Cyclophanes chirality

Inspired by the separation ability of cyclic selectors such as cyclodextrins and crown ethers, Malouk s group studied the synthesis of chiral cyclophanes and their intercalation by cation exchange into a lamellar solid acid, a-zirconium phosphate aiming at the preparation of separation media based on solid inorganic-organic conjugates for simple single-plate batch enantioseparations [77-80]. 

The inherent plane of chirality in the metal carbene-modified cyclophane 45 was also tested in the benzannulation reaction as a source for stereoselectivity [48]. The racemic pentacarbonyl(4-[2.2]metacyclophanyl(methoxy)carbene)-chromium 45 reacts with 3,3-dimethyl-1-butyne to give a single diastereomer of naphthalenophane complex 46 in 50% yield the sterically less demanding 3-hexyne affords a 2 1 mixture of two diastereomers (Scheme 30). These moderate diastereomeric ratios indicate that [2.2]metacyclophanes do not serve as efficient chiral tools in the benzannulation reaction. 

Optical Activity Caused by Restricted Rotation of Other Types. Substituted paracyclophanes may be optically active and 25, for example, has been resolved. In this case, chirality results because the benzene ring cannot rotate in such a way that the carboxyl group goes through the alicyclic ring. Many chiral layered cyclophanes (e.g., 26) have been prepared. ... 

Another cyclophane with a different type of chirality is [12][12]paracyclo-phane (27), where the chirality arises from the relative orientation of the two rings attached to the central benzene ring. Metallocenes substituted with at least two different groups on one ring are also chiral. Several hundred such... 

The Cahn-Ingold-Prelog system is unambiguous and easily applicable in most cases. Whether to call an enantiomer (R) or (S) does not depend on correlations, but the configuration must be known before the system can be applied, and this does depend on correlations. The Cahn-Ingold-Prelog system has also been extended to chiral compounds that do not contain chiral atoms.A series of new rules have been proposed to address the few cases where the rules can be ambiguous, as in cyclophanes and other systems. ... 

Racemization and rearrangement mechanisms of chiral [2.2]para cyclophanes iso.isi). 

In a tour de force in 1956, Cahn, Ingold and Prelog introduced the terms chirality axis (descriptors aR/aS) and chirality plane (descriptors pRjpS) in order to deal with compounds such as allenes, biaryls and cyclophanes. Rules for assigning the chirality sense were devised ad hoc. In 1966 the helieity concept was introduced and it was recognized that its use allows the corresponding models to be treated in an alternative way. The specific proposals, as illustrated in Table 1, however, were only published in 19821. 

Fig. 1. Plane of Chirality Enantio-morphous figures and corresponding torsional angles A—X—Y—Z 7). Molecular examples ([n]paracyclophane, [2.2]meta-cyclophane, bridged[10]anulene and ( )-cyclooctene) with descriptors (/ , S)...

On the basis of this definition (Fig. 1) the following classes of chiral compounds will be treated in this article cyclophanes, bridged anulenes and [8]anulenes, and ( )-cyclooctene and related structures. As mentioned above, metallocenes will be excluded. 

A variety of chiral [m.n]cyclophanes has been described, including [2.2](2,6> naphthalenophane (27) 49-50> and the corresponding diene 49), or [2.2](2,5)pyridino-phanes (28)51). In both cases (27, 28) achiral and chiral isomers (a, b) were isolated and their structures assigned mainly by H-nmr spectroscopy. The chiral structure... 

By a reaction sequence similar to the one outlined above for the [8][8]cyclophane 32 also the levorotating [8][10]paracyclophane 33 was obtained starting from (—)-methyl[10]paracyclophanecarboxylic acid IS6. Opposite Cotton effects of (+)-32 and (—)-33 indicated that they had opposite chiralities, and hence it followed that both (+)-32 and (+)-33 had the same chirality, namely (S). It should be noted that for (-)-14 the chirality (S) had been established 40) (cf. also Ref.62) and sections 2.9.2. and 2.9.3.) it would be somewhat surprising that its levorotatory methyl derivative 15 had (/ ) chirality as deduced from the above sequence (—)-15 - (-)(/ )-33 44). Moreover, for levorotatory [m][n]paracyclophanes (S)chirality had been proposed by application of a sector rule 63) (see also 2.9.4.). 

As usual in stereochemical research, four main approaches have been applied to the problem of assigning chiralities to optically active cyclophanes. They are listed in order of their reliabilities i) anomalous X-ray diffraction (Bijvoet method), ii) chemical correlations with compounds of known chiralities (preferably established by the Bijvoet method), iii) kinetic resolutions and/or asymmetric syntheses, iv) interpretation of chiroptical properties (mainly circular dichroism) on the basis of (sector) rules including theoretical methods. 

So far the chiralities of only three cyclophanes have been established by this unambiguous method. 

For [2.2]paracyclophane-4-carboxylic acid (25) as (—)(R) This result has been mentioned in a footnote in Ref. 1011 but seems never to have been published (see also Ref. 61). The chirality of this acid was correlated via its ( )-aldehyde with a levo-rotatory hexahelicene derivative which, according to the paracyclophane moiety at the terminal, had to adopt (A/)-helicity. Its chiroptical properties are comparable to those of hexahelicene itself101. For the (—)-bromoderivative of the latter the (A/)-helicity was established by the Bijvoet-method 102). In a later study, (—)para-cyclophane-hexahelicene prepared from (—)-l,4-dimethylhexahelicene with known chirality (which in turn was obtained with approximately 12% enantiomeric purity by asymmetric chromatography) confirmed these results. It should be mentioned that [2.2]paracyclophane-4-carboxylic acid (25) was the first planar chiral cyclophane whose chirality was determined 1041 (see also Ref.54 ). The results justmentioned confirmed the assignment (+)( ). 

For chemical correlations of planar chiral cyclophanes with centrochiral derivatives for the purpose of applying Horeau s method IOO), see the following section. 

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