Enones enantioselective dialkylzinc addition

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 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). 

Enantioselective conjugate addition of dialkylzincs to enones using chiral catalysts asymmetric synthesis of -substituted ketones... 

Catalytic Enantioselective Conjugate Addition of Dialkylzincs to Enones. A chiral nickel complex modified with DBNE and an achiral ligand such as 2,2 -bipyridyl in acetonitrile/toluene is an highly enantioselective catalyst for the addition of dialkylzincs to enones. p-Substituted ketones with up to 90% ee are obtained (eq 23). The method is the first highly enantioselective catalytic conjugate addition of an oiganometallic reagent to an enone. 

Scheme 3.S0 Enantioselective conjugate addition of dialkylzinc reagents to enones.

The preparation of silyl enol ethers from carbonyl compounds represents one of the major uses of TMSOTf. Recently, the stereochemistry and regiospecificity of such transformation has been addressed for aldehydes and -(iV-alkoxycarbonylamino) ketones, respectively. On the other hand, enantiopure silyl enol ethers can be formed by addition of TMSOTf to zinc enolates, which are obtained from the copper-catalyzed enantioselective conjugate addition of dialkylzinc reagents to cyclic (eq 36) and acyclic enones. ... 

Enantioselective additions of dialkylzincs and diphenylzinc to enones and related compounds were accomplished using catalytic amounts of Gu salts and optically active ligands, including biphenol-based phosphoramidites301-304... 

A summary of other chiral ligands with corresponding enantioselectivities in the copper-catalyzed 1,4-addition of dialkylzinc to cyclic enones is shown in Figure 5.55-58... 

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. 

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). " ... 

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. 

High levels of enantioselectivity (94-98% ee) and good chemical yield (72-95%) were observed in the catalytic conjugate addition of dialkylzinc reagents to numerous cyclic enones (eq 1) using a catalyst prepared in situ from Cu(OTf)2 and this chiral phosphoramidite ligand. Here the steric properties of the substrate and the reagent appear to be unimportant. 

The more recent development of NHC ligands, such as those derived from the imidazolium salt L30, has allowed the addition of dialkylzinc (Scheme 63) and diarylzinc reagent (Scheme 64) to simple unactivated p-substituted cyclic enones [98]. Very good yields and enantioselectivities are obtained with a wide variety of organozinc compounds only the less reactive MeaZn does not provide any conversion. 

Enantioselective copper-catalysed 1,4-additions of dialkylzincs to enones have been carried out in the presence of 1 mol% of Cu(OTf)2 and 2.5 mol% of an )V,)V,P-ligand (18) possessing a i-butyl group at the adjacent position of the nitrogen of pyridine to afford the corresponding 1,4-adducts in up to 98% ee7 ... 

Dual enantioselective control in the Cu-catalysed conjugate addition of dialkylzinc compounds to acyclic and cyclic enones has been realized in the presence of functionalized A -heterocyclic carbene ligands. " For example, a high degree of asymmetric catalysis (up to 96% ee) has been achieved using a (hydroxy amide)-functionalized azolium salt (19). Most likely the selectivity appears because of the facial selection of the enone, which is a result of steric repulsion between the alkyl group on the azolium ring and the alkyl substituent at the / -position of the enone. 

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