Enantioselective addition chiral ligands

Activation of the enantiopure (f )-BINOL-Ti(OPr )2 catalyst (2) was investigated by further addition of (i )-BINOL (Sch. 23, Table 3). The reaction proceeded quite smoothly to provide the carbonyl-ene product in higher chemical yield (82.1 %) and enantioselectivity (96.8 % ee) than without additional BINOL (94.5 % ee, 19.8 %) (Run 2 compared with Run 1). Comparison of results from enantiomer-selective activation of the racemic catalyst (89.8 % ee, R) (Table 2, Run 4) with those from use of the enantio-pure catalyst (with (96.8 % ee, R) or without (94.5 % ee, R) activator) enabled calculation that that the reaction catalyzed by the (/ )-BINOL-Ti(OPr )2/(/ )-BINOL complex R,R)-2 ) would be 26.3 times faster than that catalyzed by the (5)-BINOL-Ti(OPr )2 (2) in the racemic case (Sch. 24a). Indeed, kinetic studies show that the reaction catalyzed by the (i )-BINOL-Ti(OPr )2/(i )-BINOL complex (R,R)-2 ) is 25.6 times faster than that catalyzed by (R)-BINOL-Ti(OPr )2 (2). These results imply that the racemic ( )-BINOL-Ti(OPr )2 (2) and the half-molar amount of (i )-BINOL assemble preferentially into the (R)-BINOL-Ti(OPr )2/(R)-BINOL complex ((R,R)-2 ) and unchanged (S)-BINOL-Ti(OPr )2 (2). In contrast, the enantiomeric form of the additional chiral ligand ((5)-BINOL) activates the (R)-BINOL-Ti(OPr )2 (2) to a lesser extent (Run 3), thus providing the carbonyl-ene product in lower optical (86.0 % ee, R) and chemical (48.0 %) yields than does (R)-BINOL. 

In an extension of this work they developed a catalytic version of the reaction in which the chiral ligand (J ,J )-diisopropyltartrate (DIPT) was applied in 20 mol% [77]. In spite of the reduction of the amount of the chiral ligand similar high enantioselectivities of up to 93% ee were obtained in this work. The addition of a... 

Another important reaction associated with the name of Sharpless is the so-called Sharpless dihydroxylation i.e. the asymmetric dihydroxylation of alkenes upon treatment with osmium tetroxide in the presence of a cinchona alkaloid, such as dihydroquinine, dihydroquinidine or derivatives thereof, as the chiral ligand. This reaction is of wide applicability for the enantioselective dihydroxylation of alkenes, since it does not require additional functional groups in the substrate molecule ... 

The first example of asymmetric catalytic ring-opening of epoxides with sp2-hybridized carbon-centered nucleophiles was reported by Oguni, who demonstrated that phenyllithium and a chiral Schiff base ligand undergo reaction to form a stable system that can be used to catalyze the enantioselective addition of phenyllithium to meso-epoxides (Scheme 7.24) [48]. Oguni proposed that phenyllithium... 

Although it is known that in some cases the lithium salts of chiral amino alcohols are even better catalysts than the chiral ligands themselves, the use of metals other than lithium has rarely been investigated. The oxazaborolidines A and B and the aluminum analog C have been used as catalysts for the enantioselective addition of diethylzinc to benzaldehyde35 (Table 32). 

Combination of nickel bromide (or nickel acetylacetonate) and A. A -dibutylnorephcdrinc catalyzed the enantioselective conjugate addition of dialkylzincs to a./Tunsaturated ketones to afford optically active //-substituted ketones in up to ca. 50% ee53. Use of the nickel(II) bipyridyl-chiral ligand complex in acetonitrile/toluenc as an in situ prepared catalyst system afforded the //-substituted ketones 2, from aryl-substituted enones 1, in up to 90% ee54. 

Kragl and Dreisbach (1996) have carried out the enantioselective addition of diethyl zinc to benzaldehyde in a continuous asymmetric membrane reactor using a homogeneous soluble catalyst, described in their paper. Here a,a-diphenyl-L-proline was used as a chiral ligand, coupled to a copolymer made from 2-hydroxy ethyl methacrylate and octadecyl methacrylate, which had a sufficiently high molecular weight to allow separation by ultra-filtration (U/F). The solvent-stable polyaramide U/F Hoechst Nadir UF PA20 retained more than 99.8% of the catalyst. The ee was 80 %, compared to 98 % for a noncoupled catalyst. 

In addition to the enhanced rate of hydroalumination reactions in the presence of metal catalysts, tuning of the metal catalyst by the choice of appropriate ligands offers the possibility to influence the regio- and stereochemical outcome of the overall reaction. In particular, the use of chiral ligands has the potential to control the absolute stereochemistry of newly formed stereogenic centers. While asymmetric versions of other hydrometaUation reactions, in particular hydroboration and hydrosi-lylation, are already weU established in organic synthesis, the scope and synthetic utiHty of enantioselective hydroalumination reactions are only just emerging [72]. 

In 2003, Bonini et al. reported a new synthesis of ferrocenyloxazolines based on an iodide-mediated ring expansion of A-ferrocenoyl-aziridine-2-carboxylic esters. The thus-formed ligands were successfully employed as palladium chelates for the test reaction, since they allowed the product to be formed in quantitative yields and good to high enantioselectivities (Scheme 1.69). According to the results, it seemed that the additional chiral centre present in the oxazoline backbone of these ligands did not play a major role for the asymmetric induction and the activity of the corresponding catalysts. 

In 2004, excellent enantioselectivities of up to 98% ee were obtained by Morimoto et al. by using a phosphine-sulfonamide-containing 1,1 -binaphthyl-based ligand in the enantioselective copper-catalysed conjugate addition of ZnEt2 to several benzylideneacetones (Scheme 2.27). Similar levels of enan-tioselectivity (up to 97% ee) combined with excellent yields (up to 90%) were obtained by Leighton et al. for the copper-catalysed enantioselective addition of various alkylzincs to cyclic enones performed in the presence of other chiral phosphine-sulfonamide ligands (Scheme 2.27). ... 

On the other hand, the enantioselective 1,4-addition of carbanions such as enolates to linear enones is an interesting challenge, since relatively few efficient methods exist for these transformations. The Michael reaction of p-dicarbonyl compounds with a,p-unsaturated ketones can be catalysed by a number of transition-metal compounds. The asymmetric version of this reaction has been performed using chiral diol, diamine, and diphosphine ligands. In the past few years, bidentate and polydentate thioethers have begun to be considered as chiral ligands for this reaction. As an example, Christoffers et al. have developed the synthesis of several S/O-bidentate and S/O/S-tridentate thioether... 

In 2002, Braga et al. reported the enantioselective addition of ZnEt2 to various aldehydes performed in the presence of chiral imidazolidine disulfides derived from L-cysteine. In the presence of 5mol% of ligand, the secondary alcohols were isolated in enantioselectivities of up to 91% ee. Aromatic... 

In addition, other chiral sulfide ligands containing oxazolidines have been tested for the enantioselective addition of ZnEt2 to aldehydes, providing moderate enantioselectivities, as shown in Scheme 3.25. ... 

The enantioselective addition of ZnEt2 to benzaldehyde was also performed in the presence of chiral 2,2-disubstituted thiaprolinol derivatives as ligands by Liu et al., providing the product with an enantioselectivity of up to 81% ee (Scheme 3.29). ... 

In 2008, Juaristi et al. developed the synthesis of a series of novel chiral thioureas that were further examined as possible ligands for the enantioselective addition of ZnEt2 to benzaldehyde." The expected carbinol was isolated in... 

In 1997, Chelucci et al. developed new chiral 2-(l-p-tolylsulfinyl)alk-ylpyridines and assessed these ligands in the enantioselective addition of ZnEt2 to benzaldehyde." This produced in all cases catalysts in good yields but with low enantioselectivities (< 19% ee). An examination of the results collected in Scheme 3.33 indicates that the enantioselectivity and the configuration of the resulting carbinol were independent of both the substituent and the configuration at the carbon centre. Therefore, this suggests that the stereochemical... 

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