Dialkylzinc asymmetric addition

Asymmetric addition to ketimine in a reagent controlled manner has seldom been reported, even by 2008. When we investigated the potential for tbis asymmetric addition around 1992, there were no known examples. In 1990, Tomioka et al., reported the first asymmetric addition of alkyl lithium to N-p-methoxyphenyl aldo-imines in the presence ofa chiral (3-amino ether with 40-64% ee [8] (Scheme 1.11). In 1992, Katritzky reported the asymmetric addition of Et2Zn to in situ prepared N-acyl imine in the presence of a chiral (3-amino alcohol with 21-70% ee [15] (Scheme 1.12). In the same year, Soai et al., reported the asymmetric addition of dialkylzinc to diphenylphosphinoyl imines in the presence of chiral (3-amino alcohols with 85-87% ee [16] (Scheme 1.13). These three reports were, to the best of... 

Tanaka et al.28 have synthesised a series of (S)-chiral Schiff bases as the highly active (yield 69-99%) and enatioselective (ee 50-96%) catalysts in the reaction of addition of dialkylzinc to aldehydes. The stereochemistry of the asymmetric addition was suggested. In a transition state when S-chiral Schiff base was used as chiral source, the alkyl nucleophile attacked Re face of the activated aldehyde and formed the R-configuration alkylated product [13]. 

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... 

Hoveyda and co-workers presented the asymmetric addition of alkylzincs to small-, medium-, and large-ring nitroolefins with chiral peptide-based phosphines 57 as catalyst.87 The enantioselectivities were typically >90%. Ligand 57 also worked well in the asymmetric addition of dialkylzinc to acyclic disubstituted nitroalkenes (up to 95% ee Scheme 26).88... 

CATALYTIC ASYMMETRIC ADDITIONS OF DIALKYLZINC TO KETONES ENANTIOSELECTIVE FORMATION OF TERTIARY ALCOHOLS... 

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... 

TABLE 8.40 ASYMMETRIC ADDITION OF DIALKYLZINC REAGENTS TO ALDEHYDES, 502... 

Meanwhile, copper salt catalyzed asymmetric conjugate addition of dialkylzincs has been developed. Alexakis and coworkers reported the catalytic addition of diethylzinc to cyclohexenone using copper salt111. Feringa and coworkers developed a marvelous phosphoramidite (49)112. In the presence of 49 and Cu(OTf)2, diethylzinc adds to cyclohexenone in >98% . Recently, asymmetric addition of diphenylzinc using 49 has been reported113. Nowadays, compounds 50114, 51115, 52116, 53117 and 54118 are known as highly enantioselective catalysts. 

Much attention has been paid to asymmetric amplification where the enantiomeric excess ( ) of the product is higher than that of the chiral catalyst (equation 35)136. The first experiment on asymmetric amplification was reported by Kagan and coworkers in the Katsuki-Sharpless asymmetric epoxidation of allyl alcohols137. Asymmetric amplification has also been studied in the asymmetric addition of dialkylzincs to carbonyl compounds. 

VI. ASYMMETRIC AUTOCATALYSIS IN THE ASYMMETRIC ADDITION OF DIALKYLZINCS TO ALDEHYDES... 

Lewis acid-promoted asymmetric addition of dialkylzincs to aldehydes is also an acceptable procedure for the preparation of chiral secondary alcohol. Various chiral titanium complexes are highly enantioselective catalysts [4]. C2-Symmet-ric disulfonamide, chiral diol (TADDOL) derived from tartaric acid, and chiral thiophosphoramidate are efficient chiral ligands. C2-Symmetric chiral diol 10, readily prepared from 1-indene by Brown s asymmetric hydroboration, is also a good chiral source (Scheme 2) [17], Even a simple a-hydroxycarboxylic acid 11 can achieve a good enantioselectivity [18]. 

Reagents of this type are suitable for performing catalytic asymmetric additions to aldehydes. For example, an enantiomerically pure Lewis acid is generated in situ from Ti(OiPr)4 and the enantiomerically pure bis(sulfonamide) C. It catalyzes the enantioselective addition of functionalized (or unfunctionalized) dialkylzinc compounds to widely variable aldehydes. There is no detailed, substantiated rationalization of the underlying addition mechanism in this case. 

A different method for the catalytic asymmetric addition of a dialkylzinc compound—Et2Zn and aromatic aldehydes have almost always been used—is shown in Figure 8.31. With regard to stereoselective synthesis, this method has an importance... 

V,7V-Dialkyl derivatives of 1 have been successfully applied to the asymmetric addition of dialkylzinc reagents to aldehydes, giving products of moderate enantiomeric excess.In addition, ruthenium(II) complexes of 1 have been demonstrated to be excellent catalysts for the control of the enantioselective transfer hydrogenation of ketones to alcohols at catalyst loadings as low as 1 mol The ruthenium/1 complex has been applied to a range of ketone substrates, including cyclic enones and a-amino and alkoxy substituted derivatives. 

Chiral polymer-supported catalysts have been utilized in asymmetric addition of dialkylzinc to aldehydes because of the easy product isolation and workup [26]. In the previous section, a highly enantioselective addition of diethylzinc to aldehydes was described using M-(l-ferrocenylalkyl)-iV-alkylnorephedrines as effective catalysts. We then examined incorporation of the catalyst into polymeric systems. 

Table 3-10. Asymmetric addition of dialkylzincs to o-phthalaldehyde in the presence of chiral...

Asymmetric Addition of Dialkylzincs to Aldehydes and Imine Derivatives... 

In contrast to the PAMAM-bound catalysts, chiral dendrimers based on rigid poly(phenylethyne) and flexible carbosilane backbones without heteroatoms proved to be highly efficient catalysts in such alkylation reactions. Excellent enantioselectivities in the asymmetric addition of dialkylzincs to aldehydes (up to 93% ee) and N-diphenylphosphinyli mines (up to 94% ee) were achieved. 

As part of an ongoing research program directed toward the use of chiral aziridines in asymmetric synthesis [36], Andersson, Tanner and co-workers have recently reported the detailed results of their own findings in the field of catalytic asymmetric dialkylzinc alkylation of imines [37dj. Tanner et al. had previously communicated their success in the catalytic asymmetric addition of organolith-ium reagents to imines with C2-symmetric bis(aziridines) [37a, 37b]. This was followed by a preliminary report on the use of aziridino alcohols as well as simple aziridines for the addition of diethylzinc to M-diphenylphosphinoylimines [37c]. The most recent report is an extension of this study, and includes the detailed preparation of the ligands [37d]. 

Chiral Lewis acids derived from tartaric acid have been used in the asymmetrical addition of dialkylzinc com-... 

Finally, a completely new use of planar-chiral ferrocenes has been recently disclosed by Fu and co-workers [24]. Compounds of type 25 and 26 were prepared as racemic mixtures and obtained as pure enantiomers via semipreparative HPLC. Derivatives 25, analogues of 4-(dimethylamino)pyridine, were used as nucleophilic catalysts in the kinetic resolution of chiral secondary alcohols [24a,b]. The ami-noalcohol system 26, on the other hand, is an effective chiral ligand for the asymmetric addition of dialkylzinc reagents to aldehydes (up to 90% ee) [24c]. 

The stereoselectivity of the addition of dialkylzinc to aldehydes (Figure 8.12) has received much attention [325, 331-334]. The asymmetric addition of the alkyl group is promoted by a P-amino alcohol ligand, which is believed to form the asymmetric catalyst for the addition, containing a four-membered Zn O Zn O ring. The catalytic cycle is shown in Figure 8.13. 

Another approach to facilitate the recovery of catalytic systems relies on the use of fluorinated analogues of classic chiral ligands. The recycling options offered by the fluorous catalysts have been explored in the field of asymmetric addition of dialkylzinc reagents to aldehydes in presence of titanium tetraisopropoxide. In 2000, the groups of Chan ° and Curran reported independently the synthesis of perfluoroallqrl-substituted BINOL ligands and their evaluation in the titanium-mediated enantioselective addition of diethylzinc to aromatic aldehydes in fluorous biphasic system (Scheme 7.27). 

Langer, R, Schwink, L., Devasagayaraj, A., Chavant, P. Y. and Knochel, P. 1996. Preparation of functionalized dialkylzincs via a horon-zinc exchange Reactivity and catalytic asymmetric addition to aldehydes. J. Org. Chem. 61 8229-8243. 

Ostwald, R. et al.. Catalytic asymmetric addition of polyfunctional dialkylzincs to P-stannylated and P-silylated unsaturated aldehydes, J. Org. Chem., 59, 4143, 1994. 

With organozinc compounds in the presence of palladium, nickel or copper compounds as the catalysts, highly selective additions to carbonyl groups or carbon-carbon double bonds proceed. For example, an addition of chalcone (Ph-COCH=CH-Ph) proceeds with dialkylzinc in the presence of a nickel catalyst. The asymmetric addition proceeds by using a nickel catalyst having the chiral ligand as shown in eq. (5.17) [38,43]. 

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