Aggregates, chiral lithium amide/enolate

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. 

There are several examples of the effect of LiX on enolate aggregation leading to increased enantiomeric excess in asymmetric chemical events. Koga and co-workers developed an efficient enantioselective benzylation of the lithium enolate of 19 by using a stoichiometric amount of chiral ligand 22 with LiBr in toluene [50]. The chiral lithium amide 22 was prepared by treatment of a mixture of the corresponding amine 21 and LiBr in toluene with a solution of n-BuLi in hexane. Sequential addition of ketone 19 and benzyl bromide gave rise to 20 in 89 % yield and 92 % ee. The amount... 

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... 

Unique H-Li couplings of 0.45 and 0.89 Hz through the Li-N-C-H network have been observed by Willard and co-workers in the spectrum of a chiral enolate aggregate containing a lithium enolate and a chiral lithium amide. This is a second example of such coupling reported in the literature. For the first time scalar coupling of 0.80 Hz between proton and lithium nuclei across the H-C-C-Li path was reported by Gunther and co-workers in 1993.2 ... 

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... 

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... 

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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