Inherently chiral calix arenes

Figure 13. Survey on inherently chiral calix[4]arenes. Capital letters (A-D) characterize phenolic units which are conformationally not mobile (e.g. by larger residues attached to the oxygen). Mobile units (hydroxy or methoxy) are not indicated.

Figure 14. Synthesis of some inherently chiral calix[4]arene ethers and separation of their enantiomers.

The reason these reactions occur can be found in the relative stabilities of the anions involved. This approach could be of general use for the synthesis of inherently chiral calix[4]arenes. The stabilization of the monoanion of a mono-0-alkyl/-acyl calix[4]arene by two intramolecular hydrogen bonds explains the usually easy access to 1,3-derivatives. However, upon further deprotonation the monoanion of a 1,2-O-alkyl (1,2-O-acyl) derivative is stabilized by an intramolecular hydrogen bond (unlike the analogous 1,3-derivative) and rearrangement occurs if there is a reaction pathway available. For the phosphorotropic rearrangement the authors assume a cyclic intermediate with five-coordinated phosphorus, which is not unreasonable although an intermolecular mechanism is not strictly ruled out. 

Figure 15. Pathways to inherently chiral calix[4]arenes.

An elegant synthesis of inherently chiral calix[4]arenes 75 in the 1,3-altemate conformation (type AABB) was recently described by Gutsche et al.136 It consists of the ring opening aminolysis of calix anhydride 74, which is available from the corresponding 1,3-altemate tetraacid 73 by reaction with oxalyl chloride in yields up to 60%. 

A different principle was employed to obtain inherently chiral calix[4]arenes. This approach involves desymmetrizing C2v or Cs symmetrical calix[4]arenes or calix[4]arene analogues (see Section 4.5) by etherification. 1,3-Diethers 78a of AABB-type calix[4]arenes are (as usually) easily obtained in a stereochemically fixed syn-arrangement.146 Since the symmetry plane of the calix[4]arene skeleton does not coincide with the two symmetry planes of the diether-pattem, the whole molecule is C, symmetrical, as revealed by the NMR spectrum. The chirality has been additionally demonstrated by further splitting of the signals in the presence of Pirkle s reagent.147 For the same reasons 1,2-diether derivatives 78b of ABAB-type calix[4]arenes are chiral, although less easily accessible.148... 

Most of the inherently chiral calix[5]arenes described up to now, owe their chirality, however, to the asymmetric substitution pattern at the narrow rim, and due to the lack of other general, selective derivatization reactions are derived from 1,2-or 1,3-crown ethers. Both compounds possess a symmetry plane and can be desymmetrized by a single O-alkyl or O-acyl residue in position 3 (=5) or 4 (=5).151,152,153 In practice, 1,2-crown ethers 79 were prepared from mono-O-alkyl derivatives by reaction with the appropriate ditosylates, while 80 was obtained from the 1,3-crown-ether by subsequent O-alkylation or O-acylation using a weak base to benefit from the fact, that the first deprotonation leads to a hydrogen-bonded (4/5)monoanion. The picolyl derivatives 79 (n = 2) were resolved by HPLC... 

Each of these examples is more or less singular. Most were not studied in the context of chirality. In general, the potential of inherently chiral calix[6]arenes has yet to be explored. 

Figure 5.3 Inherently chiral calix[4 ]arenes with AAAB, AABB, and ABAC substitution patterns...

In 2009, Shimizu and Shirakawa reported the synthesis of inherently chiral calix[4]arenes containing a quaternary ammonium moiety, which were applied as chiral phase-transfer organocatalysts for Michael addition reactions. The Michael products derived from the addition of benzylmalonate to benzylace-tone and from the addition of a glycine derivative to methyl vinyl ketone, respectively, were isolated in almost quantitative yields, albeit with only low enantioselectivities (<6% ee). 

In addition, Shimizu et al. have applied novel multifunetional inherently chiral calix[4]arene to the sulfa-Michael addition of thiols to cyclohexenone. The expected Michael adducts were obtained in generally excellent yields (18-99%) but with low enantioselectivities (<25% ee). The reaction system was also applied to other cyclic and acyclic enones, providing the corresponding products with a comparable degree of enantioselectivity to that obtained with cyclohexenone. 

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... 

Unfortunately a recent classification (see [15b]) of all possible inherently chiral calix[4]arenes which can be obtained by O-alkylation is ambiguous and potentially misleading. V. BOhmer, D. Kraft, and W. Vogt Supramol. Chem. 3,299 (1994). 

Key words Regio- and stereoselective O-alkylations, conformation and conformational mobility, inherently chiral calix[4]arenes and enantiomeric HPLC resolution, A(-oxide ligands and complex-... 

Although chiral calix[4]arenes can be generated by simply attaching chiral residues at the upper [40] or lower [41-43] rim of the calixarene skeleton, recent interest has been focused on the possibility of synthesizing inherently chiral calix[4]arenes, which are build up of nonchiral subunits and consequently owe their chirality to the fact that the calixarene molecule is nonplanar. Molecular asymmetry can arise from the substitution pattern at the lower rim and/or conformation. In this respect, Shinkai has recently reported a systematic classification of all possible chiral isomers derivable from calix[4]arene, and delineated some basic concepts for the design and synthesis of chiral derivatives [44]. 

Inherently chiral derivatives can be also obtained from calix[4]arenes if three different units are incorporated in the order ABAC or if only two different phenolic units are present, provided these derivatives are fixed in conformations having no symmetry plane and center. Figure 13 gives a survey of the possibilities. For such a classification, one should keep in mind that hydroxy groups (or methoxy groups but ethoxy groups are on the borderline) can pass the annulus. Their orientation may be necessary in a description of the actual conformation of such compounds. It must not be indicated, however, if different stable stereoisomers are to be... 

Bridging with tri-functional reagents in 1,3,5-position at the wide, or at the narrow rim led to a more or less rigid skeleton. In such a series of 1,3,5-bridged calix[6]arenes 84 chirality is caused by the CTV moiety used as bridging element.157,158 The calix[6]cryptands 85a and 85b on the other hand are inherently chiral due to the 1,2,4-tri-substitution pattern on the narrow rim.159... 

Various inherently chiral complexes with C2 symmetry are also known from calix[8]arenes in solutions as well as in the crystalline state, but cannot be exhaustively reviewed here.170... 

In principle, two possibilities exist to create inherently chiral cavitands, namely the use of different linkers -X- or linkers having no symmetry plane. The first possibility was realized with cavitand 94.180 It possesses two adjacent methylene bridges and one bridging quinoxaline unit while two hydroxyl groups remain unreacted. This combination results in an asymmetric structure comparable to the AABC calix[4]arenes. 

Figure 17. Synthesis of inherently chiral C4-symmetrical calix[4]arenes 97.

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 regular incorporation of the phenolic units into calix[4]arenes has been observed, if 2-or 6-hydroxymethyl derivatives of 3,4-disubstituted phenols (including cyclic compounds like S-naphthol) are condensed under these conditions (Scheme 5). The resulting calix[4]arenes 8 assume an inherently chiral, C4-symmetrical cone conformation which can be fixed by O-alkylation (see below). In an analogous manner a 2-hydroxymethyl phenol substituted at the 4-position with a porphyrin moiety has been converted to the corresponding calix[4]arene 9 in 60% yield by treatment with NaOH in refluxing diphenyl ether. ... 

Crown ethers 38 of calix[4]arenes have been also obtained by direct O-aUcylation with ditosylates" . Their mono- and 3,4-diether derivatives (partial cone) are inherently chiral " . 

Calixquinones can be easily reduced to the corresponding calixhydroquinones (Zn/HCl or Na2S204) . The calix[8]hydroquinone 57b, however, was prepared from the octabenzyl ether 57a obtained by one-pot condensation in a mixture with the analogous calix[6]- and -[7]arene. Oxidation of 57b to the respective octaquinone was not reported, but the ewrfo-ether 57c was obtained by exhaustive 0-propylation prior to the cleavage of the benzyl ether groups . Inherently chiral derivatives of a calix[4]arene monoquinone have been obtained by 1,4-addition of various nucleophiles to the quinoid system. 

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. 

Figure 24 Possible structures for inherently chiral cone calix[4]arenes. [Figure 24 corrected on 30 March 2012].

Calix[4]arenes with unprotected OH groups in the lower rim undergo through-annulus inversion and therefore cannot be inherently chiral. The substitution of OH groups with alkyl chains (of at least n-Pr size) blocks the inversion and the resulting... 

The recent rapid development of selectively functionalized calix[6]arenes also has a large, yet unexplored potential for obtaining inherently chiral derivatives. Two different diastereomeric 1,2-dibenzylethers of t-butylcalix[6]arene (syn and anti) have been obtained, for instance, from which the anti isomer (17) is chiral (C2 symmetry) [22]. The free energy barrier for their mutual interconversion (about 27 kcal mol ) should also be sufficient to isolate the enantiomers of 17. 1,2,4-Tri-O-alkyl or -acylderivatives [23] should be separable into the enantiomers as long as neither the O-acyl nor the p-substituent can penetrate the annulus. The macrobicyclic 2,5-esters 18 obtained from 1,4-di-p-methylbenzylethers are also chiral, having Ca-symmetry in the all-syn isomer [24]. 

Inherently chiral derivatives are also known from calix[8]arenes. Dimetalla complexes were obtained with titanium (as well as with Zr, V, Sn) in which the two titanium atoms have a pseudooctahedral environment bonded to all of the eight calixarene oxygens, two of which are bridging, and two isopropoxide oxygens. The C2 symmetry was proved by single crystal X-ray analysis and in solution by two-dimensional H-NMR spectroscopy [28]. Various complexes of r-butylcalix[8]arene with lanthanide ions have a similar structure [29]. 

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