Chiral lithium amide, enantioselective Michael addition

The enantioselective aldol and Michael additions of achiral enolates with achiral nitroolefins and achiral aldehydes, in the presence of chiral lithium amides and amines, was recently reviewed354. The amides and amines are auxiliary molecules which are released on work-up (equation 90 shows an example of such a reaction). 

Mixed aggregates of chiral lithium amide and lithium ester enolate have been employed in the enantioselective conjugate addition on a,/S-unsaturated esters.27 Michael adducts have been obtained in ees up to 76% combining a lithium enolate and a chiral 3-aminopyrrolidine lithium amide. The sense of the induction has been found to be determined by both the relative configuration of the stereogenic centres borne by the amide and the solvent. 

Reactions of the lithium etiolate of cyclohexanone with E-l-nitroalkenes in the presence of chiral lithium amides have been studied by Seebach and co workers [558], and good diastereo- and enantioselectivities are obtained in a few cases. The tin enolate of TV-propionoyloxazolidinone 6.83 undergoes diastereo- and enan-tioselective Michael reactions when coordinated to chiral amine 2.13 (R = NH-l-Np) [682] (Figure 7.59). Similar reactions show low enantiomeric excesses (5 70%) however, some Michael additions catalyzed by chiral catalysts have shown high selectivities ( 7.16). 

R,2S)-Ephedrine has found most application, e.g., as a catalyst in photochemical proton transfer reactions (Section D.2.1.). and as its lithium salt in enantioselective deprotonations (Section D.2.1.). The amino function readily forms chiral amides with carboxylic acids and enamines with carbonyl compounds these reagents perform stereoselective carbanionic reactions, such as Michael additions (Sections D.1.5.2.1. and D. 1.5.2.4.), and alkylations (Section D.1.1.1.3.1.). They have also been used to obtain chiral alkenes for [1 +2] cycloadditions (Section D. 1.6.1.5.). 

Conjugate addition of the lithium salt of a chiral amine to a -substituted a, 3-unsaturated ester leads to formation of a chiral, nonracemic amino acid. Addition of the chiral, nonracemic lithium amide 5.143 (contains a phenethyl auxiliary) to 5.142 gave the amino-ester.63 Catalytic hydrogenation removed both benzylic groups (the auxiliary and the benzyl group) and acid hydrolysis of the ester moiety led to 3-amino-3-(4-benzyloxyphenyl)-propanoic acid, 5.144. The initial Michael adduct was formed with >99% dr (dr is diastereomeric ratio), leading to high enantioselectivity in 5.144 after removal of the auxiliary. 

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