Chiral lithium amides stoichiometric

Preparatively more relevant is the use of chiral lithium amide bases, which have been successfully used both for enantioselective generation of allylic alcohols from meso-epoxides and for the related kinetic resolution of racemic epoxides [49, 50]. In many instances, chiral amide bases such as 58, 59, or 60 were used in stoichiometric or over-stoichiometric quantities, affording synthetically important allylic alcohols in good yields and enantiomeric excesses (Scheme 13.28) [49-54], Because of the scope of this review, approaches involving stoichiometric use of chiral bases will not be discussed in detail. 

Examples of chiral lithium amide bases, employed mainly (over)-stoichiometrically ... 

The catalytic asymmetric rearrangement of functionalized cyclohexene and cyclopentene oxides to give chiral allylic alcohols has been studied using sub-stoichiometric amounts of a chiral lithium amide in combination with a stoichiometric amount of different lithiated imidazoles (Scheme 47).79... 

Ahlberg and coworkers have found that lithiated 1-methylimidazole (21) and lithiated 1,2-dimethylimidazole (22) work as such bulk bases in the presence of catalytic amounts of a readily accessible homochiral lithium amide 20 (both enantiomers are readily available) (see Section III.C)45,46. These new bulk bases are easily accessible by deprotonation of 1-methylimidazole and 1,2-dimethylimidazole by, e.g., n-BuLi (Scheme 72). Using chiral lithium amide 20 (20 mol%) and bulk base 21 or 22 (200 mol%) in the deprotonation of cyclohexene oxide 1 gave (S)-2 with the same enantiomeric excess (93%) as under stoichiometric conditions (Scheme 15). Apparently, any background reactions of the bulk bases are insignificant. Interestingly, no addition of DBU was needed to obtain the high enantioselectivities under these catalytic conditions. 

Liu and Kozmin used the asymmetric deprotonation of hetero-epoxides such as 106 as key step in the synthesis of chiral polyols120. The deprotonation was carried out using the chiral lithium amide pool published in the literature and both stoichiometric and catalytic deprotonations gave satisfactory results (Scheme 78). 

Deprotonation of 4-f-butyl cyclohexanone 28 with chiral lithium amide 39 (30 mol%) and bulk base 107 (240 mol%) in the presence of HMPA (240 mol%) and DABCO (150 mol%), under external quench conditions, resulted in 79% ee of the silyl enol ether 29 (Scheme 79)121. This stereoselectivity is only slightly lower than that of the stoichiometric reaction (81% ee). 

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... 

While several stoichiometric chiral lithium amide bases effect the rearrangement of raeso-epoxides to allylic alcohols [1], few examples using catalytic amounts of base have been reported. Asami applied a pro line-derived ligand to the enantioselective deprotonation of cyclohexene oxide to afford 2-cyclohexen-... 

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... 

Two further contributions illustrate how chiral lithium amides can be used as catalysts in asymmetric deprotonation reactions (Schemes 2 and 3). The first example of catalytic chiral lithium amide chemistry was reported [13] by Asami (Scheme 2). In this process an achiral base, in this case LDA, provides a stoichiometric reservoir of amidoli-thium reagent. However, deprotonation of the epoxide is affected primarily by the chiral lithium amide 11 rather than the relative excess of LDA. Turnover is possible since the resulting chiral secondary amine 10 can be deprotonated by the remaining reservoir of LDA thus regenerating the chiral base 11. For example, the deprotonation of cyclohexene oxide 8 in the presence of DBU as an additive gives the allylic alcohol 9 in 74 % ee (82 % yield) using 50 mol% of chiral base 11. 

A chiral reagent can also be used as the source of stereoinduction in the s)mthesis of an enantioenriched compound. They are used in stoichiometric quantities and some typical examples are chiral lithium amide bases to asymmetrically deprotonate a ketone, chiral reducing reagents, such as BINAL-H, to asymmetrically reduce a... 

Combination of achiral enolates vith achiral aldehydes mediated by chiral ligands at the enolate counter-ion opens another route to non-racemic aldol adducts. Again, this concept has been extremely fruitful for boron, tin, titanium, zirconium and other metal enolates. It has, ho vever not been applied very frequently to alkaline and earth alkaline metals. The main, inherent, dra vback in the use of these metals is that the reaction of the corresponding enolate, vhich is not complexed by the chiral ligand, competes vith that of the complexed enolate. Because the former reaction path vay inevitably leads to formation of the racemic product, the chiral ligand must be applied in at least stoichiometric amounts. Thus, any catalytic variant is excluded per se. Among the few approaches based on lithium enolates, early vork revealed that the aldol addition of a variety of lithium enolates in the presence of (S,S)-l,4-(bisdimethylamino)-2,3-dimethoxy butane or (S,S)-1,2,3,4-tetramethoxybutane provides only moderate induced stereoselectivity, typical ee values being 20% [177]. Chelation of the ketone enolate 104 by the chiral lithium amide 103 is more efficient - the j5-hydroxyl ketone syn-105 is obtained in 68% ee and no anti adduct is formed (Eq. (47)) [178]. 

Asymmetric formation of /i-lactams (38) in high ee has been achieved by reaction of achiral imines (36) with a ternary complex of achiral lithium ester enolate (35), achiral lithium amide, and a chiral ether ligand (37) (in either stoichiometric or catalytic amount) 45 the size and nature of the lithium amide have a considerable effect on the enantioselectivity of the ternary complex. 

Subsequent work [55-65], in particular by Asami [56-60] and Andersson [61-65], has led to the development of catalytic methods in which a sub-stoichiometric amount of a chiral diamine such as 61 or 62 is used with an over-stoichiometric quantity of an achiral lithium amide base such as LDA (Scheme 13.29). Examples of catalytic epoxide isomerizations using the Asami diamine 61 or the Andersson... 

In a lithium amide promoted deprotonation, one lithium amide molecule is consumed for each deprotonated epoxide molecule. Since chiral hthium amides are expensive reagents, there is a strong desire to develop less costly synthetic procedures for stereoselective deprotonations. Catalysis has the potential to solve the problem. What are needed are bulk bases capable of regenerating the chiral hthium amide from the chiral diamine produced in the deprotonation reaction. There have been some attempts along this line, e.g., by Asami and co-workers, who used the non-chiral hthium amide LDA as bulk base and the chiral hthium amide 4 as catalyst [9,12,39-41]. However, the stereoselectivity was considerably lower than what had been achieved in absence of the bulk base, i.e., under stoichiometric conditions. Most likely, the decreased stereoselectivity in the presence of bulk LDA is due to competing deprotonation by LDA to yield racemic product alcohol. The situation is illustrated in Scheme 9. 

A modified protocol was elaborated that starts from the corresponding silyl enol ether that is cleaved into the lithium enolate by methyl lithium in the presence of lithium bromide and the free amine 2 [2a]. Both procedures, however, suffer from the fact that either the lithium amide base 1 or the chiral amine 2 has to be applied in stoichiometric amounts. Fortunately, the presence of 1 equiv. of lithium bromide and 2 equiv. of the additive AfAfdV W -tetramethylpropylenediamme permitted to reduce the amount of the valuable chiral amine 2b to 5mol%... 

Several new catalytic asymmetric protonations of metal enolates under basic conditions have been published to date. In those processes, reactive metal enolates such as lithium enolates are usually protonated by a catalytic amount of chiral proton source and a stoichiometric amount of achiral proton source. Vedejs et al. reported a catalytic enantioselective protonation of amide enolates [35]. For example, when lithium enolate 43, generated from racemic amide 42 and s-BuLi, was treated with 0.1 equivalents of chiral aniline 31 followed by slow addition of 2 equivalents of ferf-butyl phenylacetate, (K)-enriched amide 42 was obtained with 94% ee (Scheme 2). In this reaction, various achiral acids were... 

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