Addition of Alkylzincs

Even if hundreds of chiral catalysts have been developed to promote the enantioselective addition of alkylzinc reagents to aldehydes with enantioselectivities over 90% ee, the addition of organozinc reagents to aldehydes is not a solved problem. For example, only very few studies on the addition of vinyl groups or acetylides and even arylzinc reagents to aldehydes have been published, in spite of the fact that the products of these reactions, chiral allylic, propargylic and aryl alcohols, are valuable chiral building blocks. 

This must reflect activation of the carbonyl group by magnesium ion, since ketones are less reactive to pure dialkylzinc reagents and tend to react by reduction rather than addition.141 The addition of alkylzinc reagents is also promoted by trimethylsilyl chloride, which leads to isolation of silyl ethers of the alcohol products.142... 

Either Cul or CuCN (10 mol %) in conjunction with BF3 and TMS-C1 catalyze addition of alkylzinc bromides to enones. 

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... 

Scheme 6.16. Zr-catalyzed enantioselective addition of alkylzinc reagents to imines utilizes peptidic ligands and can be used to prepare a variety of aromatic amines in high optical purity.

As shown in Eq. (4), parallel screening of ligand libraries has allowed us to establish that a closely related peptide-based phosphine ligand promotes the catalytic asymmetric conjugate addition of alkylzincs to nitroalkenes [14]. Not only are the corresponding alkyl nitrones obtained efficiently and in high diaster-eo- and enantioselectivity, appropriate acid workup can deliver the derived ketone directly. 

Scheme 9.24. Zr-catalyzed asymmetric three-component addition of alkylzincs to imines.

The first examples of catalytic asymmetric conjugate addition of alkylzinc reagents to trisubstituted nitroalkenes, such as PhC(Me)=CHN02, leading to the formation of nitroalkanes bearing a quaternary carbon stereogenic centre, have been reported. Reactions are promoted by the readily available amino acid-based phosphine (211)... 

Palladium catalysed cyclic carbozincation of u>-iodoalkenes and copper promoted conjugate addition of alkylzincs to nitroalkenes preparation of 1-butyl-1-(3-nitro-2-phenylpropyl)cyclopentane60... 

Complexation of propargyl aldehydes to cobalt also enhances the reactivity and enantioselectivity of the addition of alkylzinc reagents. This fact was used to create non-racemic enyne-ol 88 reacting the aldehyde 86 with bis-homoallylzinc in the presence of a chiral frzs-(sulfonamide) and Ti(OlPr)4. The resulting complexed substrate 87 underwent the PKR promoted by TMANO in a one pot fashion (Scheme 25) [122]. 

Michael acceptor is a powerful tool for carbon-carbon bond formation with simultaneous introduction of a new stereogenic center The binaphthyl derived phosphoramidite els, , )- ligand showed remarkable stereoselectivities in copper-catalyzed 1,4-addition of alkylzinc reagents to a,3-unsaturated carbonyl compounds. ... 

The most effective route to aminoalcohol (493) was established by screening various stereochemically homogeneous N,N-disubstituted-, N-monosubstitut-ed-amino alcohols and iminoalcohols as chiral additives to promote asymmetric addition of alkylzinc to N-diphenylphosphinoyl imine (492). The addition reactions that were performed in the presence of this compound resulted in excellent enantioselectivity (Figure 94a). 

The addition of aryl groups to C=N bonds can be achieved using cooper-catalyzed asymmetric reactions with organometallic reagents. The addition of alkylzinc and related reactions is quite common in literature [47] whereas copper-catalyzed asymmetric arylation of imines is somewhat harder to find. We wish to report some successful examples of this type of catalysts. 

Walsh approached the formation of epoxides with adjacent secondary alcohols through the asymmetric addition of alkylzinc reagents to a,p-unsaturated aldehydes followed by diastereoselective epoxidation (Scheme 4.26) [60]. Aldehyde 132 reacted with Et Zn in the presence of catalyst 133 to yield zinc alkoxide 134. Introducing to the system followed by Ti(OiPr) led to the isolation of epoxy alcohol 135 in high yield and enantiomeric excess and with good diaste-reocontrol. This one-pot process was proposed to occur through the intermediacy of a zinc peroxide that forms upon the addition of to the system. 

Scheme 2-141. Lewis-acid accelerated addition of alkylzincs to carbonyl groups.

Catalytic Enantioselective Additions of Alkylzinc Reagents to Imines... 

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