Cyclophane enantioselectivity

S R ratio = 5 1) [22]. Yanada and Yoneda constructed the deazaflavinophane 26, which exhibits complete facial selectivity in its oxidation and reduction reactions, e.g. the reduction with NaBD to afford 27 [23], Belokon and Rozen-berg used scalemic 4-formyl-5-hydroxy[2.2]para-cyclophane (FHPC) 28 in the synthesis of a-ami-no acids (ee 45-98 %) [24], An alternative approach to FHPC was more recently reported by Hopf [25]. Other interesting advances in the area of chiral cyclophanes include the homochir-al [2.2]paracyclophane-derived amino acids 29 and 30 [26], as well as (5)-PHANEPHOS (31) [27], which has been shown to be an effective ligand for highly enantioselective Ru-catalyzed asymmetric hydrogenations of -ketoesters and... 

Figure 78 A chiral, water-soluble cyclophane for enantioselective binding [104]...

Cationic Rh(I)/BINAP-type bisphosphine complexes as catalysts for chemo-, regio-, and enantioselective [2 + 2 + 2] cycloadditions to afford substituted benzenes, cyclophanes, and N-heterocycles 07SL1977. 

Amino acids may be bound in water by molecules with hydrophobic cavities. Cyclodextrin derivatives were studied extensively. Enantioselectivities are usually modest, with some exceptions. For example, a diphenoxyphos-phoryl-substituted p-cyclodextrin bound serine with 3.6 1 enantioselectivity " and an a-cyclodextrin with a pyr-idinium substituent showed 10 1 enantioselectivity toward the same substrate.Synthetic cyclophanes were also used. The bipyridinium-based macrocycle 36 bound DOPA 37 with 13 R S selectivity in acidic aqueous solution. 

With water as solvent, hydrophobic interactions can be used to drive complex formation. Cyclodextrins were widely used to study hydrophobic binding, and they often show enantioselectivity. However, strong enantiodiscrim-ination is rare, especially for less-functionalized substrates. synthetic water-soluble receptors gave similar results. For example, cyclophane 65 bound the enantiomers of menthol 66 in the ratio 5 4. - while macrocycle 67 bound Naproxen derivatives 68 in D20/Me0H (60 40) with 1.9 ] enantioselectivity. " ... 

The Saigo group disclosed the first highly enantioselective self-annulation of enals catalyzed by the cyclophane-type chiral NHC to afford y-butyro-lactones (91-99% ee for the trans isomers). a,a,a-Trifluoroacetophenone... 

Hochmuth, D.H. Koenig, W.A. Determination of the rotational energy barrier of planar-chiral cyclophanes using dynamic enantioselective gas chromatography and computer simulation. Liebigs Ann. 1996, 6, 947-951. 

SCHEME 21.22 Enantioselective synthesis of planar chiral cyclophanes. 

Interesting planar chiral tripodal cyclophanes have also been synthesized with high enantioselectivity by the cationic rhodium(I)/Me-Duphos complex-catalyzed [2+2+2] cycloaddition of branched triynes (Scheme 21.25) [29]. 

Reduction via inclusion complexes has received considerable attention because it allows both the diastereo- and enantioselectivity of the reaction to be controlled. Cyclodextrins and water-soluble cyclophanes are the most frequently used hosts in aqueous medium. P-CD/ketone (1 1) complexes suspended in NaBH4 aqueous alkaline solution give the corresponding alcohols quantitatively but with modest ee [75]. An improvement is obtained by using crystalline a-, P- and y-CD inclusion complexes of achiral amine-boranes at 0°C in heterogeneous aqueous medium [76]. Under these conditions, 1-phenylethanone and 4-phenyl-2-butanone give the (5) and (R) alcohol with 91% and 89% ee, respectively. 

The first synthesis of planar meto-cyclophanes was achieved in 2007 through rhodium catalysis as well, with moderate yields but excellent enantioselectivities (Scheme 7.2) [6]. 

Scheme 7.2 Enantioselective [2-I-2-I-2] cycloaddition affording meto-cyclophanes.

In efforts to generate receptors for the enantioselective complexation of naproxen derivatives, e.g. 12a/b, in aqueous solution, we prepared a series of optically active, water-soluble cyclophanes (13 -17) with tqx>lar cavities shtqied by the major giwves of the 2,2 ,6,6 - and 2,2 ,7,7 -tetraoxa-l,r-binaphthyl units [30,31]. The synthesis of macrocycle 15 is shown in Scheme 6. 

Tanaka et al. examined chiral Rh-catalyzed intramolecular cycloaddition using triynes with substituents at both ends and obtained [7] to [lOJmeto-cyclophanes with high enantioselectivity. This is the first example of catalytic and enantioselective synthesis of planar-chiral cyclophanes using the [2+ 2+ 2]-cycloaddition approach (Scheme 8.14) [11a]. The tether structure of the 1,6-diyene moiety of the triynes affected the stereoselectivity, and the reaction of ester-tethered triynes realized almost perfect enantioselectivity (Scheme 8.15) [11a]. 

The intermolecular reaction of propiolate, which is an unsymmetrical alkyne, and diynes with shorter tethers afforded [7] to [9]para-cyclophanes with moderate to good ee (Scheme 8.17) [12]. The first enantioselective synthesis of a dioxa[7]para-cyclophane, which has a structurally strained benzene ring due to a short ansa chain, should be evaluated comprehensively. 

Shibata et al. disclosed the reaction of branched triynes in which a 1,6-diyne moiety and alkyne are connected by a rigid 2-aminophenyl tether. An intramolecular [2 + 2 + 2] cycloaddition gave tripodal cyclophanes in high yield with excellent ee (Scheme 8.18) [13a]. It is noteworthy that the [15]cyclophane skeleton (n = 10) can be constructed efficiently without racemization. This is the first example of the enantioselective synthesis of tripodal cyclophanes. 

Enantioselective reaction was achieved by cationic rhodium/chiral diphosphine complexes. The intramolecular reaction of linear triynes gave planar-chiral meta-cyclophanes in excellent ee. The intermolecular reaction of diynes with alkyne afforded planar-chiral para-cyclophanes with strained benzene ring in moderate to excellent ee. The intramolecular reaction of branched triynes gave planar-chiral tripodal-cyclophanes in excellent ee. 

Jeletic MS, Ghiviriga I, Abboud KA, Veige AS. A new chiral di-N-heterocyclic carbene (NHC) cyclophane ligand and its application in palladium enantioselective catalysis. Dalton Trans. 2010 39 6392-6394. 

The oxidation of cyano-Gilman cuprates has enabled the synthesis of new cyclophanes. Moreover, while BuhCuLi-LiCN has been reported to effect vinylallene formation by the 1,5-substitution of enyne acetates, it has been revealed that the application of Bu"3P to the reaction system considerably enhances the enantioselectivity of the synthesis. " Recent kinetic isotope studies into the chlorotrimethylsilane-mediated addition of lithiocuprates to cyclo-hexenone have suggested that reaction proceeds via an intermediate rr-com-plex. ... 

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