Enones copper catalyzed

The reversal of the stereoselectivity is attributed to the ability of chlorotrimethylsilane to trap the initially formed cuprate-enone complex, thereby suppressing equilibration of the diastereomeric complexes. The copper-catalyzed 1,4-addition of Grignard reagents to 5-substituted 2-cyclo-hexenone also proceeded with very high trans diastereoselectivity22. 

A series of chiral phosphinous amides bearing pendant oxazoline rings (50, Ri=H,Tr R2=H,Tr, 51, Ri=H,Tr R2=H,Tr and 54, Ri=H,Tr R2=H,Tr in Scheme 41) have been used as ligands in the copper-catalyzed 1,4-addition of diethylzinc to enones. Two model substrates have been investigated, the cyclic 2-cyclohexenone and the acyclic trans-chalcone. The addition products are obtained quantitatively in up to 67% ee [171]. 

In 1993, Alexakis et al. reported the first copper-catalyzed asymmetric conjugate addition of diethylzinc to 2-cyclohexenone using phosphorous ligand 28 (32% ee).36 An important breakthrough was achieved by Feringa et al. with chiral phosphoramidite (S,R,R)-29 (Figure 1), which showed excellent selectivity (over 98% ee) for the addition of 2-cyclohexenone.37 Since then, efficient protocols for the conversion of both cyclic and acyclic enones, as well as lactones and nitroalkenes, have been developed featuring excellent stereocontrol. 

A remarkable number of chiral phosphorus ligands (phosphoramidites, phosphites, and phosphines with modular structures) have been introduced into the copper-catalyzed conjugate addition of R2Zn reagents, and high enantio-selectivities (>90%) are now possible for all three different classes of substrates 2-cyclohexenones and larger ring enones, 2-cyclopentenones, and acyclic enones. 

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... 

Q.-L. Zhou, A. Pfaltz, Chiral Mercaptoaryl-oxazolines as Ligands in Enantioselective Copper-Catalyzed 1,4-Additions of Grignard Reagents to Enones, Tetrahedron, 1994, 50, 4467-4478. 

Organoaluminum reagents have been used in the copper-catalyzed conjugate addition to enones with some success. Iwata and co-workers (182) demonstrated that dimethoxyphenyl oxazoline (247) provides modest selectivities in the copper-catalyzed conjugate addition of trimethylaluminum to 3,4,4-trimethylcyclohexadi-enone to provide the adduct in 68% ee, Eq. 145. The use of TBSOTf is crucial to attain high conversion and selectivity in this process. Woodward and co-workers (183) subsequently reported that a Cu(I) complex of thiocarbamate 248 provides modest facial discrimination in the addition of trimethylaluminum to a linear enone to afford 245b in 51% ee, Eq. 146. The authors note that this catalyst system decomposes under the reaction conditions at ambient temperature. 

Manganese-copper-catalyzed conjugate addition of organomagnesium reagents to a,p-enones is a general synthetic method. Table I shows that the reaction can be successfully performed even with enones of low reactivity. 30% Manganese chloride is necessary to obtain good yields. In most cases, however, 0.1% cuprous chloride is sufficient.3... 

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). 

Figure 3.2. Cyclic enone ring-size versus optimal ligand structure in the copper-catalyzed asymunetric 1,4-addition of diethylzinc.

Acyclic Enones as Substrates Compared to cyclic enones, acyclic enones are generally more challenging substrates for the copper-catalyzed asymmetric 1,4-addition reactions. Several ligands have been reported that can achieve high ee when p-aryl acyclic enones are used as substrates in the 1,4-addition of diethyl-zinc (Figure 3.5). ° ... 

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). " ... 

Examples, like the application of enantiopure ioiuc hquids in the copper catalyzed enantioselective 1,4-addition of diethyl zinc to enones giving up to 76% ee, will not be presented [178], since here the chiral ionic liquid, CIL, acts as a ligand for a metal catalyzed reaction. 

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