Metacyclophanes, synthesis

Metacyclophane synthesis. Parham and Rinehart14 synthesized a new elass of metacyclophanes by reaction of (1) with 2 equiv. of phenyl(triehloromethyl)mercury in boiling benzene the intermediate dichlorocyclopropane (2) suffers spontaneous ring opening to give the cyclophane (3) in 73% yield (pure). 

Breitenbach, J. and Vogtle, E, Macrocyclizations with TosMIC-yielding [3 ]metacyclophanes, Synthesis, 41, 1992. 

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). 

The usefulness of this pyrolytic method is emphasized by the synthesis of i>i-[3410][7]metacyclophane [400]. 

The first total synthesis of the metacyclophane alkaloid (+ )-lythranidine (73) was achieved by Fuji et al. (82). 

Although a number of alkaloids belonging to the simple arylquinolizidine class and the lactonic type had been synthesized, no successful synthesis of cyclophane alkaloids was accomplished until that of lythranidine (94), a unique alkaloid with a 2,6-trans disubstituted piperidine structure, was reported (28, 29). Quinolizidine metacyclophane alkaloids lythrancepines II (95) and III (96) have also been synthesized recently (30, 31). A review on the synthesis of lythranidine (94) is available in Japanese (32). 

Figure 2-47 after Cinquini et al. [75] who painstakingly documented the analogy with the pomaceous model. Only examples of the reverse coupe du roi had been known prior to their work. Thus Anet et al. [76] reported the synthesis of chiral 4-(bromomethyl)-6-(mercaptomethyl)[2.2]metacyclophane. They then showed that two homochiral molecules can be combined to form an achiral dimer as shown in and illustrated by Figure 2-48. 

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. 

Related work in our group led to the synthesis of the cyclophanes 21-23 (Scheme 7) [20]. It was found that 21 adopted the syn conformation exclusively and 23 adopted the anti conformation exclusively. However, cyclophane 22 was observed to exist in a ca. 6 1 antv.syn ratio at equilibrium. The two conformers can be separated by flash chromatography and the return to the equilibrium ratio monitored by H NMR. Noteworthy here is the direct observation of an anti to syn flip of a [2.2]metacyclophane. There have been only two other reports of such anti to syn flips [21], Also noteworthy is the chemical shift of the internal proton of the inner ring of anti-22, which appears at S 3.03. 

Calixarenes [77] are defined as [l.n]metacyclophanes with its basic structural unit consisting of phenolic groups linked by ortho-methylene groups. Two examples are shown in Fig. 25. Several reviews are available on this subject [77-79]. These compounds can be synthesized by the acid- or base-catalyzed condensation reaction of a substituted phenol with formaldehyde or an aldehyde (Fig. 26). Calixarenes have also been synthesized by a stepwise reaction that sequentially add phenolic groups followed by a cyclization step. More efficient convergent synthesis have also been developed [80-82], The bowl-like structural conformation generally... 

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]. 

Thallium trifluoroacetate has not enjoyed widespread use as a reagent for quinone synthesis, possibly because it is still a relatively new reagent but more probably because of its toxicity. One example of its use lies in the synthesis of metacyclophanes and related compounds as reported by Tashiro et al Thus the r-butylphenol (59) gave the bisquinone (61), while the phenol (60) afforded the monoquinone (62). An alternative and more practical synthesis of the bisquinone (61) for large scale work involved dealkylation to afford the bisphenol (63) which was then treated with sodium nitrite to give the bisoxime (64). Hydrolysis of the bisoxime did not give the quinone (61), but it could be obtained by zinc/acetic acid reduction of the bisoxime followed by oxidation with nitric acid (Scheme 13). 

Catalytic amounts of dichloro[l,3-bis(diphenylphosphino)propane]nickel(II) [Ni(dppp)Cl2] enable di-Grignard reagents to selectively cyclocouple with aromatic 1,3-dichlorides in THF [81]. Yields are better for pyridinophanes 103a (10-33%) than for metacyclophanes 103b (best yield 22% for n= 10) [Eq. (42)]. The method has been applied to the synthesis of macrocyclic polyethers [81,82]. 

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