Mixed aggregates chiral lithium amides

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. 

Lithium enolates of ketones and esters can be generated by the action of chiral lithium amides. If the base is used in stoichiometric amounts, the lithium cation of the endate bears the chiral amine as a ligand. If the amide is used in excess, chiral mixed aggregates can be formed [77, SS7, 558, 559], These lithium... 

Scheme 2.23 Dimeric structures of chiral lithium amide bases and their mixed aggregates with lithium halides.

Highly enantioselectivity assumed to originate from a mixed aggregate 171 of the trans-lithium enolate of t-butyl propionate 169 and the chiral lithium amide 170 was observed in aldol additions to various aldehydes, as exemplified in Scheme 5.55. Thus, the acylated aldols obtained with benzaldehyde formed in a diastereomeric ratio of 92 8 in favor of the anti-product, with an enantiomeric excess of 94% ee [83]. More recent studies on the structures of mixed aggregates between lithium enolates and chiral amide bases (see also Chapter 3) provided an insight in this type of enantioselective conversion. 

The use of chiral lithium amide bases in combination with achiral protonating agents provides as striking argument for the internal proton return in mixed eno-late aggregates. The concept was verified first by Hogeveen and Zwart [233] and thereafter studied intensively by Vedejs and coworkers who used Lewis acids for reprotonation [234]. The method is illustrated for the deracemization of naproxen amide 466 that is converted into a mixture of cis- and traws-enolates 468 in the ratio of 93 7 by treatment with 2 equiv. of s-butyllithium, followed by 2 equiv. of... 

Keywords Chiral lithium amide (CLA) Dipolar interactions Mixed AggregAtes (MAA) Structure-reactivity relationship Synergy... 

SCHEME 59. Various types of solid-state mixed aggregates involving ketone lithium enolates (A) pinacolone enolate/lithium amide [LiHMDS/CH2C(OLi)Bu-i, 2 DME]230 (B) pentan-3-one enolate/2 chiral lithium amide232 (C) pinacolone enolate/lithium amide/LiBr [LiHMDS/2 Cl HCtOI.ijBu-f/LiBr, 2 TMEDA]235... 

Li-C couplings have been collected for a series of lithium reagents by Reich and co-workers, who studied their chelation and aggregation with potential 5-, 6-, and 7-ring chelating ether and amine ortho substituents. The couplings have been also applied by Hilmersson and Malmros in their studies on mixed dimer and mixed trimer complexes of -BuLi and a chiral hthium amide. 

Asymmetric deprotonation of a prochiral compound having a sufficiently acidic C-H bond can be performed by a lithium amide generated from an enantio-pure secondary amine or by an organolithium reagent in the presence of a chiral tertiary amine [557, 559]. A chiral mixed aggregate is usually formed [77, 81, 974], and the reaction of this intermediate with electrophiles (including proton sources) can lead to a predominant enantiomer. 

Alkylations of lithium enolates of ketones in the presence of chiral bases has been widely studied [77, 559, 1008], but disappointing results were often obtained. However, Koga and coworkers performed asymmetric alkylations of cyclohexanone and tetralone lithium enolates in toluene at low temperatures [108, 1017]. The enolates are generated from the Li amide of chiral diamine 2.4 (X = CH2. R = MeOCH2CH2OCH2CH2). The presence of LiBr is essential to observe a high enantioselectivity (Figure 5.8), and the involvment of mixed aggregates is implied. 

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