Enantioselective dendrimer

Does the chiral core unit permit enantioselective (dendrimer) host/(substrate) guest complexation in the interior of the dendrimer scaffold ... 

An interesting case in the perspective of artificial enzymes for enantioselective synthesis is the recently described peptide dendrimer aldolases [36]. These dendrimers utilize the enamine type I aldolase mechanism, which is found in natural aldolases [37] and antibodies [21].These aldolase dendrimers, for example, L2Dl,have multiple N-terminal proline residues as found in catalytic aldolase peptides [38], and display catalytic activity in aqueous medium under conditions where the small molecule catalysts are inactive (Figure 3.8). As most enzyme models, these dendrimers remain very far from natural enzymes in terms ofboth activity and selectivity, and at present should only be considered in the perspective of fundamental studies. 

In 2008, these authors reported a new strategy to attach chiral trans-l-arenesulfonylamino-2-isoborneolsulfonylaminocyclohexane to an achiral Frechet dendron (polyether having a repeated 3,5-dioxybenzyl structure) by a radical approach.The dendrimers obtained were successfully used in the enantioselective nucleophilic alkylation and arylation of ketones, providing... 

Togni and co-workers have used the convergent methodology to link phosphine-containing chiral ferrocene ligands on the cyclophosphazene core to obtain dendrimeric structures of the type 37 (Fig. 21) (201). The reaction with the cyclophosphazene end occurs by the replacement of the P-Cl bond and by the formation of the P-0 bond. The dendrimers contain twelve and sixteen ferrocene moieties respectively. The phosphine units present can coordinate to Rh(I) to afford metallic dendrimers, which have been shown to be excellent catalysts for the enantioselective hydrogenation of dimethyl itaconate. The product... 

Chiral //A(oxazolinc) ligands disubstituted at the carbon atom linking the two oxazolines by Frechet-type polyether dendrimers coordinated with copper(II) triflate were found to provide good yields and moderate enantioselectivities for Mukaiyama aldol reactions in water that are comparable with those resulting from the corresponding smaller catalysts.291 AgPF6-BINAP is very active in this reaction and the addition of a small amount of water enhanced the reactivity.292... 

The synthesis of chiral dendrimers from various building blocks, their - difficult - structure determinations, and their - potential - use in physiological applications, in bioassays, and in enantioselective catalysis are reviewed. 

Fig. 17. Chiral acetonide building blocks 36-39, protected 3rd-generation dendrimer 40 and deprotected 2nd-generation dendrimer 41, derived from enantioselectively dihydroxylated styrenes and cinnamic alcohols [74-76]...

In 1994 we published the first chiral dendrimers built from chiral cores and achiral branches [ 1,89], see for instance dendrimer 57 with a core from hydroxy-butanoic acid and diphenyl-acetaldehyde and with twelve nitro-groups at the periphery (Fig. 21). As had already been observed with starburst dendrimers, compound 57 formed stable clathrates with many polar solvent molecules, and it could actually only be isolated and characterized as a complex [2 (57- EtO-Ac (8 H20))]. Because no enantioselective guest-host complex formation could be found, and since compounds of type 57 were poorly soluble, and could thus not be easily handled, we have moved on and developed other systems to investigate how the chirality of the core might be influencing the structure of achiral dendritic elongation units. 

The latter effect has been demonstrated by Meijer et al., who attached chiral aminoalcohols to the peripheral NH2-groups of polypropylene imine) dendrimers of different generations [100]. In the enantioselective addition of diethyl-zinc to benzaldehyde (mediated by these aminoalcohol appendages) both the yields and the enantioselectivities decreased with increasing size of the dendrimer (Fig. 28). The catalyst obtained from the 5th-generation dendrimer carrying 64 aminoalcohol groups at its periphery showed almost no preference for one enantiomer over the other. This behavior coincides with the absence of measurable optical rotation as mentioned in Sect. 3 above. The loss of activity and selectivity was ascribed to multiple interactions on the surface which were... 

Attached to the periphery of a lst-generation dendrimer, Ti(OCHMe2)2-com-plexes of the six TADDOL moieties in 84 catalyze - in homogeneous solution -the enantioselective addition of diethylzinc to benzaldehyde with about the same selectivity ((S) (R) 97 3) as do six monomeric TADDOL units [105],but, with a molecular weight of only 3833 Da, dendrimer 84 had to be separated by column chromatography rather than by ultrafiltration methods. 

Verkade and co-workers have shown the usefulness of their phosphazanes in various stoichiometric as well as catalytic reactions <1999PS(144)101>. Compound 290 was used to promote the cyanohydration of benzaldehyde with trimethylsilyl cyanide (TMSCN). The cyanohydrin was isolated in 95% yield, but no enantioselectivity was noticed <2002JOM(646)161>. Compounds 291 and 292 were attached to dendrimers and shown to be effective in the catalysis of Michael reactions, nitroaldol reactions, and aryl isocyanate trimerizations <2004ASC1093>. 

Recently Togni et al. [19] focussed on the preparation of asymmetric dendrimer catalysts derived from ferrocenyl diphosphine ligands anchored to dendritic backbones constructed from benzene-1,3,5-tricarboxylic acid trichloride and adamantane-l,3,5,7-tetracarboxylic acid tetrachloride (e.g. 11, Scheme 11). In situ catalyst preparation by treatment of the dendritic ligands with [Rh(COD)2]BF4 afforded the cationic Rh-dendrimer, which was then used as a homogeneous catalyst in the hydrogenation reaction of, for example, dimethyl itaconate in MeOH. In all cases the measured enantioselectivity (98.0-98.7%) was nearly the same as observed for the ferrocenyl diphosphine (Josiphos) model compound (see Scheme 11). 

Brunner et al. [26] synthesized and applied so-called dendrizymes in enan-tioselective catalysis. These catalysts are based on dendrimers which have a functionalized periphery that carries chiral subunits, (e.g. dendrons functionalized with chiral menthol or borneol ligands). The core phosphine donor atoms can be complexed to (transition) metal salts. The resultant dendron-enlarged 1,2-diphosphino-ethane (e.g. 16, see Scheme 17) Rh1 complexes were used as catalysts in the hydrogenation of acetamidocinnamic acid to yield iV-acetyl-phenylalanine (Scheme 17) [26]. A small retardation of the hydrogenation of the substrate was encountered, pointing to an effect of the meta-positioned dendron substituents. No significantly enantiomerically enriched products were isolated. However, a somewhat improved enantioselectivity (up to 10-11% e.e.) was... 

A stochiometric approach was applied by Van Koten and co-workers [29], who used chiral carbosilane dendrimers as soluble supports in the in situ ester enolate-imine condensation in the synthesis of /Mactams (e.g. 19, Scheme 20). The formation of the /Mactam products proceeded with high trans selectivity, and with the same level of stereoinduction as was earlier established in reactions without the dendritic supports, (i.e. the use of the enantiopure dendritic support did not affect the enantioselectivity of the C-C bond formation). After the reaction, the dendrimer species could be separated from the product by precipitation or GPC techniques and reused again. 

Pugh VJ, Hu QS, Zuo X et al (2001) Optically active BINOL core-based phenyleneethyny-lene dendrimers for the enantioselective fluorescent recognition of amino alcohols. J Org... 

Lactams were obtained in 80-95% conversion with high trans-selectivity (de >95%) but only moderate enantioselectivity ee ca. 30%). The stereoinduction results from the relatively remote stereocentres located at the linker units. For support recovery the authors performed nanofiltration experiments and it was found that the recovered dendrimers could be easily reused as substrate carriers. 

Kollner et al. (29) prepared a Josiphos derivative containing an amine functionality that was reacted with benzene-1,3,5-tricarboxylic acid trichloride (11) and adamantane-l,3,5,7-tetracarboxylic acid tetrachloride (12). The second generation of these two types of dendrimers (13 and 14) were synthesized convergently through esterification of benzene-1,3,5-tricarboxylic acid trichloride and adamantane-1,3,5,7-tetracarboxylic acid with a phenol bearing the Josiphos derivative in the 1,3 positions. The rhodium complexes of the dendrimers were used as chiral dendritic catalysts in the asymmetric hydrogenation of dimethyl itaconate in methanol (1 mol% catalyst, 1 bar H2 partial pressure). The enantioselectivities were only... 

Their results show that the chemical yields of 1-phenylpropanol and the enantioselectivities decreased with increasing generation of the dendrimer when G5 was used, almost no enantioselectivity was observed (57% yield, 7% ee), a result that was attributed to the dense packing of the chiral end groups at the periphery. 

Similar results were obtained by Suzuki et al. (55) in their investigation of enantioselective addition of Et2Zn to various N-diphenylphosphinylimines with PAMAM dendrimers functionalized with 4 and 8 chiral amino alcohol groups. They observed 92% ee for the monomeric ligand, 43% ee for GO, and 30—39% ee for G1 when using N-diphenylphosphinylbenzaldimine as the substrate. Again, a high local concentration of chiral active sites leads to a decrease in enantioselectivity. 

Significantly, the more rigid dendrimers 53-54 and 11-14 (described in Section II) prepared by Sato 45) and Kolner 29) showed no drop in enantioselectivity for higher generations of the dendrimer for the addition of to N-... 

Since the pioneering studies of asymmetric catalysis with core-functionalized dendrimers reported by Brunner (88) and Bolm (89), several noteworthy investigations have been described in this field. Some examples of the dendritic effects observed in enantioselective catalysis with dendrimers having active sites in the core were discussed in Section II, such as the catalytic experiments with TADDOL-cored dendrimers described by Seebach et al. (59) the asymmetric addition of Et2Zn to aldehydes catalyzed by core-functionalized phenylacetylene-containing dendrimers reported by Hu et al (42)-, the asymmetric hydrogenation investigations with (R)-BINAP core-functionalized dendrimers synthesized by Fan et al. (36) or the results... 

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