Chiral lithium amides amide-amine

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). 

F. Mixed Complexes between Chiral Lithium Amides containing Amines... 

Stoddart and coworkers40 have synthesized a chiral lithium amide with C2-symmetry and two chelating methoxy groups from the amine (R,R)-di(a-methoxymethylbenzyl)amine (7). This lithium amide was crystallized from a hexane solution and X-ray analysis revealed a dimeric structure where both lithiums are tetracoordinated, (Li-7)2. 

C. Mixed Complexes between Alkyllithiums and Chiral Lithium Amides with Chelating Amine Groups... 

Majewski and coworkers developed polymer-supported chiral lithium amides and applied them to the aldol reaction (Scheme 33)74. The amide precursor amines were prepared either from the insoluble Merrifield resins or from copolymerized styrene and 4-chloromethylstyrene yielding soluble polymer (SP). 

The finding that the use of LDA as bulk base results in non-enantioselective deprotonation indicated that bulk bases which are much less reactive toward the epoxide substrate compared with the chiral lithium amide are needed. But they should be strong enough to regenerate the chiral amide from the amine formed in the epoxide rearrangement. 

In order to further develop the field of enantioselective catalytic deprotonation, it was necessary to develop bulk bases that show low reactivity toward the epoxide but have the ability to regenerate the chiral catalyst. Thus, the bulk bases should show low kinetic basicity toward the substrate, but be thermodynamically and kinetically basic enough to be able to regenerate the chiral lithium amide from the amine produced in the rearrangement. 

Malhotra introduced monodentate amines derived from a-pinene as chiral lithium amide precursors118. Using 20 mol% of the base 105 with excess LDA resulted in 95% ee of the corresponding (R)-allylic alcohol (Scheme 76). 

Although the number of chiral lithium amides used for asymmetric deprotonations are numerous, as indicated above, there is only a small number of ligands that have found frequent use. In this section, syntheses of some amine precursors of these chiral lithium... 

The diamine precursor 108 to the chiral lithium amide 4 introduced by Asami is accessible by different routes starting from (, >)-proline. In Asami s own synthesis, (S)-CBZ-proline was activated by DCC and then coupled by an amine such as pyrrolidine (Scheme 80). The reduction of the formed amide could then be carried out with LiAlHj or BH3, with the latter giving a cleaner reaction. After deprotection, the diamine was obtained by distillation in 44-48% yield from (.S j-CBZ-prolinc. 

The crucial role of the secondary liberated amine was also reported in experiments involving deprotonation with lithium (/ )-A -ethyl(l-phenylethyl)amide and reprotonation at —70°C with 2R,3R, racemic, and meso-DPTA, yielding, respectively, 70, 39, and 24% ee of the (5)-enantiomer. In the two last cases, significant inductions were obtained with the sole secondary chiral amine as chiral inductor in the medium. Since these first results, chiral lithium amides have been widely used for asymmetric synthesis. 

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... 

Chiral lithium amide bases have been used successfully in the asymmetric deprotonation of prochiral ketones [55, 56]. WUliard prepared polymer-supported chiral amines from amino acid derivatives and Merrifield resin [57]. The treatment of cis-2,6-dimethylcyclohexanone with the polymer-supported chiral lithium amide base, followed by the reaction with TMSCl, gave the chiral silyl enol ether. By using polymeric base 96, asymmetric deprotonation occurred smoothly in tetrahydrofuran to give the chiral sUyl enol ether (, S )-102 in 94% with 82% ee (Scheme 3.28). 

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... 

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). 

Both dimethylphenylphosphine-borane (107) and -sulfide (108) are enantio-selectively deprotonated by a lithiumalkyl (—)-sparteine complex as demonstrated by subsequent reaction with electrophiles to give products with e.e. values of 80-87% (Scheme 8). Oxidative coupling of (109) in the presence of copper(II) pivalate gives the (S. S)-isomer (110) as the major product. Asymmetric metalla-tion and silylation of diphenylphosphinyl ferrocene (111) using the chiral lithium amide base derived from di(l-methylbenzyl)amine has been reported to give an... 

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. 

The first examples of chiral lithium amides to be used to generate a chiral organolithium species were reported by Marshall in 1987 [81] in his pioneering work into [2,3]-sigmatropic rearrangements (Hodgson et al,in this volimie) for which the Hthiiun amide 39 (Fig. 4) was used (up to 60% ee) the amine precursors to both 39 and enf-39 are commercially available. 

Treatment of a (2.2.1)-bicyclic amine with BuLi gives a chiral lithium amide that undergoes highly stereoselective Michael additions to a, -unsaturated esters (eq 70). Treatment with A-iodosuccinimide releases the chiral auxiliary as the bornylalde-hyde and furnishes the optically active /3-amino esters. 

In an effort to develop a more efficient method to S5mthesize enantioenriched allylic amine substrates for [2,3]-rearrangements, Davies and Smyth reported an asymmetric conjugate addition with chiral lithium amide 74 tScheme 1S.16T ° The resulting aminoester 75 was reduced to alcohol 76, which was treated with m-CPBA to furnish chiral amine iV-oxide 77. 

To date, several dozens of chiral lithium amide bases have been applied for enantioselective enolate formation. A collection including only several of these bases (72, 74-78) is given in Scheme 2.21. The Overberger amine [76], introduced under its lithiated form 72a by Simpkins group, still seems to be the most widely applied for this type of enantioselective bond disconnection. 

Enantioselective deprotonation of prochiral 4-alkylcyclohexanones using certain lithium amide bases derived from chiral amines such as (1) has been shown (73) to generate chiral lithium enolates, which can be trapped and used further as the corresponding trimethylsilyl enol ethers trapping was achieved using Corey s internal quench described above. 

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