Dialkylzinc reagents, addition enantioselectivity

Since the addition of dialkylzinc reagents to aldehydes can be performed enantioselectively in the presence of a chiral amino alcohol catalyst, such as (-)-(1S,2/ )-Ar,A -dibutylnorephedrine (see Section 1.3.1.7.1.), this reaction is suitable for the kinetic resolution of racemic aldehydes127 and/or the enantioselective synthesis of optically active alcohols with two stereogenic centers starting from racemic aldehydes128 129. Thus, addition of diethylzinc to racemic 2-phenylpropanal in the presence of (-)-(lS,2/ )-Ar,W-dibutylnorephedrine gave a 75 25 mixture of the diastereomeric alcohols syn-4 and anti-4 with 65% ee and 93% ee, respectively, and 60% total yield. In the case of the syn-diastereomer, the (2.S, 3S)-enantiomer predominated, whereas with the twtf-diastereomer, the (2f ,3S)-enantiomer was formed preferentially. 

Polymer-supported amino alcohols and quaternary ammonium salts catalyze the enan-tioselective addition of dialkylzinc reagents to aldehydes (Table 31). When the quaternary ammonium salt F is used in hexane, it is in the solid state, and it catalyzes the alkylation of benzaldehyde with diethylzinc in good chemical yield and moderate enantioselectivity. On the other hand, when a mixture of dimethylformamide and hexane is used as solvent, the ammonium salt is soluble and no enantioselectivity is observed21. 

The polymer-bound catalysts A-C. (Table 31) are prepared by reaction of the corresponding amino alcohols with partially chloromethylated 1 -2% cross-linked polystyrene. In the case of A, the enantioselectivity of the addition of dialkylzincs to aldehydes is higher than with the corresponding monomeric ephedrine derivatives (vide supra). Interesting insights into the mechanism of the alkylation of aldehydes by dialkylzinc reagents can be obtained from the experi-... 

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... 

Pu and co-workers incorporated atropisomeric binaphthols in polymer matrixes constituted of binaphthyl units, the macromolecular chiral ligands obtained being successfully used in numerous enantioselective metal-catalyzed reactions,97-99 such as asymmetric addition of dialkylzinc reagents to aldehydes.99 Recently, they also synthesized a stereoregular polymeric BINAP ligand by a Suzuki coupling of the (R)-BINAP oxide, followed by a reduction with trichlorosilane (Figure 10).100... 

The numerous studies prior to 1996 on Cu-catalyzed additions of Grignard reagents to cydohexenone as a model substrate revealed that, with a few exceptions, enantioselectivity was exclusively found with either cyclic substrates (Grignard reagents) or acyclic substrates (dialkylzinc reagents) (Scheme 7.2). 

Correspondingly, the catalytic 1,4-addition of dialkylzinc reagents to 3-nitro-coumarin 89 (Scheme 7.24), with a fixed trans orientation of the aryl and nitro groups, proceeds with excellent yields (90-99%), high diastereoselectivity (d.r. up to 20 1), and enantioselectivities of up to 92%. Hydrolysis of the lactone moiety in 90 was accompanied by decarboxylation, providing an asymmetric synthesis of 8-aryl-nitroalkane 91. 

In the first method, a dialkylzinc reagent bearing an acetal moiety at the d-posi-tion is used (Scheme 7.25(b)). The catalytic 1,4-addition is followed by acetal hydrolysis and aldol cyclization of the 4-substituted cycloalkanone, affording 6,6- (92), 6,7-, (93) and 6,8- (94) annulated ring systems with high enantioselectivities (>96% ees) [80]. In addition, dimethyl-substituted decalone 95, with a structure frequently found in natural products, is readily obtained in enantiomerically pure form. 

The use of copper catalysts based on chiral phosphorus ligands to assist 1,4-additions of dialkylzinc reagents has in recent years produced major breakthroughs, with excellent enantioselectivities. A number of monodentate and bidentate phos-phoramidites, phosphites, phosphonites, and phosphines are now available as chiral ligands for alkyl transfer to a variety of cyclic and acyclic enones. So far. 

The use of vinyl epoxides as substrates in enantioselective copper-catalyzed reactions, on the other hand, has met with more success. An interesting chiral ligand effect on Cu(OTf)2-catalyzed reactions between cyclic vinyloxiranes and dialkylzinc reagents was noted by Feringa et al. [51]. The 2,2 -binaphthyl phosphorus amidite ligands 32 and 43 (Fig. 8.5), which have been successfully used in copper-catalyzed enantioselective conjugate additions to enones [37], allowed kinetic resolution of racemic cyclic vinyloxiranes (Scheme 8.26). 

However, very few catalyst systems reported to date are highly effective for both p- aryl and p-alkyl acyclic enone substrates in the copper-catalyzed asymmetric 1,4-addition. Ligand 27, developed by Hoveyda, shows high enantioselectivity in the 1,4-addition of dialkylzinc reagents to various acyclic enones (Figure 3.6). " ... 

Asymmetric addition of a dialkylzinc reagent to an aldehyde, catalyzed by a Lewis base or a Lewis acid, is a viable alternative to enantioselective reduction of ketones as means to prepare enantiomerically enriched alcohols like 605 and... 

An amino alcohol was found to accelerate the addition reaction of diethlylzinc to aldehyde [8], and then chiral amino alcohols were proved to be efficient chiral catalysts for asymmetric alkylation by using dialkylzinc reagents [9], Oguni reported a remarkable asymmetric amplification in chiral amino alcohol-promoted alkylation (Scheme 9.4). In the presence of (-)-l-piperidino-3,3-dimethyl-2-butanol (5) of 11% ee, benzaldehyde is alkylated enantioselectively to give (/ )-l-phenylpropanol with 82% ee [10]. Asymmetric amplification was also observed by Noyori using partially resolved (2.S )-3-exo-(dimethylamino)isobomeol (6) [11]. 

High enantioselectivity has been achieved on addition of diethylzinc to benzaldehyde catalysed by a chiral diamine, (,S )-2-(A,A -disubstitutcd aminomethyl)pyrrolidine,116 and by chiral helical titanate complexes of tetradentate ligands.117 Enantioselective additions of dialkylzinc reagents to A,-(diphcnylphosphiiioyl)imines, promoted by aziridino alcohols,118 and to the carbon-nitrogen double bond of the nitrone 3,4-dihydroisoquinoline A-oxide, promoted by dicyclopentyl(R,R)-tartrate,119 have also been reported. 

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