Enantioselective receptor

The first example of the use of a chiral-core dendrimer as enantioselective receptor in molecular recognition processes was reported by Diederich (see Fig. 4.70). This dendrimer, designated as a dendrocleff, acts as enantioselective receptor for monosaccharides. It bears a central axially chiral 9,9 -spirobi[9H-fluorene] unit which is linked via two 2,6-bis(carbonylamino)pyridine spacer groups, each in 2,2 position, with triethylene glycol monomethyl ether dendrons [14b]. Both... 

The chemical and more importantly biological activity of any chiral substance depends on its stereochemistry. That is why the design, synthesis, and structure-activity relationships of enantioselective receptors are still very vital areas of research. Chiral synthetic ligands are supposed to open new possibilities in enantioselective catalysis and enantioseparations of racemic chiral compounds, they can be active in different parts of membrane transport and, finally, they can help us in understanding many vital processes in the biological world. 

In practice it means that the exchange of one enantiomer for another is accompanied by the loss or profound change of at least one of these interactions. The study of enantioselective receptors consists in the measurement of the difference in Gibb s free energy caused by these two processes. The magnitude of this difference is directly proportional to the efficiency of chiral recognition. 

Despite the relatively large number of enantioselective receptors of cations and neutral species, reports on the effective chiral recognition of anions are still rare. However, there are a number of reports in the literature describing the recognition of carboxylic acids, and amino acids in particular, performed in aqueous solution at a pH where the carboxylic group has to be at least partly ionized. These reports are also included in this review. 

Voshell SM, Lee SJ, Gagne MR (2006) The discovery of an enantioselective receptor for (—)-adenosine from a racemic dynamic combinatorial library. J Am Chem Soc 128 12422-12423... 

Lawless. L.J. Blackburn, A.G. Ayling, A.J. Perez-Payan. M. Davis, A.P. Steroidal guanidines as enantioselective receptors for N-acyl a-amino acids. Part 1. 3a-Guanylated carbanates derived from cholic acid. J. Chem. Soc., Perkin Trans. 1 2001. 1329-1341. 

Impellizzeri G, Maccarrone G, Rizzarelli E et al (1991) 6-Deoxy-6-JV-histamino B cyclodextrin copper(II) complex, a new enantioselective receptor for aromatic amino acids. Angew Chem Int Ed Engl 30(1348) 1349... 

Liu SY, Law KY,Hea YB etal (2006) Fluorescent enantioselective receptor for S-mandelate anion based on cholic acid. Tetrahedron Lett 47 7857-7860... 

In this chapter we have, in our opinion, presented the most important motifs that have been used to construct anion receptors effective in chiral recognition. The carbohydrates have been successfully applied for modification of binding pocket of anion receptors as well as chiral barriers modulating discrimination of enantiomers. The works described in this chapter illustrate that in the design of new enantioselective receptors, important are not only individual anion binding motifs but also their arrangement in the space. 

Fig. 23. Prototypical receptor molecules for chiral (enantioselective) substrate recognition.

Biocatalysis has emerged as an important tool for the enantioselective synthesis of chiral pharmaceutical intermediates and several review articles have been published in recent years [133-137]. For example, quinuclidinol is a common pharmacophore of neuromodulators acting on muscarinic receptors (Figure 6.50). (JJ)-Quinudidin-3-ol was prepared via Aspergillus melleus protease-mediated enantioselective hydrolysis of the racemic butyrate [54,138]. Calcium hydroxide served as a scavenger of butyric acid to prevent enzyme inhibition and the unwanted (R) enantiomer was racemized over Raney Co under hydrogen for recycling. 

The reductive amination of ketones can be carried out under hydrogen pressure in the presence of palladium catalysts. However, if enantiopure Q -aminoketones are used, partial racemization of the intermediate a-amino imine can occur, owing to the equilibration with the corresponding enam-ine [102]. Asymmetric hydrogenation of racemic 2-amidocyclohexanones 218 with Raney nickel in ethanol gave a mixture of cis and trans 1,2-diamino cyclohexane derivatives 219 in unequal amounts, presumably because the enamines are intermediates, but with excellent enantioselectivity. The two diastereomers were easily separated and converted to the mono-protected cis- and trans- 1,2-diaminocyclohexanes 220. The receptor 221 has been also synthesized by this route [103] (Scheme 33). 

The enantioselective nitro-aldol reaction catalyzed by (R)-LLB is effectively applied to the synthesis of three kinds of optically active (3-receptor blocking drugs (5)-metoprolol,123a (S)-propanolol,123b and ( -pindolol1230 (Scheme 3.17). 

The aforementioned polymer-supported bis-pyridyl ligand has also been applied in microwave-assisted asymmetric allylic alkylation [140], a key step in the enantio-selective synthesis of (R)-baclofen (Scheme 7.118), as reported by Moberg and coworkers. The ( (-enantiomer is a useful agonist of the GABAb (y-aminobutyric acid) receptor, and the racemic form is used as a muscle relaxant (antispasmodic). Under microwave heating, the enantioselectivity could be improved to 89% when using toluene as solvent (see also Scheme 6.52) [140],... 

The easily available hexa-O-benzylsucrose (187) was used as a starting material for the preparation of macrocyclic receptors. Several derivatives of type 188 with various cavities and different number of nitrogen and oxygen atoms were prepared (Fig. 60).78 The azacrown macrocycles showed remarkable enantioselectivity towards a-phenylethylammonium cations. For example diazacrown derivative 188 (Y = O X = NBn n = 2) did... 

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