Enantioselectivity chiral additives

The Darzens reaction has been performed enantioselectively, by coupling optically active a-bromo-p-hydroxy esters with aldehydes.Chiral phase-transfer agents have been used to give epoxy ketones with modest enantioselectivity. Chiral additives have proven to be effective. 

For the separation of racemic mixtures, two basic types of membrane processes can be distinguished a direct separation using an enantioselective membrane, or separation in which a nonselective membrane assists an enantioselective process [5]. The most direct method is to apply enantioselective membranes, thus allowing selective transport of one of the enantiomers of a racemic mixture. These membranes can either be a dense polymer or a liquid. In the latter case, the membrane liquid can be chiral, or may contain a chiral additive (carrier). Nonselective membranes can also... 

The first reports on enantioselective addition reactions of achiral organometallic reagents, modified by aprotic chiral additives, described the addition of Grignard reagents to prostereogenic carbonyl compounds in the presence of ( + )-(/ ,/J)-2,3-dimethoxybutane (l)4 5, (-)-tetrahydro-2-methylfuran (2)6, (-)-l-[(tetrahydro-2-furanyl)methyl]pyrrolidine (3)7 or (-)-sparteine (4)8. The enantioselectivity, however, was poor (0-22% ee). 

A remarkable effect of the reaction temperature on the enantioselectivity of the addition of butyllithium to benzaldehyde was found with polystyrene-bound cvs-enofo-S-dimethylamino -(benzyloxy)bornane (8)12. When the soluble monomeric ligand 9 was tested, the enantioselectivity increased with decreasing temperature (53% ee at — 78 C). In contrast, the polymer-bound chiral additive 8 showed an optimum at — 20 C (32% ee). Although the enantioselectivity of this addition reaction is low, an advantage of a polymer-bound chiral auxiliary is that it can be removed by a simple filtration. 

The highest ee s reported to date for the addition of achiral organometallic reagents in the presence of aprotic chiral additives were observed with the C2-symmetric diamines 10, 11 and 12 (Table 25)13 — 15. Enantioselectivities as high as 89% ee were observed with chiral auxiliary 1012. Addition of phenyllithium to pentanal proceeds with lower enantioselection that the analogous addition of butyllithium to benzaldehydeu. Generally, the enantioselcctivity in-... 

The methyltitanium reagents 37 modified by the chiral 2-pyrrolidinemethanols 36 also did not show satisfactory enantioselectivities in addition reactions to aromatic aldehydes35. Noteworthy, however, is the fact that the enantioselectivity substantially increases with the change from A-methyl to A-acyl substituents. 

Despite the undefined nature of the organometallic species, chirally modified organotita-nium reagents are useful tools in enantioselective synthesis. In particular, the binaphthol-mod-ified phenyltitanium reagent 41 shows excellent enantioselectivity in additions to aromatic aldehydes34-40,41. 

The complexation of achiral metal enolates by chiral additives, e.g., solvents or complexing agents could, in principle, lead to reagent-induced stereoselectivity. In an early investigation, the Reformatsky reaction of ethyl bromoacetate was performed in the presence of the bidentate ligand (—)-sparteine20. The enantioselectivity of this reaction varies over a wide range and depends on the carbonyl Compound, as shown with bcnzaldehyde and acetophenone. 

The reaction of butyllithium with 1-naphthaldehyde cyclohexylimine in the presence of (/C )-l,2-diphenylethane-1,2-diol dimethyl ether in toluene at —78 °C, followed by treatment with acetate buffer, gave 2-butyl-1,2-dihydronaphthalene-l-carbaldehyde, which was then reduced with sodium borohydride in methanol to afford (1 R,2.S)-2-butyl-1 -hydroxymcthyl-1,2-dihydronaphthalene in 80% overall yield with 91 % ee83. Similarly, the enantioselective conjugate addition of organolithium reagents to several a,/J-unsaturated aldimines took place in the presence of C2-symmetric chiral diethers, such as (/, / )-1,2-butanediol dimethyl ether and (/, / )- ,2-diphenylethane-1,2-diol dimethyl ether. 

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. 

The reaction is somewhat selective for the cis diastereomer. The use of chiral additives in this reaction leads to aziridines enantioselectively. 

An enantioselective Michael addition reaction was also accomplished in an inclusion complex with a chiral host compound. Treatment of a 1 1 complex of 10c and 66b with 2-mercaptopyridine (137) in the solid state gave (+)-138 of 80% ee in 51% yield. By a similar method, 3-methyl-3-buten-2-one (139) gave (+)-140 of 49% ee in 76% yield [30]. 

The hydrogenation of a cinnamate was also investigated as a first step to determine kinetics and finally to come to a quantitative determination of kinetic models and parameters in asymmetric catalysis [64]. The enantiomeric excess of enantioselective catalytic hydrogenations is known to be dependent on pressure, chiral additives and mixing. Such dependences are often due to kinetics, demanding appropriate studies. 

A series of chiral p-hydroxysulfoximine ligands have been synthesised by Bolm et al. and further investigated for the enantioselective conjugate addition of ZnEt2 to various chalcone derivatives. The most eiScient sulfoximine, depicted in Scheme 2.33, has allowed an enantioselectivity of up to 72% ee to be obtained. These authors assumed a nonmonomeric nature of the active species in solution, as suggested by the asymmetric amplification in the catalysis with a sulfoximine of a low optical purity. 

In 2004, Yang and Tseng reported the synthesis of a series of new chiral amino thiol ligands derived from L-valine, which were further employed (1 mol%) in the enantioselective alkenylzinc addition to aldehydes, providing an efficient route for chiral ( )-allylic alcohols with enantioselectivities of up to >99% ee, as shown in Scheme 3.67. ... 

A number of other chiral catalysts can promote enantioselective conjugate additions of silyl enol ethers, silyl ketene acetals, and related compounds. For example, an oxazaborolidinone derived from allothreonine achieves high enantioselectivity in additions of silyl thioketene acetals.323 The optimal conditions for this reaction also include a hindered phenol and an ether additive. 

The chiral enamines provide the opportunity for the enantioselective Michael addition to nitroalkenes, as shown in Eq. 4.68, where the ketone is obtained as a single diastereomer with... 

Seebach and coworkers have developed enantioselective conjugate additions of primary dialkylzinc reagents to 2-aryl- and 2-heteroaryl-nitroalkenes mediated by titanium-TADDO-Lates (Eq. 4.90). x a TADDOLs and their derivatives are excellent chiral auxiliaries.9611... 

Catalytic enantioselective nucleophilic addition of nitroalkanes to electron-deficient alke-nes is a challenging area in organic synthesis. The use of cinchona alkaloids as chiral catalysts has been studied for many years. Asymmetric induction in the Michael addition of nitroalkanes to enones has been carried out with various chiral bases. Wynberg and coworkers have used various alkaloids and their derivatives, but the enantiomeric excess (ee) is generally low (up to 20%).199 The Michael addition of methyl vinyl ketone to 2-nitrocycloalkanes catalyzed by the cinchona alkaloid cinchonine affords adducts in high yields in up to 60% ee (Eq. 4.137).200... 

To carry out enantioselective alkylation of 2-thiazolyl nitrone (319) (Scheme 2.136), chiral additives presented in Fig. 2.22 and Lewis acids (MgBr2, Et2AlCl,... 

The enantioselective conjugate addition of dialkylzinc to nitroalkenes using other phosphoramidite,79,79a 83a sulfonamide,84 and binaphthol-based thioether ligands65 has also been studied in the past few years. Particularly noteworthy are the efficient chiral monodentate phosphoramidite ligands (S,R,R)-29 and (A,A)-55 developed by Feringa et al. and Alexakis et al., respectively, for this reaction. (S,R,R)-29 provided excellent enantioselectivities (up to 98% ee) for acyclic nitroalkenes (Scheme 25).80 It also worked well for other nitroolefin substrates such as 3-nitrocoumarin 7068 and methyl 3-nitropropenoate 7185. 

Ojima and co-workers found that chiral monodentate phosphoramidite (S,R,R)-35 was highly effective for the enantioselective conjugate addition of diethylzinc to acyclic nitroalkenes (up to 99% ee).86... 

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