Chiral lithium amides stereoselective

C—H insertion reaction occurs in a stereoselective manner. Various attempts based on chiral lithium amide bases gave only moderate enantioselectivities. More efficiently, the reaction is carried out by means of s-butyl- or wo-propy 1-lithium in the presence of (—)-sparteine under these conditions, the bicyclic alcohol 92 was obtained in 74% yield and 83% ee. This concept has been extended to various meio-epoxides, an example of which is shown in equation 52. ... 

Stereoselectivity in dearomatising cyclisations may be controlled by a number of factors, including rotational restriction in the organolithium intermediates202 203 and coordination to an exocyclic chiral auxiliary.197 Most usefully, by employing a chiral lithium amide base, it is possible to lithiate 441 enantioselectively (see section 5.4 for similar reactions) and promote a cyclisation to 442 with >80% ee.204... 

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. 

So far, chiral lithium amides for asymmetric deprotonation have found use only with a few types of substrates. The following sections deal with deprotonation of epoxides to yield chiral allylic alcohols in high enantiomeric excess, deprotonation of ketones, deprotonation of tricarbonylchromium arene complexes and miscellaneous stereoselective deprotonations. These sections are followed by sections in which various chiral lithium amides used in stereoselective deprotonations have been collected and various epoxides that have been stereoselectively deprotonated. The review ends with a summary of useful synthetic methods for chiral lithium amide precursors. 

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). 

Asymmetric rearrangement of cyclohexene oxide. Cyclohexene oxide is rearranged to (S)-2-cyclohexene-l-ol in 92% ee by the chiral lithium amide (2) prepared from n-butyllithium and 1. Several related (S)-2-(disubstituted aminomethyOpyrrolidines prepared from (S)-proline are almost as stereoselective. ... 

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During the last decades, a number of chiral lithium amides have been developed for stereoselective deprotonation of, e.g., epoxides. For example, the lithium amide lithium (5 )-2-(pyrrolidin-l-yl-methyl)pyrroli-dide (4) was for a long time the most stereoselective base used in epoxide deprotonations. It gives 90% of the (5 )-enantiomer and 10% of the (/ )-enantiomer upon deprotonation of cyclohexene oxide 2 in THF solution (Scheme 2) [4-6]. 

Until recently, progress in the field of stereoselective deprotonations had been achieved by trial and error since detailed knowledge about the nature of reagents and activated complexes was lacking. The structure of the chiral lithium amide was modified in the hope of achieving improved stereoselectivity and occasionally an increased stereoselectivity was obtained [7-13], The development has been governed by the need for reactive lithium amides yielding stereoselectivities of close to 100%. 

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. 

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The developed model for the deprotonation activated complexes described above has been used as a starting point for structural modification of the lithium amide in order to increase the energy difference between the diastereomeric-activated complexes and thus the stereoselectivity. Computational chemistry has been used to predict the stereoselectivity with modified chiral lithium amides. Some of these designed novel lithium amides have been synthesized and investigated experimentally with respect to their stereoselectivity. One of these is the lithium amide 5 (shown in Scheme 8 as monomer 5a) which, like the previously discussed lithium amides, appear to be a dimer (5b or 5c) in THF solution as shown by multinuclear NMR spectroscopy and computational chemistry [19,38]. 

Amide 5 appears to be slightly less reactive than 4 in the deprotonation of 2 but as predicted the stereoselectivity was improved. The enantiomer composition of the deprotonation product was now 96.5% (5)-alcohol and 3.5% (R)-alcohol [19,22]. However, a kinetic investigation revealed that the composition of the activated complexes was different from that assumed in the theoretical model. The reaction orders showed that an activated complex is built from one molecule of chiral lithium amide dimer and one molecule of epoxide 2. Such activated complexes have been computationally modelled by the use of PM3 and optimized structures are displayed in Fig. 5 [19]. 

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. 

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. 

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]. 

As an alternative to the use of auxiliaries for the asymmetric alkylation of carboxylic acid derivatives, in 2011, Zakarian and Stivala reported on the direct stereoselective alkylation of arylacetic acids with chiral lithium amide bases.This method offers an alternative to traditional auxiliary-based methods and operates through the formation of enediolates also, it builds on earlier work by Shioiri and Ando and by Koga and Matsuo . Zakarian and Stivala examined several C2-symmetric tetramines for their enan-tiodirecting power. After significant experimentation, conditions were established that used 4 equivalents of -BuLi and a slight excess of the tetramine that provided clean formation of the desired product. The enantioselectivity was found to be dependent on the quality of the -butyllithium. The reaction scope was examined with a variety of... 

The lithium derivative of the chiral chelating diamine (3 )-2-(l-pyrrolidinylmethyl)-pyrrolidine (6) has been used extensively in stereoselective synthesis, i.e. in the deprotonation of ketones and rearrangement of epoxides to homoallylic alcohols. The lithium amide has been crystallized from toluene solution, and X-ray analysis revealed that it forms a ladder-type tetramer with the two pyrrolidine nitrogens solvating the two lithiums at the end of the ladder38, (Li-6)4. 

The Birch reduction has been applied to electron-deficient pyrroles substituted with a chiral auxiliary at the C(2)-position <1999TL435>. Using either (—)-8-phenylmenthol or (- -)-/ra /-2-(ot-cumyl)cyclohexanol as auxiliaries, high levels of stereoselectivity were obtained. Pyrrole 911, prepared from the l/7-pyrrole-2-carboxylic acid 910 in 90% yield, was reduced under modified Birch conditions (Scheme 176). The best conditions involved lithium metal (3 equiv), liquid ammonia and THE at —78°C. The addition of A, A -bis(2-methoxyethyl)amine (10 equiv) helped to reduce side reactions caused by the lithium amide formed in the reaction <1998TL3075>. After 15 min, the Birch reductions were quenched with a range of electrophiles and in each case 3,4-dehydroproline derivatives 912 were formed in excellent yields and with good diastereoselectivities. 

Asynunetric Deprotonation/Protonation of Ketones. Lithium amides of chiral amines have been used for performing asymmetric deprotonations of symmetrically substituted (prochiral) ketones. The resulting optically active enols orenol derivatives (most frequently enol silanes) are highly versatile synthetic intermediates. Particularly useful for this purpose are chiral amines possessing Cj symmetry, such as (1). For example, reaction of 4-r-butylcyclohexanone with the lithium amide of (R,R)-(1) (readily prepared in situ by treatment of (1) with n-Butyllithium) is highly stereoselective the resulting enol silyl ether possesses an 88% ee (eq 4). ... 

Other Enantioselective Reactions. Enantioselective epoxide elimination by chiral bases has been demonstrated. More recently, the enantioselective [2,3]-Wittig rearrangement of a 13-membered propargylic ally lie ether has been performed using the lithium amide of (f ,f )-(l) as the base for deprotonation (eq 15). For this particular substrate, THF is a better solvent than ether, although pentane produces better results in a related transformation (eq 16). In fact, a change in solvent in this type of reaction has been shown to lead to a reversal of the stereoselectivity of the transformation. ... 

Sodium amide, o LDA, l.illMI)S. " NaHMDS, KHMDS, ° sodium and magnesium methoxide or ethoxide, and DBU are less frequently used. The nature of the cation present in the Homer-Wadsworth-Emmons reaction depends on the chosen base and greatly influences the stereoselectivity of the reaction. The chiral lithium 2-aminoalkoxides (17 ,2S) have been used as chiral bases for the enantioselective reaction between diethyl cyanomethylphosphonate and 4-terz-butylcyclohexanone." ... 

Lithium enolates of propionamides of chiral amines undergo stereoselective 1,4-addition reactions to a,P-unsaturaled esters. The highest selectivities are obtained with C2-symmetric amides derived from 1.65 (R = CH OCH QMie) bearing a substituent that is capable of metal chelation (Figure 7.61). After hydrolysis, diacid 7.95 is obtained with a good selectivity [161]. Some nonracemic natural... 

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