Asymmetric conjugate addition organolithium reagents

Organolithium compounds are highly reactive and have been used in a variety of organic transformations. A major problem in the development of catalytic asymmetric conjugate additions of organolithium reagents to a,/3-unsaturated carbonyl compounds is that the high reactivity of RLi may cause both low chemoselectivity (1,2- vs. 1,4-addition) and low enantioselectivity. 

The C2 symmetric chiral diether 28" and the naturally occurring chiral diamine, (—)-sparteine (29), have been the most successful external chiral ligands for asymmetric conjugate addition of organolithium reagents. The rest of this review highlights organolithium addition, which is mediated or sometimes catalyzed by 28 or 29. 

SCHEME 2. Asymmetric conjugate addition of organolithium reagents with stoichiometric chiral ligands. Adapted with permission from Acc. Chem. Res., 40, 179-188 (2007). Copyright 2007 American Chemical Society... 

The chromium complex 46 of benzaldehyde imine is also a good substrate for asymmetric conjugate addition of organolithium reagents, where the reaction was mediated by a stoichiometric amount of chiral diether 18 in toluene to give, following propargylic electrophile incorporation, the cyclohexadienal 48 in up to 93% ee (Scheme 13) [38]. SAMP [(S)-l-amino-2-(methoxymethyl)pyrrolid-ine] hydrazones were used effectively in diastereoselective nucleophilic additions to (arene)Cr(CO)3 complexes [39]. 

An auxiliary approach was developed by Meyers, who found that unsaturated oxazolines such as 58 participate in asymmetric conjugate addition reactions with organolithium reagents (Equation 11) [74, 75]. With these substrates, a wide variety of chiral /1-substituted acids, including 59, were obtained with excellent enantioselectivity [75]. The yields were highest for substrates lacking allylic protons, as y-deprotonation was observed as a competing unwanted side reaction. 

The first prominent catalytic asymmetric addition of an organolithium reagent was realized in the reaction of 1-naphthyllithinmwith l-fluoro-2-naphthy-laldehyde imine in the presence of the chiral diether 1 to afford chiral binaphthyls in over 82% ee (Scheme 2). Merely a catalytic amount of 1 (5 mol %) is required to effect the reaction, in which an enantioselective conjugate addition-elimination mechanism is operative [18]. 

The chelation control methodology of Meyers provided a highly selective conjugate addition of organolithium reagents to a chiral oxazoline. The diastereose-lective asymmetric addition of various organolithiiuns to a,P-unsaturated chi-... 

Tomioka documented the use of organolithium reagents in enantioselec-tive conjugate additions to conjugated imines (Equation 31) [136]. The readily available chiral diether 173 served to mediate such additions with high asymmetric induction for example, the addition of PhLi to 172 furnished aldehyde 174 in 94% ee after hydrolysis of the imine adduct. In subsequent developments, Tomioka reported the enantioselective preparation of biaryls in which a naphthyllithium participates in a nucleophilic aromatic substitution catalyzed by only 5mol% of 173 (see insert on the left) and delivers the product in 82% ee [137]. 

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