2-Cyclohexenone copper catalyzed

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. 

Figure 21. Selectivity of copper-catalyzed conjugate addition of Et2Zn to cyclohexenone in the presence of several ligands.

The first application of a copper-catalyzed conjugate addition of diethylzinc to 2-cyclohexenone, using chiral phosphorous ligand 12, was reported by AlexaHs (Fig. 7.1) [35]. An ee of 32% was obtained. 

Phosphoramidites 13, derived from 2,2 -binaphthol, proved to be versatile ligands for copper-catalyzed 1,4-additions of Et2Zn to chalcone and 2-cyclohexenone (Scheme 7.9) [37]. 

Scheme 7.9. Copper-catalyzed 1,4-addition to cyclohexenone and chalcone, with phosphoramidites as chiral ligands.

Tab. 7.2. Copper-catalyzed enantioselective 1,4-addition of R2Zn to 2-cyclohexenone using BINOL-type ligands.

Tandem 1,4-addition to cycloalkenones constitutes an extremely versatile and elegant methodology for the synthesis of 2,3-disubstituted cycloalkanones, as is evident from its application in areas such as prostaglandin synthesis. Noyori et al. have reported the use of organozinc reagents in copper-catalyzed tandem additions [64]. The zinc enolate resulting from the catalytic enantioselective 1,4-addition of Et2Zn to cyclohexenone reacts readily with an aldehyde in a subsequent aldol condensation. 

We have recently discovered that phosphoramidite 18 is also an excellent ligand for copper-catalyzed kinetic resolution of chiral 2-cyclohexenones (Scheme 7.15). Chiral 2-cyclohexenones are attractive building blocks for a variety of natural products, but their synthesis usually requires multistep routes from chiral starting materials [65]. The development of the new kinetic resolution was the product of two impor-... 

The copper-catalyzed conjugate addition of methyhnagnesium iodide to cyclohexenone and trapping of the resulting enolate as its trimethylsilyl enolate, followed by TrSbCle-catalyzed Mukaiyama reaction, are the first steps of an elegant synthesis of enantiomeri-caUy pure clerodanes (equation 45). 

The copper-catalyzed conjugate addition of methyl magnesium iodide to cyclohexenone and trapping the enolate as its trimethylsilyl enol ether, followed by a trityl hexachloro-antinomate-catalyzed Mukaiyama reaction, is apphed to / -(—jcarvone. C-2, C-3 functionalized chiral cyclohexanones are converted into their a-cyano ketones, which are submitted to Robinson annulation with methyl vinyl ketone. Highly functionalized chiral decalones are obtained that can be used as starting compounds in the total synthesis of enantiomerically pure clerodanes (equation 70). 

TABLE 1. Enantioselective copper-catalyzed conjugate addition of Giignard reagents to 2-cyclohexenone ... 

The coordination of NHC ligands greatly enhances the copper-catalyzed asymmetric addition of diethylzinc to cyclohexenone [45]. Employing imi-dazolinylidene ligands with chiral centers in the heterocycle, the alkylation of a-enones [46,47] was systematically studied by the groups of Mangeney and Alexakis [10,48-50]. A summary of the results obtained is presented in Table 1. 

The copper-catalyzed addition of butyl Grignard reagent to cyclohexenone was reported by using selenium-oxazoline-based ligand 35 which gave butylcy-clohexanone 36 in 62% ee (Scheme 4) [24]. 

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