Asymmetric conjugate addition enone

Asymmetric conjugate addition of dialkyl or diaryl zincs for the formation of all carbon quaternary chiral centres was demonstrated by the combination of the chiral 123 and Cu(OTf)2-C H (2.5 mol% each component). Yields of 94-98% and ee of up to 93% were observed in some cases. Interestingly, the reactions with dialkyl zincs proceed in the opposite enantioselective sense to the ones with diaryl zincs, which has been rationalised by coordination of the opposite enantiofaces of the prochiral enone in the alkyl- and aryl-cuprate intermediates, which precedes the C-C bond formation, and determines the configuration of the product. The copper enolate intermediates can also be trapped by TMS triflate or triflic anhydride giving directly the versatile chiral enolsilanes or enoltriflates that can be used in further transformations (Scheme 2.30) [110],... 

Scheme 2.30 Copper-catalysed asymmetric conjugate addition of organozincs to enones...

Fig. 2.25 Palladium catalysts and postulated intermediates in the asymmetric conjugate addition of phenyl boronic acids to cyclohex-2-enone...

Yamaguchi and coworkers have found that proline rubidium salts catalyze the asymmetric Michael addition of nitroalkanes to prochiral acceptors. When (25)-L-prolines are used, acyclic ( )-enones give (S)-adducts. Cyclic (Z)-enones give (R)-adducts predominantly (Eq. 4.139).203 Recently, Hanessianhas reported that L-proline (3 7% mol equiv) and 2,5-dimethylpiperazine are more effective to induce catalytic asymmetric conjugate addition of nitroalkanes to cycloal-kanones.204... 

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. 

Chiral binaphthylthiophosphoramide 52b and binaphthylselenophosphoramide 53 have been developed by Shi and co-workers, and high enantioselectivity (up to 97%) has been achieved in the asymmetric conjugate addition of acyclic enones under the optimized conditions.58... 

Recently considerable attention has been given to chiral 72-bonded olefin spectator ligands for the asymmetric conjugate addition.122 Hayashi and Carreira independently reported that new chiral diene ligands 83,123 84,124 and 85125 showed high enantioselectivities in Rh(i)-catalyzed conjugate addition of arylboronic acids to enones (Scheme 41). 

Phosphite compounds, which have been discussed in the context of their application in asymmetric hydrogenation reactions (see Section 6.1.2.6), can also be used to effect the copper salt-mediated asymmetric conjugate addition of diethylzinc to enones.74 As shown in Scheme 8-33, in the presence of diphosphite 92 and copper salt [Cu(OTf)2], the asymmetric conjugate addition proceeds smoothly, giving the corresponding addition product with high conversion and ee. In contrast, the monophosphite 93 gave substantially lower ee. 

In addition to the asymmetric conjugate addition involving an enone substrate and a relatively inactive nucleophile, there exists another kind of reaction in which a deactivated substrate and a normal nucleophile are involved. For example, under proper conditions, ordinary organometallic compounds such as... 

Scheme 8-35. LSB-promoted catalytic asymmetric conjugate addition of thiols to enones. Reprinted with permission by Am. Chem. Soc., Ref. 76.

To investigate the effect of the substituents in the arenethiolate structure, four differently substituted copper arenethiolates, 25-28, were tested as catalysts, but very low ees were obtained in all cases [34]. The oxazolidine complex 26, developed by Pfaltz et al. [36] and used successfully in asymmetric conjugate addition reactions to cyclic enones, gave a completely racemic product with allylic substrate 20a. 

Woodward et al. have used the binaphthol-derived ligand 40 in asymmetric conjugate addition reactions of dialkylzinc to enones [46]. Compound 40 has also been studied as a ligand in allylic substitutions with diorganozinc reagents [47]. To allow better control over selectivity in y substitution of the allylic electrophiles studied, Woodward et al. investigated the influence of an additional ester substituent in the jS-position (Scheme 8.25). 

Asymmetric Conjugate Addition with Enones and Enals. 149... 

Dicarbonyl donors are excellent Michael donors in asymmetric conjugate addition to a,p-nnsatnrated ketones. Wang and co-workers [79] applied chiral Cinchona-thiourea catalyst 131 to various carbon donors in the addition to aromatic enones. A diverse array of nucleophiles, mainly 1,3-dicarbonyls proceeded smoothly in the conjugate addition to a,p-unsaturated enone 132 (Scheme 29). 

MeOC6H4, respectively. The titanium enolates were converted into silyl enol ethers 54 by treatment with chlorotrimethylsilane and lithium isopropoxide. Additionally, cyclic enones lb and Ic, and linear enones Id and le, are also good substrates for the asymmetric conjugate addition of phenyltitanium triisopropoxide, giving the corresponding arylation products with over 97% enantioselectivity. 

Asymmetric conjugate addition of CH3MgBr. The reaction of the a,/ -enone 2 with CHjMgBr in the presence of copper(I) bromide and 1 results in asymmetric conjugate addition to give 3 (equation I). The optical yield (68%) is the highest that has been reported for such a reaction. 

Scheme 4. Cu-catalyzed asymmetric conjugate additions to various cyclic and acyclic enones with peptidic phosphines as the chiral ligand...

Pyrrolidin-2-yltetrazole has been found to be a versatile organocatalyst for the asymmetric conjugate addition of nitroalkanes to enones.45 Using this catalyst, this transformation requires short reaction times, tolerates a broad substrate scope, and possibly proceeds via generation of an iminium species. 

An efficient way to create, enantioselectively, all-carbon quaternary centres, by the unprecedented asymmetric conjugate addition of Grignard reagents to enones has been developed using a copper catalyst and a chiral diaminocarbene ligand of the corresponding salt (19) or (20).87... 

The copper-catalysed asymmetric conjugate addition of dialkylzinc to enones (174 n = 1 or 2) generates homochiral zinc enolates (175), which can be trapped in situ with activated allylic electrophiles to produce (176). High trans selectivity (85 15 to... 

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