Inherently chiral bridges

The disulfide group is inherently chiral, with the preferred torsion angle about the S-S bond being -90°. Both right- and left-handed disulfide bridges occur in proteins.305 306... 

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... 

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. 

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. 

Scheme 1.12. A tandem sequence of Michael-type addition and [4 + 2] cycloaddition diastere-oselectively affords highly functionalized 1,2,3,4-derivatives of Cgo (type ( )-169) with two adjacent bridges and a noninherently chiral functionalization pattern. Deprotonation of ( )-169 and subsequent alkylation leads to an inherently chiral addition pattern in ( )-170.

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). ... 

Since cis-3, trans-3, and trans-2 bis-adducts of 50 with identical addends are chiral as a result of inherently chiral functionalization patterns [10, 44-46], it was of interest to explore whether Bingel macrocyclizations with bismalonates bridged by non-racemic tethers would provide an enantioselective synthesis of these compounds. An overall enantioselective synthesis of optically active Cgg bis-adducts had been achieved previously by asymmetric Sharpless bis-osmylation [77] however, this sequential bis-func-tionalization lacks the regioselectivity of the Bingel macrocyclization, and therefore requires tedious regioisomer separations. 

In a first report on the mono-addition of benzyne to Cyg [86], the fourth product isomer (34%) besides 43,10 and ( )-42 (Fig. 5) was suggested to result from an unusual transequatorial 1,4-addition mode. The result is a Cy-symmetrical molecule with an inherently chiral functionalization pattern in which the positions C(7) and C(23) (Fig. 6) are bridged. This equator-spanning addition mode was also proposed to occur in CygClig [85,124] (cf. Fig. 11) as well as in multiple benzyne adducts of Cyg [86,125]. 

The observed chirality in helicates can arise from the inherent asymmetric spiral arrangement of the molecular components, even if the building blocks are achiral or alternatively, it may result from the use of chiral bridging agents so that the chirality is fiansferred to the coordinated... 

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. 

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. 

Thus an inherently chiral ABi diphosphonato cavitand ( )-166 bearing a single quinoxaline bridging moiety was synthesized and resolved by the chiral HPLC. 

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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