Metacyclophane, preparation

Closely related to the spherands are the calixarenes , [ln]metacyclophanes, prepared by base-catalyzed condensation of / -substituted phenols with formaldehyde [6]. These are attractive building blocks, their phenolic hydroxyl groups being ordered in well-shaped cyclic arrays [6-8] which can be functionalized [7-14] to give novel guest inclusion blocks. The combination of structural elements of both... 

Obviously carboxy derivatives such as 11-19 are simple chiral structures suitable for optical resolutions through diastereomeric salts. For this purpose carboxylic groups have been introduced into [10]- and [8]paracyclophane either by chloro-methylation and oxidation of the carboxaldehydes obtained thereof 39,44) or by lithiation and subsequent carboxylation40). Electrophilic substitution of strained paracyclophanes is not advisable since it may initiate rearrangement to the more stable metacyclophanes. Carboxy[7]paracyclophane (72) was first prepared in 1972 by ring contraction of a diazoketone derived from 4-carboxy[8]paracyclophane (75) 45). 

This was first experimentally verified for the [2.2]metacyclophane-4-carboxylic acid (55) which had to be prepared by an elaborate 7-step synthesis 771 in order to avoid an electrophilic substitution which might have led to a transanular ring closure (as had been observed in so many cases of [2.2]metacyclophanes)12). The resolution of 55 was accomplished via salt formation with (-t-)-l-phenylethylamine and gave the levorotatory acid ([a]D —9° in CHC13) which then was transformed into several optically active derivatives. The enantiomeric purity of 55 (and therefore of all compounds correlated with it) was confirmed by nmr spectroscopy of the diastereo-meric esters with (—)-l-phenylethanol77) as well as by HPLC of its diasteromeric naphthylamides 55). 

Similarily, the 4,14-dicarboxylic acid 56 with C2-symmetry could also be resolved via its 1-phenylethylamine salts and its configuration unambiguously correlated with the monocarboxylic acid 55 through the monobromo derivative 5878). Accordingly 55 and 56 with the same sign of optical rotation have the same chirality. Many racemic and optically active homo- and heterodisubstituted 4,12- and 4,14-disubstituted [2.2]metacyclophanes have been prepared and chemically correlated 78,79) mainly to study their chiroptical properties78). Whereas 4,12-homodisubstituted compounds have a center of inversion ( -symmetry) and are therefore achiral meso-forms , the corresponding 4,14-isomers are chiral with C2-symmetry. All heterodisubstituted products are chiral (Q-symmetry see also Section 2.9.4 for the discussion of their chiroptical properties and their use as models for the application of the theory of chirality functions). 

The racemic 4- and 6-methyl[2.2]metacyclophane-l-ones (62 and 63, prepared by unambiguous multi-step syntheses)841 were incubated with Rhodoturula rubra to afford mixtures of the levorotatory ketone 62 and the corresponding epimeric (axial-and equatorial-positioned) (—)-carbinols from racemic 62, whereas the isomeric 63... 

Also asymmetric syntheses have recently been successfully employed for the preparation of optically active [3.2]metacyclophanes (see also 2.7.2) ... 

Some quinolizidine metacyclophane alkaloids have vicinal dioxygen substitution in the quinolizidine ring. Lythrancine V (115) is an example of this type. In model studies, the vicinal diacetate 116 was prepared from 117 through four steps (36). 

Dimethyl-2,5-dithia[6]metacyclophane (15) and 9,13-dimethyl-2,6-dithia [7]metacyclophane (16) were prepared and their enantiomers were (partially) separated by chiral HPLC (on a Daicel OD column) [26]. The CD spectra of these two metacyclophanes were also investigated by the preliminary theoretical calculations. It was shown that the spectra depend strongly on the number of carbon atoms incorporated in the bridging dithiaalane chain, whose dihedral angles play an important role. The electronic excitations of the sulfur s lone-pair electrons were revealed to be critical in theoretically describing the observed Cotton effects. 

Analogous l-thia-10-aza[2.2]metacyclophane derivatives (27-31) were prepared and their enantiomers were partially resolved by chiral HPLC (on a Daicel OT(+) column). Their CD spectra were compared in dioxane, but the absolute As values were not reported [41],... 

Several other [2.2]metacyclophanes were prepared as chiral ligands for com-plexation with tricarbonylchromium. These ligands formed the corresponding chromium complexes stereoselectively and their CD spectra were also studied [42]. 

A unique metacyclophane-type 1,2-diphenylmaleimide D-8 was prepared by Takeshita and Yamato. Because of steric congestion, D-8 can be resolved into enantiomers possessing axial chirality. After optical resolution, the enantiomers were thermally stable and showed photochromism while preserving their chirality [40]. 

Lai and co-workers have also prepared a series of dithia[n.3.3](l,3,5)crownophanes <20030L2781, 2005TL2431>. In order to prepare 115-117, they attempted a synthetic route via a dithia[3.3]metacyclophane derivative <2005TL2431> however, the procedure was unsuccessful because of the significant steric hindrance of the ortho-methyl and opposite aryl groups. An alternative synthesis of 115-117 is showed in Scheme 17. In this method, 115, 116, and 117 were obtained in 15%, 20%, and 31% yields, respectively. 

Crown-tetrathia[3.3.3.3]metacyclophanes 118-120, which have two crown moieties and one metacyclophane unit, have been prepared via intermolecular coupling reactions <2005T9248> as shown in Scheme 18. The X-ray crystal analysis of 119 showed that the compound adopted a perpendicular conformation in which two aromatic rings were inclined to be perpendicular to the opposite aromatic rings. The variable-temperature ll NMR spectra for 119 and 118 suggested that the energy barrier for interconversion of 119 was estimated to be 12.1 kcalmol-1, whereas 118 showed two non-interconvertible conformers at room temperature, which tended to interconvert at elevated temperature however, many conformers coexisted at low temperature. 

The application of reaction conditions as optimized in the preparation of the dithia[2.2]phane 88 allowed Meurer and Vogtle [83] to synthesize the first helically chiral dihetera[2.2]metacyclophanes 91 and 92 in 1.9 and 9% yield. It was impossible to isolate these cyclophanes in all the previous attempts where cesium salts had not been applied [84, 85]. 

As an intermediate of their synthesis of [2.2]metaparacyclophane-quinones, Tashiro et al. obtained 70, that could not be completely demethylated with boron tribromide [37], Using the tert-butyl group as a positional protecting group, these authors also tried the synthesis of [2.2]metacyclophanes 72a/b containing in-traannular halide-substituents [38], The preparation of the difluoro compound... 

They also prepared related phanes by sulfone pyrolysis such as [3.3]metaparacy-clophane 207 (40% yield) and [3.3]metacyclophane 209 (52% yield). The synthesis of a cyano-disubstituted [3.3]phane 211 is described in a separate publication by the same authors [71]. 

The thermal Balz-Schiemann reaction has been used for the preparation of many fluoroaro-malic compounds from the corresponding amines, such as the anticanccr agent 10,53 the es-trogen-sulfoconjugalion inhibitor II.54 the asymmetric acceptor monofluorotetracyano-quinodimethane (12),55 the fltioro[2.2]metacyclophane 13.5b and others.57... 

A series of [m.3.1]propellanols (21, m = 16, 13, 12, 5) have been prepared from the corresponding bicyclic allylic alcohols 20. These were used for the preparation of metacyclophanes. 

In an effort to expand the available synthetic tools for the preparation of various metacyclophanes and pyridinophanes, C.B. Reese and co-workers prepared [6](2,4)pyridinophane derivatives by treating 4,5,6,7,8,9-hexahydro-1H-cyclo-octa[it>]pyrrole with dichloro- and dibromocarbene respectively. The dihalocarbenes predominantly inserted into the most substituted (more electron rich) double bond of the pyrrole ring in modest to poor yields. 

Trans-r-butylation and de-r-butylation reactions are facile processes, and form the basis of many applications of the r-butyl group as a positional protective group. This aspect was well reviewed by Tashiro, and is also discussed in Section I.8.3.2. Tashiro and coworkers have more recently applied the trans-r-butylation and de-r-butylation reactions to prepare metacyclophanes (39) and related compounds. 

Metacyclophanes and related compounds 1. Preparation and nuclear magnetic resonance spectra of 8,16-disubstituted [2.2]metacyclophanes, M. Tashiro and T. Yamato, J. Org. Chem., 1981, 46, 1541. 

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