Chiral calixarenes inherent chirality

The chirality of the compounds discussed so far, especially of those in Section 2 is caused entirely by the chirality of their substituents. Due to their nonplanar shape, calixarenes offer various additional possibilities to produce chiral derivatives, the chirality of which is not based on a chiral group or subunit but on the absence of a symmetry plane, an inversion center, or an alternating axis in the molecule as a whole. This means, that opening of the macrocyclic structure would lead to an achiral linear molecule. Such molecules may therefore be called inherently chiral which should not be confused with the term intrinsically chiral,110 A graph whose chirality is independent of its embedding in the three-dimensional space is intrinsically chiral, while the inherent chirality defined above is due to the three-dimensional structure. 

The phenolic units of a calixarene can also become structurally different by the attachment of different alkyl or acyl residues to the oxygens, which may simultaneously lead to the necessary conformational restriction. A recent paper describes a rational way to synthesize tetraethers with four different O-alkyl groups in the cone conformation,118 which is outlined in Figure 12. The last four compounds in this sequence are inherently chiral.119... 

If the phosphorotropic rearrangement is combined with selective electrophilic substitution of free phenolic units (e.g. bromination) and hydrolysis of ester or phosphate groups a variety of inherently chiral calixarenes becomes available,130 as demonstrated by the examples in Figure 15. 

The possible number of inherently chiral structures and conformers further increases if the calixarene contains both different phenolic units and different bridges in the macrocyclic skeleton. For example, two chiral monoethers 88a,b are available from dihomooxacalix[4]arenes (one -CH2-0-CH2- bridge instead of -CH2-).17188b is the preferred product of the mono-O-alkylation, since the negative charge of the respective phenoxide anion is better stabilized by intramolecular hydrogen bonds due to the smaller distance between the phenoxide anion and the hydroxy groups. Tetraketone derivatives (Y = CH,-C(0)-R) in the two possible partial cone conformations, have been prepared in moderate yields. 

The area covered is very widespread and the role of the calixarene molecules reach from a simple platform or skeleton on which to assemble chiral centers to an inherent part of the chiral structure. Biologically active molecules or derivatives are involved as well as artificial ligands and their metal complexes. Chiral calixarenes have been used as stationary phases in analytical separations or as host molecules in sensors. Basic properties of calixarenes, such as their conformational stabilities, have been studied with chiral derivatives as well as more... 

What could be further developments Enantioselective catalysts may be named as one important field. The construction of calixarene-based, eventually biomimetic, catalysts is still in its infancy.291 The simultaneous attachment of catatytically active groups in combination with chiral functions or with the inherent chirality of the calixarene skeleton itself opens numerous possibilities that are far from being exhausted. Even the combination of achiral calixarenes with chiral catalysts may lead to useful results.292... 

For earlier reviews on inherently chiral calixarenes and related compounds see (a) Bohmer, V. Kraft, D. Tabatabai, M. J. Incl. Phenom. Mol. Recogn. 1994,19,17-39. (b) Otsuka, H. Shinkai, S. Supramolecular Science 1996,3,189-205. 

Siegel, J. Biali,S.E. Mislow, K. J. Am. Chem. Soc. 1987,109,3397. In the present case, however, the directionality of the hydrogen bonds is the only stereogenic element and consequently all inherently chiral calixarenes would be cycloenantiomers. The expression cycloenantiomers was also used for instance for rotaxanes composed of wheel and an axle, which both are achiral by themselves but have a structural directionality Yamamoto, C. Okamoto, Y. Schmidt, T. Jager, R. Vogtle, V. J. Am. Chem. Soc. 1997,119, 10547-10548. 

Interest in phosphorus-containing calixarenes continues. Structures reported include hexa(diethoxyphosphoryloxy)calix[6]arene (8), inherently chiral 1,2-bridged calix[4]arene diphosphates, and a calixarene like C3 symmetric receptor with a phosphate function at the cavity bottom. " The purification of phosphate substituted calixarenes has been studied by chiral HPLC and by normal reverse phase HPLC. Mono(6-0-diphenoxyphosphoryl)-P-cyclodextrin (9) and mono(6-0-ethoxyhydroxyphosphoryl)-p-cyclodextrin (10) have been synthesised and show enantioselective inclusion of D and L amino acids e.g. 3.6 for D/L serine in the case of 9). ... 

A complete survey on calixarenes was far beyond the scope of this chapter. We therefore concentrated mainly on the chemistry, namely the synthesis and the (basic) chemical modification of calixarenes, which form the basis for aU fnrther stndies. Fnrther interesting aspects, such as inherent chirality of calixarenes, catalytic or biomimetic effects , larger structures formed via self-assembly in solution or in mono- and multilayers could be stressed only shortly. Important properties snch as complexation of cations , anions and of nentral gnests , including fnUerenes , conld not be treated at all. The same is tme for applications arising from these properties in snch different areas as sensor techniqnes , chromatographic separations or treatment of nuclear wastes . In all these cases, the reader is referred to special reviews. 

A more subtle way to generate a chiral calixarene is to create dissymmetry or asymmetry within the molecule itself One of the means for doing this with a calix[4]arene is to establish a substitution pattern of AABC or ABCD on the upper or lower rim, producing a compound that is inherently chiral in all possible conformations. Tabulations of the cone, partial cone, 1,2-alternate, and... 

Chirality in calixarenes and resorcinarenes can be essentially of two different types, depending on the method used for generating it. The first type, called chirality by attachment, consists of the introduction of a chiral, nonracemic, moiety onto the calixarene or resorcinarene framework. The second type, often referred to as inherent chirality, has been particularly studied for calix[4]arenes, and it is usually observed when three (AABC) or four different phenolic units are present in the macrocycles (Figure 24). As this type of chirality is linked to the nonplanar shape of calix[4]arenes, the well-known ring inversion of these compounds must be avoided through functionalization at the lower rim to obtain stable enantiomers. 

The search for inherently chiral calixarenes has been steadily pursued since the very beginning of calixarene... 

Inherent chirality Chirality that does not originate from a stereogenic element, but from the presence of a curvature in the structure. Originally coined for calixarenes, this term is also used for jullerenes and uranyl-salophen complexes. 

Often symmetry operations cannot be used in a simple way to classify chiral forms because, e.g., the molecule consists of a number of conformations. Therefore, independent of the symmetry considerations, a chemical approach to describe chiral molecules has been introduced by the use of structural elements such as chiral centers, chiral axis, and chiral planes. Examples for a chiral center are the asymmetric carbon atom, i.e., a carbon atom with four different substituents or the asymmetric nitrogen atom where a free electron pair can be one of the four different substituents. A chiral axis exists with a biphenyl (Figure 3.2) and chiral planes are found with cyclo-phane structures [17]. Chiral elements were introduced originally to classify the absolute configuration of molecules within the R, S nomenclature [16]. In cases where the molecules are chiral as a whole, so-called inherent dissymmetric molecules, special names have often been introduced atropiso-mers, i.e., molecules with hindered rotation about a helical molecules [18], calixarenes, cyclophanes [17], dendrimers [19], and others [20]. 

Bridges between aromatic rings of calixarenes and resorcinarenes are commonly considered chemically inert. Therefore, substitution of the bridges is the least common among modifications due to synthetic difficulties. However, in some cases, the modifications can be introduced prior to the cyclization step, as in 49 (Fig. 2.13) [55, 56]. Another possibility involves using thiacalixarenes. Oxidation of the adjacent sulfide functional groups in an a/ifi-relationship leads to an inherently chiral structure 50 [57]. It should be noted however, that inherent chirality in this case is inextricably boimd to stereogenic centers at the sulfur atoms. 

The unique feature of calixarenes is their concave structure that clearly distinguishes the upper and lower rims. When the inversion of the concave structure is hindered, an asymmetric/dissymmetric substitution pattern leads to the formation of chiral structures (Fig. 2.14). This type of chirality is known as inherent chirality. Calix[4]arenes were the first scaffolds for which the term inherent chirality was... 

Fig. 2.15 General rules for stereochemical notation for inherently chiral calixarenes. In till cases R denotes an unspecified substituent...

Fig. 2.16 Inherent chirality of calixarenes introduced by (a, b) lower rim substitution (c, d) spacial alignment (e) directional bridging...

Yet another approach for differentiation of substituents at the lower rim involves directional bridging. The bridge can be placed at any position, however, in practice, the most convenient location is the lower rim oxygen atoms (Fig. 2.16e). For example such directional linkages composed of carboxamide [72] or ester [73] moieties were introduced by a cyclization reaction to give inherently chiral calixarene 60 possessing C2 symmetry. 

Fig. 2.19 Inherently chiral calixarenes (including resorcinarenes) obtained by edge substitution...

Abstract. Due to the nonplanarity of the basic In-metacyclophane system, calixarenes and resorc-arenes can be transformed into molecules with inherent chirality. Various attempts to achieve this goal are reviewed. Special emphasis is given to derivatives with Cn-symmetry, including derivatives of spherand calixarenes and other calixarene-like macrocycles. 

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