Chiral compounds crown ether

Table 6. Michael Addition of Carbonyl Compounds to Enones and Enoates with Crown Ethers or Quaternary Salts as Chiral Catalysts Crown Ethers ...

Crown-ethers can incorporate protonated primary amine compounds by formation of ion-dipole bonds with the oxygen atoms of the chiral selector. Crown-ethers have been widely used for the separation of several pharmaceuticals both in aqueous and non-aqueous media." ... 

In this section, we shall examine the various approaches by which crown compounds that have their chiral elements associated in some way with fused ring systems can be constructed. A selection of the wide and growing range of saturated chiral diols—many of them derived finom readily available carbohydrates—which have been incorporated, as relatively inexpensive sources of chirality, into crown ether derivatives are displayed in Figure IS. It may be noted that the saturated chiral diols rely for their chirality on centers of the classical type (C abcd)—not so the chiral dihydroxy compounds associated with the unsaturated systems listed in Figure 16. These examples reveal that axes and planes of chirality join with less conventional chiral centers (C aaaa) in being sources of chirality in optically active crown ethers. 

Appllca.tlons. The first widely appHcable Ic separation of enantiomeric metallocene compounds was demonstrated on P-CD bonded-phase columns. Thirteen enantiomeric derivatives of ferrocene, mthenocene, and osmocene were resolved (7). Retention data for several of these compounds are listed in Table 2, and Figure 2a shows the Ic separation of three metallocene enantiomeric pairs. P-Cyclodextrin bonded phases were used to resolve several racemic and diastereomeric 2,2-binaphthyldiyl crown ethers (9). These compounds do not contain a chiral carbon but stiU exist as enantiomers because of the staggered position of adjacent naphthyl rings, and a high degree of chiral recognition was attained for most of these compounds (9). 

Cyclic low molecular weight compounds. Chiral separations using chiral crown ethers immobilized on silica or porous polymer resins were first reported in the... 

Enantioresolution in capillary electrophoresis (CE) is typically achieved with the help of chiral additives dissolved in the background electrolyte. A number of low as well as high molecular weight compounds such as proteins, antibiotics, crown ethers, and cyclodextrins have already been tested and optimized. Since the mechanism of retention and resolution remains ambiguous, the selection of an additive best suited for the specific separation relies on the one-at-a-time testing of each individual compound, a tedious process at best. Obviously, the use of a mixed library of chiral additives combined with an efficient deconvolution strategy has the potential to accelerate this selection. 

Addition of a chiral carrier can improve the enantioselective transport through the membrane by preferentially forming a complex with one enantiomer. Typically, chiral selectors such as cyclodextrins (e.g. (4)) and crown ethers (e.g. (5) [21]) are applied. Due to the apolar character of the inner surface and the hydrophilic external surface of cyclodextrins, these molecules are able to transport apolar compounds through an aqueous phase to an organic phase, whereas the opposite mechanism is valid for crown ethers. 

This molecule has no chiral carbons, nor does it have a rigid shape, but it too has neither a plane nor an alternating axis of symmetry. Compound 32 has been synthesized and has, in fact, been shown to be chiral. Rings containing 50 or more members should be able to exist as knots (33, and see 37 on p. 114 in Chapter 3). Such a knot would be nonsuperimposable on its mirror image. Calixarenes, ° crown ethers, catenanes, and rotaxanes (see p. 113) can also be chiral if suitably substituted. For example, A and B are nonsuperimposable mirror images. 

Chiral Recognition. The use of chiral hosts to form diastereomeric inclusion compounds was mentioned above. But in some cases it is possible for a host to form an inclusion compound with one enantiomer of a racemic guest, but not the other. This is caUed chiral recognition. One enantiomer fits into the chiral host cavity, the other does not. More often, both diastereomers are formed, but one forms more rapidly than the other, so that if the guest is removed it is already partially resolved (this is a form of kinetic resolution, see category 6). An example is use of the chiral crown ether (53) partially to resolve the racemic amine salt (54). " When an aqueous solution of 54 was... 

Problem In the synthesis of a chiral crown ether, compound (19) was needed. Suggest a synthesis for it. 

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. 

Asymmetric phase-transfer catalysis using chiral nonra-cemic onium salts or crown ethers has now grown into a practical method whereby a large number of reactions can be performed and some optically pure compounds can be produced effectively on a large scale. 

Since the first report of the nonequivalence phenomenon, approximately 40 chiral substances have been reported to induce enantiomeric nonequivalence in the NMR spectra of a host of solutes. These CSAs are encountered in subsequent discussions. Two qualities considered to be essential in the design of the first reported experiment (3) are evident in nearly all CSA-solute combinations. In all cases, the CSA and the solute have the common feature of complementary functionality, which permits their interaction. Both are in general hydrogen bond donors or acceptors the CSAs are acids, amines, alcohols, sulfoxides, or cyclic compounds such as cyclodextiins, crown ethers, or peptides, which attractively interact with appropriate enantiomeric solutes, engendering different spatial environments for their nuclei. In nearly every case the CSA contains a group of high diamagnetic anisotropy near its asymmetric center, a feature... 

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. ... 

Crown-ether CSPs have the ability to include some chiral molecules stereoselectively. These CSPs are well suited for the separation of amino acids and compounds containing a primary amine at or near the stere-ogenic centre. The most used commercially available crown-ether CSP is Crownpak CR (-I-), developed by Daicel (Osaka, Japan). 

Therefore, the chiral cyanohydrins are valuable and versatile synthons as their single hydroxyl asymmetric centre is accompanied by at least one other chemical functionality. Thus with careful functional group protection, differential and selective chemical transformations can be performed. Such synthetic techniques lead to production of interesting bioactive compounds and natural products. These products include intermediates of j3-blockers 15 1117], j3-hydroxy-a-amino acids 16 [118],chiral crown ethers 17 [lll],coriolic acid 18 [120], sphingosines 19 [121], and bronchodilators such as salbutamol 20 [122] (Fig. 3). 

Carbohydrates remain an attractive source of chirality in preparation of ligands for asymmetric catalysis. Functionalized phospholanes, 192 [167], and chiral bisphosphinites 193 [168] with an attached crown ether unit were obtained recently from D-mannitol and from phenyl 2,3-di-0-allyl-4,6-0-benzylidene-p-D-glucopyranoside, respectively (Figure 18). Compounds 194 and 195 were obtained in the photochemical addition of H2P(CH2)3PPH2 onto the crresponding alkenes - Pd-complexes of these new bisphosphines were successfully applied as catalysts in the copolymerization of CO and... 

The functionality that is often necessary for a chiral crown ether to serve a particular purpose can usually be introduced by the synthetic chemist without too much difficulty. The practice here, however, can be very much more demanding on account of the promiscuous receptor properties of the compounds that have to be separated and isolated pure from reaction mixtures containing many components. 

The various strategies available for the synthesis of crown ethers have been analyzed (12, 17-19, 43) and reviewed (1-10, 20) at considerable length. In principle, the problem of introducing chirality into crown compounds can be tackled in three different ways. 

Closely related to the synthetic work reported in the previous section is the incorporation (131) of a 2,5-anhydro-3,4Hdi-0-methyl-D-mannitol residue (Figure 15) into the 18-crown-6 derivative d-91. Other derivatives of D-mannitol that have been built into crown ether receptors include l,4 3,6-dianhydro-D-maiuiitol (132), l,3 4,6-di-0-methylene-D-marmitol (13 134), and 1,3 4,6-di-O-benzylidene-D-mannitol (134). Examples of chiral crown compounds containing these residues include dd-92, dd-93, d-94, and d-95. Although not derived from carbohydrates—but rather (135) from the terpene, (-t-)-pulegone—... 

Very recently, the synthesis of a series of chiral poly(9,9 -spirobiflu-orene)crown ethers [e.g., (SS)-139, (SSSS)-140, (SSSSSS)-141, and (S55SSS5S)-142] with 26-, 52-, 78-, and 104-membered rings have been described (162). The last three are rare examples of compounds with C4, 5, and Cg synunetries, respectively. They were isolated chromatographically from a reaction mixture consisting of (S)-2,2 -bisbromomethyl-9,9 -spirobifluorene, ethylene glycol, KOr-Bu, and Csl in tolune. 

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