Asymmetric crown ethers

The property of chiral recognition shown by asymmetric crown ethers towards chiral substrates clearly mirrors the asymmetry of natural interactions and processes. This field is covered in Section 5.21.3.2.2. 

Considerable developments are taking place in this area as evidenced by the wide range of syntheses reported below. An important review of progress to date Carbohydrate derivatives in the asymmetric synthesis of natural products has been provided by Fraser-Reid and Anderson. A further review covers the preparation of asymmetric crown ethers from carbohydrates. Highly abbreviated Schemes are used in this report because space does not permit the reproduction of the lengthy routes used in many of the syntheses. 

Curtis, W. D., D. A. Laidler, J. F. Stoddard, J. B. Wolstenholme, and G. H. Jones Enantiomeric Differentiation by a Chiral Symmetrical Crown Derived from L-Iditol. Carbohyd. Res. 57, C 17 (1977) Laidler, C. L., and J. F. Stoddard Chiral Asymmetrical Crown-Ethers. Carbohyd. Res. 55, C 1 (1977) Laidler, D. A., and J. F. Stoddard Stereoselectivity in Complexation of Primary Alkylammonium Cations by the Diastereotopic Faces of Chiral Asymmetric Crowns. Chem. Commun. 1977, 481. 

Early work on the use of chiral phase-transfer catalysis in asymmetric Darzens reactions was conducted independently by the groups of Wynberg [38] and Co-lonna [39], but the observed asymmetric induction was low. More recently Toke s group has used catalytic chiral aza crown ethers in Darzens reactions [40-42], but again only low to moderate enantioselectivities resulted. 

An asymmetric surrounding of thallium(I) in a crown ether (or cryptand) is especially surprising as these polyethers generally provide a highly symmetric surrounding for the coordinated cation. In fact, alkali-metal cations Hke sodium. 

Asymmetric Lewis-Acid Catalyzed. Another important advance in aqueous Mukaiyama aldol reaction is the recent success of asymmetric catalysis.283 In aqueous ethanol, Kobayashi and co-workers achieved asymmetric inductions by using Cu(OTf)2/chiral >A(oxazoline) ligand,284 Pb(OTf)2/chiral crown ether,285 and Ln(OTf)3/chiral Mv-pyridino-18-crown-6 (Eq. 8.105).286... 

In an Hg22+ asymmetrically complexed by two crown-ethers of different ring size, an extremely high coupling constant /( "Hg, 9Hg) of 284 kHz between the magnetically inequivalent Hg nuclei has been observed.4 3... 

A lead(II) triflate-crown ether complex functions as a chiral Lewis-acid catalyst for asymmetric aldol reactions in aqueous media (Scheme 86).352 This is the first example of a chiral crown-based Lewis acid that can be successfully used in catalytic asymmetric reactions. 

Structural details in CpNa(15-crown-5) 8499 show the Cp and the crown ether to be arranged in an almost coplanar manner with the oxygen atoms coordinated in a slightly asymmetric manner to sodium (Na-O 2.42-2.55 A). The Cp ring displays an asymmetric metal coordination mode with two close (2.67 and 2.71 A), two medium (2.85 and 2.91 A), and one longer Na-C distance (2.99 A). The asymmetric metal coordination may be accredited to the small sodium... 

Recently, Miethchen modified diphosphinite 97 d with a crown-ether linker in the 1,4-positions in order to study the effect on enantioselectivity in Rh-cata-lyzed asymmetric hydrogenation reactions [99]. Introduction of the crown ether in the 1,4-position of the carbohydrate allows the enantioselectivity to be tuned, based on a strong effect of the formation of cryptate species with alkali ions. 

The Darzens reaction can also proceed in the presence of a chiral catalyst. When chloroacetophenone and benzaldehyde are subjected to asymmetric Darzens reaction, product 89 with 64% ee is obtained if chiral crown ether 88 is used as a phase transfer catalyst (Scheme 8-30).69... 

The first successful results of the asymmetric Michael addition under phase transfer catalyzed conditions were achieved by use of ingeniously designed chiral crown ethers 13 and 52.1441 The 3-keto ester 49 reacted with methyl vinyl ketone by use of 13 to give the Michael product 50 with excellent enantioselectivity but in moderate yield, as shown in Scheme 18. The Michael addition of methyl 2-phenylpropionate 51 to methyl acrylate afforded the diester 53 by use of another crown ether 52 in good yield with good enantioselectivity.1441 Various chiral crown ethers were studied to... 

Scheme 18. Asymmetric Michael reaction by use of crown ethers.

S. Aoki, S. Sasaki, K. Koga, Simple Chiral Crown Ethers Complexed with Potassium tert>Butoxide as Efficient Catalysts for Asymmetric Michael Additions , Tetrahedron Lett. 1989, 30, 7229-7230. 

E. Brunet, A. M. Poveda, D. Rabasco, E. Oreja, L. M. Font, M. S. Batra, J. C. Rodrigues-Ubis, New Chiral Crown Ethers derived from Camphor and Their Application to Asymmetric Michael Addition. First Attempts to Rationalize Enantioselection by AMI and AMBER Calculations , Tetrahedron Asymmetry 1994, 5, 935-948. 

L. Toke, P. Bako, G. M. Keserii, M. Albert, L. Fenichel, Asymmetric Michael Addition and Deracemization of Enolate by Chiral Crown Ether , Tetrahedron 1998, 54, 213-222. 

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. 

Chiral recognition by crown ethers with asymmetric carbon atoms 406... 

CHIRAL RECOGNITION BY CROWN ETHERS WITH ASYMMETRIC CARBON ATOMS... 

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... 

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 incoiporation of two asymmetric precursors into chiral crown ethers with C2 symmetiy must be carried out with total constitutional and stereochemical control during the reaction sequence. This has been accomplished elegantly during the synthesis of the three chiral benzo-15-crown-5 derivatives (SS)-79, and (5S)- 0 from (S)-lactic acid (122, 123). 

H and 13C NMR have also been widely used to study the binding of alkylammonium cations to crown ethers. The shift in substrate proton resonances can give detailed information of the preferred structure of the complex. This is particularly important in the study of chiral recognition by asymmetric receptors (79CSR85) (Section 5.21.3.2.2) and also the development of bioorganic models and catalysts (Section 5.21.5.1.1). 

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