic cavity, thus allowing the reception of ionic species in the former and neutral species in the latter. Most of the above mentioned macrocycles are known for their capability to serve as cation receptors. 

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