Macrocycles chiral crown ethers

Kobuke et al. [40] demonstrated that the podand 28 only forms weak complexes with alkali metal ions. However, when a chiral macrocyclic crown ether structure is formed by complexation with boric acid, alkali metal ions are bound much more strongly (Scheme 10). Stiffening, provided by covalent B-O bonds, improves the preorganization of the ligands that is required for the complexation of metal ions. 

The monobenzhydiyl derivative of (S)-binaphthol has played an important role, not only in the synthesis of chiral bisbinaphthyl crown ether derivatives, for example, (55)-124, containing two different bridges between the two binaphthyl units, but also in the provision of an entry into the constimtionally isomeric derivative (5S)-125. Rational stepwise syntheses of macrocyles containing three binaphthyl units have been devised and applied to the synthesis of (SSS)-126 and (RSS)-127. Cleariy, in all these procedures, the C2 symmetry of the chiral building block restricts the number of products (to one ) and defines the symmetries of the macrocycles formed. 

Chiral cyclodextrins, crown ethers, and macrocyclic antibiotics in chiral separations using capillary electrophoresis 00CRV3715. 

There are many types of chiral selectors that have been applied to the separation of enantiomers by CE, but the most common are native and derivatized CDs. Other chiral selectors, which have been applied to CE separations, include natural and synthetic chiral micelles, crown ethers, chiral ligands, proteins, peptides, carbohydrates, and macrocyclic antibiotics [105,111-114]. A review by Blanco and Valverde [114] describes the separation capabilities of various chiral selectors and provides criteria for their choice in terms of molecular size, charge, and the presence of specific functional groups or substructures in the analytes. 

In our work we have developed methods to build heavily modified crown-like systems in which the chiral components are amino acids. The general structural type is illustrated by (24a, b). In this case the macrocyclic crown ether system has been badly broken by extra substituents and heteroatoms (amide nitrogen, ester ether oxygen) of lowered basicity. 

Many chiral compounds can be used as selectors, for example, chiral metal complexes, native and modified cyclodextrins, crown ethers, macrocyclic antibiotics, noncyclic oligosaccharides, and polysaccharides all have been shown to be useful for efficient separation of different types of compounds. 

In the preceding section it was shown that the stability of crown-ether complexes with alkylammonium salts depends on the relationship between the structures of the crown ethers and the ammonium ions. How critically this relationship determines the complex stability will become clear in this section, which deals with the discrimination between the two enantiomers of racemic salts by chiral macrocyclic ligands. 

In summary, it can be stated that for screening approaches in CE, only CD derivatives have been used. Other chiral selectors occasionally applied in CE, such as crown ethers, macrocyclic antibiotics, and chiral surfactants [39], were not found to be involved in (generic) screening approaches for chiral separations. 

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. 

Crown-ethers are macrocyclic polyethers capable of forming host-guest complexes, especially with inorganic and organic cations. Modification of the crown-ether by the introduction of four carboxylic groups makes it possible to use this class of compounds as chiral selectors in CE. ... 

Based on the theory, the separation of enantiomers requires a chiral additive to the CE separation buffer, while diastereomers can also be separated without the chiral selector. The majority of chiral CE separations are based on simple or chemically modified cyclodextrins. However, also other additives such as chiral crown ethers, linear oligo- and polysaccharides, macrocyclic antibiotics, chiral calixarenes, chiral ion-pairing agents, and chiral surfactants can be used. Eew non-chiral separation examples for the separation of diastereomers can be found. 

The chiral 1,2-diols that have been incorporated into crown ether derivatives that cany substituents but have no fused rings associated with the elements of chirality in the macrocycles are listed in Figure 14. We shall now examine some of the ways in which these chiral building blocks have been used. 

Chirality derived from the readily accessible a-amino acids has been incorporated into the side chains of aza and diaza macrocyclic polyethers. A number of procedures suitable for peptide synthesis have proved (178) to be unsuitable for acylating the relatively unreactive secondary amine groups of aza crown ethers. Eventually, it was discovered that mixed anhydrides of diphenylphos-phinic acid and alkoxycarbonyl-L-alanine derivatives do yield amides, which can be reduced to the corresponding amines, e.g., l-172. By contrast, the corresponding bisamides of diaza-15-crown-S derivatives could not be reduced and so an alternative approach, involving the use of chiral A-chloroacetamido alcohols derived from a-amino acids, has been employed (178) in the synthesis of chiral receptors, such as ll-173 to ll-175, based on this constitution. 

In view of the importance of chiral resolution and the efficiency of liquid chromatographic methods, attempts are made to explain the art of chiral resolution by means of liquid chromatography. This book consists of an introduction followed by Chapters 2 to 8, which discuss resolution chiral stationary phases based on polysaccharides, cyclodextrins, macrocyclic glyco-peptide antibiotics, Pirkle types, proteins, ligand exchangers, and crown ethers. The applications of other miscellaneous types of CSP are covered in Chapter 9. However, the use of chiral mobile phase additives in the separation of enantiomers is discussed in Chapter 10. 

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. 

The chiral recognition mechanisms in NLC and NCE devices are similar to conventional liquid chromatography and capillary electrophoresis with chiral mobile phase additives. It is important to note here that, to date, no chiral stationary phase has been developed in microfluidic devices. As discussed above polysaccharides, cyclodextrins, macrocyclic glycopeptide antibiotics, proteins, crown ethers, ligand exchangers, and Pirkle s type molecules are the most commonly used chiral selectors. These compounds... 

---