Chiral crown compounds

Stereospecific synthesis, starting from chiral precursors, has been exploited in many different ways (91, 92). Apart from the usual demands incurred during synthetic work, symmetry considerations (49, 50, 56-59, 91) impose an additional constraint upon the design and synthesis of chiral crown compounds. Generally speaking, it is desirable to prepare... 

Figure II. Some synthetic strategies leading to chiral crown compounds with homotopic faces stalling from chiral piecuisois with C2 symmetry.

Figure 13. Two synthetic strategies leading to chiral crown compounds with heterotopic faces starting from asymmetric precursors. Note that, although the product obtained in (b) has Cj symmetry, the symmetry element does not exchange the environment of the two faces.

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—... 

The incorporation of two nonidentical chiral residues, each supporting C2 symmetry, into a mactocyclic poly ether affords a chiral crown compound with C2 symmetry provided its structure is constitutionally symmetrical. Thus, base-promoted reaction of the half-crown diol prepared from (5)-birraphthol with the half-crown ditosylate d-72 synthesized tom diacetone-manrritol affords (144) the 20-crown-6 derivative (S)-d-113 with C2 symmetry. When d-72 is condensed in like fashion with (/ 5)-binaphthol, then the diastereoisomeric 20-crown-6 derivative (/ )-d-114 can be separated chromatogiaphically tom (S)-d-113. In this matmer, (/ 5)-binaphthol is resolved by the carbohydrate unit during the synthesis. 

A number of chiral crown compounds containing more than one macrocyclic polyether ring have been described in the literature. They have been derived... 

Interesting bis(aza-crown)-substituted chiral crown compounds have been prepared (Lukyanenko et al., 1986). The precursor bis(aza-crown)-substituted chiral diol was prepared by two pathways (method D-5). In the first pathway. 

The well known chiral carbon skeleton designated as binaphthyl hinge has been introduced into asymmetric synthesis and resolution of racemates in the form of the derivatives of 2,2 -dihydroxy-l,r-binaphthyl (84, binaphthol). The application of chiral crown compounds containing this binaphthyl tmit for the separation of amino acids and amino acid esters by use of liquid/liquid chromatography has been described particularly by Cram et al. in detail... 

Stoddart has reviewed (in a published lecture) the work of his group on chiral crown compounds derived from carbohydrates. Ip a series of notes they have outlined continued investigations of the precise effects of stereochemistry of ring substituents (as defined by the monosaccharide starting materials) on complexing ability and chiral recognition. 

In the field of carbanion reactions and C-C bond formation (nucleophilic additions). Cram and Gogan have, in a brilliant work [230], demonstrated that chiral crown compounds... 

Other approaches to chiral crown compounds depend on the inclusion of trans-1,2-cyclohexanediol units,or sulphoxide functions, in the ring for their chirality. 

A large number of chiral crowns have been prepared by numerous groups. The reader is directed to the tables at the end of this chapter to obtain an overview of these structures. It would not be useful to try to recount the synthetic approaches used in the preparation of all of these compounds we have chosen rather to subdivide this mass of compounds into three principal groups. The groups are (1) Cram s chiral binaphthyl systems (2) chiral crowns based on the tartaric acid unit and (3) crowns incorporating sugar subunits. These are discussed in turn, below. 

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

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. 

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). 

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. 

Figure 14. Chiral 1,2-diols that have been incorporated into monocyclic crown compounds. Listed under (o) are piecursors with C2 symmetry obtained from L-taitaric acid and L-thieitol, as well as from (5S)-hydrobenzoin as its p-methoxy analog, under (b) are precursors with Cj symmetiy obtained from D-mannitol and L-iditol, and under (c) are asymmetric precursors obtained from (5)-lactic acid, (5)-mandelic acid, and L-glyceraldehyde dithioethylacetal.

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. 

Figure 15. Saturated chiral diols that have been incorporated into fused-ring ail-oxygen crown compounds.

Figure 19. The synthesis of crown compounds containing racemic and chiral 9,9 -spirobifluorene units.

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