Lithium amides chiral catalysts

Stork and Takahashi took -glyceraldehyde synthon from the chiral pool and condensed it with methyl oleate, using lithium diisopropyl amide as catalyst for the mixed aldol reaction, leading to The olefinic linkage is a latent form... 

Kinetic resolution can also be accomplished via eliminative pathways. Thus, the enantiomerically enriched allylic alcohol 102 can be prepared from the meso epoxide 96 with up to 96% ee by the action of LDA in the presence of the chiral diamine 101 and 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU). The DBU is believed to function as an aggregation modifier, and the active catalyst is theorized to be a heterodimer of the lithium amide (deprotonated 101) and DBU, although some nonlinear effects have been observed at low DBU concentrations <00JA6610>. Dipyrrolidino derivatives (e.g., 104) have also demonstrated utility with regard to kinetic resolution <00H1029>. 

Asymmetric conjugate addition of lithium amides to alkenoates has been one of the most powerful methods for the synthesis of chiral 3-aminoalkanoates. High stereochemical controls have been achieved by using either chiral acceptors as A-enoyl derivatives of oxazolidinones (Scheme 4) 7 7a-8 chiral lithium amides (Schemes 5 and 6),9-12 or chiral catalysts.13,14... 

Like in other fields of asymmetric synthesis, catalysis is in focus. Catalysts for stereoselective synthesis utilizing chiral lithium amides are being developed to make such synthesis more useful in the laboratory as well as in industry. The progress made is also reviewed in detail below. 

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. 

A number of other chiral catalysts have been reported, among them the proline (111), lithium amides (112) and the tetrahydrofiirylamine (113). Hie optical yields of the products isolated, however, are only moderate at best. Hie use of optically active 2-methyltetrahydrofuran in Grignard reactions has also been reported however, minimal induction is observed. ... 

Highly enantioselective chiral catalysts other than P-amino alcohols for the addition of diethylzinc to aromatic aldehydes include the chiral bipyridylalka-nol5 [9], the oxazaborolidine 6 [10], the aminothioate 7 [11], the amino di-sulfide8 [12],the amino thioester9 [13], and the lithium amide ofpiperazine 10... 

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). 

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. 

Again, the achiral base 17 provides a reservoir of amidolithium reagent to allow catalyst turnover by deprotonation of 14 formed in situ (Scheme 3). Clearly, the kinetics of the reaction are such that deprotonation at the ketone a-carbon by the achiral lithium amide 17 is much slower than deprotonation at the 2° nitrogen of the chiral amine 14. Although the catalytic efficiency is modest, it is remarkable that catalysis of this type can be achieved. 

Sddergren, M.J. and Anderson, PG. (1998) New and high enantioselective catalysts for the rearrangement of mejo-epoxides into chiral allylic alcohols. Journal of the American Chemical Society, 120, 10760-10761 S6dergren, M.J., Bertilsson, S.K. and Anderson, P.G. (2002) Allylic alcohols via catalytic asymmetric epoxide rearrangement. Journal of the American Chemical Society, 122, 6610-6618 Bertilsson, S.K. and Anderson, P.G. (2002) Asymmetric base-promoted epoxide rearrangement achiral lithium amides revisited. Tetrahedron, 58, 4665-4668. 

Despite these fascinating properties, there have been very few studies on the development of asymmetric organobase catalysts [31,39,89], compared with the dramatic progress in polymer-supported chiral lithium amide based asymmetric transformations [90]. It can be expected that new effective polymer-supported chiral superbase reagents will be discovered in the near future. 

Our approach to this goal is rather rational in the sense that our design of chiral lithium amides is based upon a detailed understanding of the nature of the activated complexes involved. Such knowledge is obtained in the interplay of experimental and computational chemistry [6,14-25]. Experiments have been used to obtain both the compositions of the reactant chiral lithium amide and the activated complexes in solution and computational chemistry has been applied to obtain structures and energies. This has put us in a position to modify systematically the chiral lithium amide and to predict the stereoselectivity computationally. Selected lithium amides have been synthesized and investigated with respect to reactivity and stereoselectivity. Improved catalysts have been achieved. 

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. 

Chiral lithium diphenylbinaphtholate (2) has been found to be an effective catalyst for the enantioselective aldol-Tishchenko reaction, affording 1,3-diol derivatives with three contiguous chiral centres and high stereoselectivities (up to 99% ee) ° A direct, highly enantioselective alkylation of arylacetic acids via enediolates using a readily available chiral lithium amide (3) as a stereodirecting reagent has been developed. This approach circumvents the traditional attachment and removal of chiral auxiliaries used currently for this type of transformation. 

The proUne-derived diamidobinaphthyl dilithium salt S,S,S)-66, which is dimeric in the sohd state and can be prepared via deprotonation of the corresponding tetraamine with n-BuLi, represents the first example of a chiral main-group-metal-based catalyst for asymmetric intramolecular hydroamination reactions of aminoalkenes [241], The unique reactivity of (S,S,S)-66, (Fig. 17) which allowed reactions at or below ambient temperatures with product enantioselec-tivities of up to 85% ee (Table 17) [241, 243] is believed to derive from the close proximity of the two lithium centers chelated by the proline-derived substituents. More simple chiral lithium amides required significantly higher reaction temperatures and gave inferior selectivities. 

R,2S)-Ephedrine has found most application, e.g., as a catalyst in photochemical proton transfer reactions (Section D.2.1.). and as its lithium salt in enantioselective deprotonations (Section D.2.1.). The amino function readily forms chiral amides with carboxylic acids and enamines with carbonyl compounds these reagents perform stereoselective carbanionic reactions, such as Michael additions (Sections D.1.5.2.1. and D. 1.5.2.4.), and alkylations (Section D.1.1.1.3.1.). They have also been used to obtain chiral alkenes for [1 +2] cycloadditions (Section D. 1.6.1.5.). 

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