Addition of Dialkylzinc Reagents to Aldehydes

In 2004, Yang and Tseng reported the synthesis of a series of new chiral amino thiols and corresponding amino thioacetate ligands derived from 

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, these authors have developed the synthesis of chiral aziridine 

In the same area, these authors have also tested a p-amino thiol ligand containing a bicyclo[2.2.1] ring system, the 2-azanorbornylmethanethiol, which gave 

An examination of the catalytic abilities of C2-symmetric chiral A-(p-mer-captoethyl)pyrrolidines in the enantioselective addition of ZnEt2 to a variety of 

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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. 

Table 26. Addition of Dialkylzinc Reagents to Aldehydes under Chiral Catalysis...

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. 

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... 

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

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. 

Enantioselective carbonyl addition of dialkylzinc reagents to aldehydes is one of the most important and fundamental asymmetric reactions [2,15]. Several chiral titanium complexes have been developed to accelerate this type of reaction (Sch. 3) [16,18-26] since Ohno and Kobayashi achieved high enantioselectivity in the presence of Ti(OPr )4 and chiral disulfonylamide [16,17]. Seebach has also demonstrated that TADDOL-derived titanium complexes function as efficient asymmetric catalysts [18]. 

The slow nucleophilic addition of dialkylzinc reagents to aldehydes can be accelerated by chiral amino alcohols, producing secondary alcohols of high enantiomeric purity. The catalysis and stereochemistry can be interpreted satisfactorily in terms of a six-membered cyclic transition state assembly [46,47], In the absence of amino alcohol, dialkylzincs and benzaldehyde have weak donor-acceptor-type interactions. When amino alcohol and dialkylzinc are mixed, the zinc atom acts as a Lewis acid and activates the carbonyl of the aldehyde. Zinc in this amino alcohol-zinc complex is regarded as a kind of chirally modified Lewis acid. Various kinds of polymer-supported chiral amino alcohol have recently been prepared and used as ligands in dialkylzinc alkylation of aldehydes. 

Comma, P. J. Beck, A. K. Seebach, D., A Simple Batch Reactor for the Efficient Multiple Use of Polymer-bound a,a,a ,a -Tetraaryl-l,3-dioxolane-4,5-dimethanol Titanates in the Nucleophilic Addition of Dialkylzinc Reagents to Aldehydes. Org. Process Res. Dev 1998, 2,18. 

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]. 

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). 

A series of C(2) symmetrical 1 2 Ni/ligand complexes derived from a-amino amides have been studied for the enantioselective addition of dialkylzinc reagents to aldehydes. Different structural elements on the ligands seem to play an important role in determining the observed enantioselectivity. Through optimization of structure and reaction conditions, the best ligand (33) provided secondary alcohols in excellent yields and enantioselectivity of up to 99% ee for the (i )-enantiomer. A transition state model has been proposed to explain the observed enantioselectivities based on computational calculations at the DFT level. 

The enantioselective addition of dialkylzinc reagents to aldehydes is not limited to the homonuclear zinc complexes described above. Seebach has shown that Ti-TADDOL complexes can be effective catalysts for the preparation of a wide range of secondary alcohols (Equation 16) [102], The addition of Et2Zn to aldehydes is carried out with catalyst 165 in combination with 1.2 equiv Ti(Oi-Pr)4 to furnish products in 82-99% ee [17. 103). The use of excess Ti(Oi-Pr)4 is noteworthy, as it is of mechanistic significance. Catalyst turnover is only observed in this system because of the ability of the Ti(Oi-Pr)4 to serve as a reservoir for the alkoxide product. It is remarkable, however, that the presence of excess Ti(Oi-Pr)4 does not lead to any diminution in the enantioselectivity of the product formed. This represents a dramatic example of ligand-accelerated catalysis in C-C bond-forming reactions. 

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