Paracyclophanes planar chirality

In 2004, Bolm et al. reported the use of chiral iridium complexes with chelating phosphinyl-imidazolylidene ligands in asymmetric hydrogenation of functionalized and simple alkenes with up to 89% ee [17]. These complexes were synthesized from the planar chiral [2.2]paracyclophane-based imida-zolium salts 74a-c with an imidazolylidenyl and a diphenylphosphino substituent in pseudo ortho positions of the [2.2]paracyclophane (Scheme 48). Treatment of 74a-c with t-BuOLi or t-BuOK in THF and subsequent reaction of the in situ formed carbenes with [Ir(cod)Cl]2 followed by anion exchange with NaBARF afforded complexes (Rp)-75a-c in 54-91% yield. The chela-... 

Some other enantioselective approaches have been attempted, still with moderate enantioselectivities, by making use of in situ systems containing a chiral NHC precursor. Luo and co-workers reported on the use of the bidentate chiral imidazo-lium salt 16, derived from L-proUne, in combination with [RhCia-COCcod)], leading to an enantiometic excess of around 20% [30]. The use of chiral imidazolium salt 17 in combination with [RhCl(CH2=CHj)j]j by Aoyama afforded slightly better ee (Fig. 7.3) [31 ]. So far, Bohn and co-workers have obtained the best enantioselectivities (up to 38% ee) for the catalytic addition of phenylboronic acid to aromatic aldehydes by using planar chiral imidazolium salts 18, derived from paracyclophane, in combination with [Rh(OAc)2]2 [32]. 

In order to study the role of the [2.2]paracyclophane-type planar chirality in asymmetric induction, Hou et al. have developed the synthesis of novel S/N-... 

The substance 4,12-dibromo[2.2]paracyclophane is the key intermediate en route to several functional C2-symmetric planar-chiral 4,12-disubstituted[2.2]paracydo-phanes. Braddock and coworkers have shown that this important intermediate can be obtained by microwave-assisted isomerization of 4,16-dibromo[2.2]paracydo-phane, itself readily prepared by bromination of [2.2]paracyclophane (Scheme 6.88) [182], By performing the isomerization in N,N-dimethylformamide as solvent (microwave heating at 180 °C for 6 min), in which the pseudo-para isomer is insolu-... 

Pye and Rossen have developed a planar chiral bisphosphine ligand, [2.2]PHANE-PHOS, based on a paracyclophane backbone (Scheme 1.6) [69]. Moreover, the ortho-phenyl substituted NAPHOS ligand, Ph-o-NAPHOS, has been successfully applied for the rhodium-catalyzed hydrogenation of a-dehydroamino acid derivatives [70]. 

Optically active chochins were prepared by the Hofmann route 641 starting from (i )(—)-4-methyl[2.2]paracyclophane (38) with known chirality 54,67) (see 2.9.). Introduction of the trimethyl-ammoniomethyl group (via acetylation and subsequent transformations) afforded (—)-39 which was then cross-coupled with the ammonium base 36 to give a mixture of [2.2]paracyclophane and the levorotatory[3] and [4]chochins (40,43) with ( )-chirality in these cases the descriptors (/ ) and (5) specify the planar chirality of the inner rings(s) as shown in Fig. 2, in accordance with the rules presented in Section 1.2. 

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 (+)( ). 

The development of ferrocene 9 was part of our studies on planar-chiral compounds, which also involved the synthesis of other scaffolds such as chromium-tricarbonyl arenes [15], sulfoximidoyl ferrocenes [16], and [2.2]paracyclophanes [17]. In aryl transfer reactions, however, ferrocene 9 proved to be the best catalyst in this series, and it is still used extensively today. 

The element of planar chirality plays a pivotal role in many modern ligand systems. The particularly huge success of ferrocenyl ligands has not been matched by any other chiral backbone to date. Metallocene and metal-arene-based ligand backbones exhibit the common feature that they become planar chiral only upon addition of (at least) two substituents on one ring fragment. [2.2]Paracyclophanes, however, need only one substituent (Fig. 2.1.3.1) to be chiral. 

The use of planar-chiral [7] and central-chiral ligands based on paracyclophane systems was still a relatively unexplored frontier, with notable exceptions in the reactions examined by the Rozenberg group [8] and the Berkessel group [9]. 

S. Erase, Planar chiral ligands based on [2.2]paracyclophanes, in Asymmetric Synthesis - The Essentials (Eds. M. Christmann, S. Erase), Wiley-VCH, Weinheim, 2006. 

In addition, chiral dendrimers (see Section 4.2) can be resolved with the aid of HPLC into their enantiomers, if the silica gel material used as stationary phase has optically active substances bound to its surface [9]. Since the chiral stationary phase (CSP) [10] undergoes different intensities of interaction with the enantiomeric dendrimers, they are retained to different degrees, and in the ideal case two completely separated (baseline separated) peaks are obtained. This separation technique was successfully applied inter alia to racemic mixtures of planar-chiral dendro[2.2]paracyclophanes, cycloenantiomeric dendro[2] rotaxanes, topologically chiral dendro[2]catenanes [11] as well as topologically chiral, dendritically substituted molecular knots (knotanes) [12] (Section 4.2.3). 

Bidentate oxazoline-imidazolylidene ligands, in which both units are linked by a chiral paracyclophane, have been studied in Bolm s group [129]. In this case, the planar chirality of the pseudo-orfho-paracyclophane is combined with the central chirality of an oxazoline (Scheme 48). Compounds 70 were tested in the asymmetric hydrogenation of olefins displaying moderate selectivity (ee s of up to 46% for dimethylitaconate in the presence of 70b). 

Paracyclophane[4,5-(/]oxazol-2(3/7)-one (152) exhibiting planar chirality has been used as chiral auxiliary in asymmetric Diels-Alder (DA) and Michael reactions via a,P-... 

Apart from the role of cyclophanes as a model system for studying the electronic interaction between the aromatic moieties, chiral [2.2]paracyclophanes have also been utilized as planar chiral ligands in asymmetric catalysis. Recent advances and applications in this area have been reviewed [5, 6]. The synthesis of heterocyclic compounds based on [2.2]paracyclophane architecture, where the long-distance electronic communication and the planar chirality play significant roles in their application, has also been reported recently [7]. Although the preparation and application of chiral cyclophanes in asymmetric synthesis has attracted much attention for a long time, their chiroptical properties, especially the CD spectra, have rarely been paid attention or even completely ignored. 

The CD spectra of enantiopure pyridinophane 17 and bipyridine derivative 18 were reported. Both spectra were relatively complicated compared to those of substituted [2.2]paracyclophanes, apparently showing 6-8 positive/negative Cotton effect peaks. While the lAel value for the main band of compound 18 (20-30 M-1 cm-1) was reduced to half that of compound 17 (30-50 M 1 cm ), the spectrum of planar chiral bipyridine 18 was very sensitive to the added metal salts. The absolute configuration was determined by comparison with the theoretical spectrum at the DFT/SCI level [31]. 

The CD spectral investigation of optically active bi[10]paracyclophanes (47), in which two planar and one axial chirality elements are incorporated, was reported in the literature [57]. The experimental CD spectrum of enantiomerically pure (RV,SP)-47, which was derived from the corresponding diastereomeric tetra-(S )-camphanoate, was found to be in good agreement with that calculated for the (aA)-isomer, but approximately the mirror image of the spectrum computed for the (aSHsomer (Fig. 11). Thus, the CD spectrum can be interpreted mostly in terms of the axial chirality, indicating that the effects from the planar chirality of cyclophane units were more or less cancelled out. 

Ma et al. [10] chose a different catalytic reaction to show the chiral inducement of the planar chiral [2,2]-paracyclophane functionalised NHC ligand. The rhodium(I) catalysed reaction between a boronic acid and the prochiral cyclohexenone results in the addition of the boronic acid s substituent to the olefinic double bond of cyclohexenone (see Figure 5.32). In the present case, the product is (5)-3-phenylcyclohexanone with 61-98 % ee. The lowest chiral resolution is observed with the least hindered [2,2]-para-cyclophane group. 

For planar chirality, the only convincing example up to date is the use of [2,2]-paracyclophane wingtip groups and here auxiliary substituents on the paracyclophane enhance the chiral resolution, probably due to an additional atropisomeric effect, hindrance of rotation aronnd the C-N bond. 

Compound (35) is an example of a bipyridine ligand with planar chirality. This ligand was synthesized by reacting a cyano-substituted [2.2]paracyclophane pyridyl derivative with acetylene and cyclopentadienylcycloocta-l,5-dienecobalt in toluene by the Bonnemann reaction.133... 

Although planar chirality has not been found in nature so far, biological tools can be used for resolution of planar chiral molecules. The synthesis of enantio-merically pure (S)-4-formyl[2.2]paracyclohane (>99% ee) (S)-155 and (R)-4-hydroxymethyl[2.2]paracyclophane (R)-156 (>78% ee) was achieved by bioreduction in 49 and 34% yield respectively. From several mircoorganisms screened only one strain of the yeast Saccharomyces cerevisiae showed a stereospecific reduction of the planar chiral substrate. Despite the high enantiomeric ratio it was necessary to maintain the conversion of the process at almost 50% in order to obtain high enantiomeric excesses of both substrate and reduction product [101]. 

Scheme 50. Synthesis of planar chiral [2.2]paracyclophanes by biotransformation [101]...

Recently the first use of the paracyclophane backbone for the placement of two diphenylphosphano groups to give a planar chiral C2-symmetric bisphos-phane was reported [102]. The compound 159 abbreviated as [2.2]PHANEPHOS was used as a ligand in Rh-catalyzed hydrogenations. The catalytic system is exceptionally active and works highly enantioselective [ 103]. The preparation of [2.2]PHANEPHOS starts with rac-4,12-dibromo[2.2]paracyclophane (rac-157), which was metalated, transmetalated and reacted with diphenylphosphoryl chloride to give racemic bisphosphane oxide (rac-158). Resolution with diben-zoyltartaric acid and subsequent reduction of the phosphine oxides led to the enantiomerically pure ligand 159. 

We were able to synthesize chiral dendri- rations. In addition, the circular dichrograms mers with stable planar-chiral building blocks clearly indicate that chiral dendrimers based to avoid racemisation. [47] In contrast to the on derivatives of [2.2]paracyclophanes can results of Seebach et al. these dendrimers be employed for complexation of certain show increasing chirality with inreasing gene- metal cations. 

As continuation of this work, a planar chiral [2.2]paracyclophane monophosphine has been applied successfully as an organocatalyst in asymmetric allylic amination of MBH adducts. Up to 71 % ee was achieved using (i )-298 as a catalyst (Scheme 3.127). ... 

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