Chiral calix arenes

Chiral calix[4]arene dimelamines are weakly CD active, while on the contrary chiral double rosettes show strong absorptions with Aemax ... 

Fig. 10 Chiral Calix[4]arene tetraurea unit bearing stereogenic centers on the urea residues...

For an analogous example including a rigid, chiral calix[4]arene like building block see Okada, Y., Miao, Z., Akiba, M. and Nishimura, J. 

Chiral calix[4]arene podands were made using A-benzyl histidine methyl ester.33 These histidyl calixarenes 12a,b were studied in complexation experiments with Co(H), but no use was made of their chirality. The same is true for a chiral calix[4]arene capped tetraphenyl porphyrin which is C4-symmetrical due to the four L-alanine derived linkers.34... 

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...

Table 5.1 Chiral calix[4 ]arenes via upperjlower rim substitution... 

Smith et have prepared 11 chiral calix[4]arenes, calix[4]resorcarenes, and anionic cyclodextrin derivatives and investigated the properties of their lanthanide (Yb, Dy +) complexes as chiral lanthanide shift reagents (LSR). Baldovini et alP report an application of a camphor-derived chiral complex, Yb(hfc)3 (hfc = tris[3-(heptafluoropropylhydroxymethylene)-(- -)-camphorate]) to differentiate the C NMR spectra of enantiomers of bornyl acetate. 

Also, the use of prolinamide derivatives bearing a stereogenic axis such as in the spiro compound 57 (Fig. 4.4) has been further explored in the reaction of acetone (26.5 equiv.) with several aliphatic and aromatic aldehydes at -25°C. Although its high activity permitted to reduce the amount of catalyst to only 1 mol%, the results were in general modest (50-87% yield, 19-76% ee) [116]. More complicated chiral calix[4]-arene based prolinamide 58 (10 mol%) required the use of acetic acid (20 mol%) as co-catalyst to give the aldol products derived from cyclohexanone (7.3 equiv.) and several aromatic aldehydes, with moderated yields and selectivities (35-93% yield, 66-88% de, 50-79% ee) [117],... 

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. 

When this concept is applied to the stereochemistry of pillar[n]arene, rotation of the units triggers the planar-chiral inversion from pS to pR or from pR to pS. Pillar[5]arenes are cyclic pentamers, therefore they have eight possible conformers pS, pS, pS, pS, pS), (pR, pR, pR, pR, pR), (pR, pS, pS, pS, pS), pS, pR, pR, pR, pR), pR, pR, pS, pS, pS), pS, pS, pR, pR, pR), R, pR, pS, pR, pS) and pS, pS, pR, pS, pR), namely la/b, 2a/b, 3a/b and 4a/b, respectively. In many cases, these conformers interconvert at 25 °C. Thus, inhibition of the rotation of the units contributes to the separation of these planar-chiral pillar[5]arene enantiomers. In calix[ ]arenes, modification of alkyl substituents can slow the rotational motion of the phenolic units, and can immobilize the conformation of calix[n]arenes. Thus, we first introduced various lengths of allq l chains, such as ethyl, propyl, butyl, pentyl, hetg l and dodecyl chains to both rims of the pillar[5]arene. ... 

A unique example of a chiral calix[4]arene functionalized at the upper rim with an amino acid is the aminophosphonic acid derivative 8 (Fig. 2.2). Its synthesis using Pudovik-type addition was reported recently by the group of Kalchenko... 

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. 35.12 Schematic representation of AuNPs capped with the chiral calix[4]arene derivative 21 and selected CD spectra of TOABr-stabllized AuNP(TOABr) black), AuNPs stabilized with 21a and 21b (red), and with a racemic mixture of the two enantiomers (blue) (Adapted with permission from Ref. [53] Copyright 2009 American Chemical Society)...

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]. 

Organocatalysis Continuing efforts to harness the cooperative activity of bifunctional organocatalysts have led to the examinations of chiral calix[4]arenes containing amino phenol stractures and chiral per-6-amino-P-cyclodextrin in the asymmetric sulfa-Michael reactions to cyclic and acylic enones.The preliminary results indicated that further structural modification would be required to allow more efficient asymmetric catalyst systems. 

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