Lithium enolates enantioselective aldol reaction

Asymmetric Aldol Reactions. Lithium enolates, derived from an ester, and LDA react with aldehydes enantioselectively in the presence of the chiral amide 2 (eq 3). When benzaldehyde is employed, the major diastereomer is the anrt-aldol with 94% ee, while the minor yn-aldol is only 43% ee. In this reaction, the lithium amide 2 coordinates to an additional lithium atom. There are four additional examples of aldehydes with the same ester enolate. 

Covalently bonded chiral auxiliaries readily induce high stereoselectivity for propionate enolates, while the case of acetate enolates has proved to be difficult. Alkylation of carbonyl compound with a novel cyclopentadienyl titanium carbohydrate complex has been found to give high stereoselectivity,44 and a variety of ft-hydroxyl carboxylic acids are accessible with 90-95% optical yields. This compound was also tested in enantioselective aldol reactions. Transmetalation of the relatively stable lithium enolate of t-butyl acetate with chloro(cyclopentadienyl)-bis(l,2 5,6-di-<9-isopropylidene-a-D-glucofuranose-3-0-yl)titanate provided the titanium enolate 66. Reaction of 66 with aldehydes gave -hydroxy esters in high ee (Scheme 3-23). 

The approach for the enantioselective aldol reaction based on oxazolidinones like 22 and 23 is called Evans asymmetric aldol reaction.14 Conversion of an oxazolidinone amide into the corresponding lithium or boron enolates yields the Z-stereoisomers exclusively. Reaction of the Z-enolate 24 and the carbonyl compound 6 proceeds via the cyclic transition state 25, in which the oxazolidinone carbonyl oxygen and both ring oxygens have an anti conformation because of dipole interactions. The back of the enolate is shielded by the benzyl group thus the aldehyde forms the six-membered transition state 25 by approaching from the front with the larger carbonyl substituent in pseudoequatorial position. The... 

Enantioselective aldol reaction -hydroxy esters.2 The lithium enolate 4 of t-butyl acetate reacts with an aldehyde in the presence of 2 to form P-hydroxy esters 6 in 90-96% ee. 

The most smdied O-bonded transition metal enolates are titanium enolates . The reason for their success has beeu recognized in the fact that titanium enolates show an enhanced stereochemical control in C—C bond-forming reactions over simple lithium enolates and the possibility of incorporating chiral ligands at the titanium centre, a possibility which has lead to enantioselective aldol reactions with excellent enantiomeric excess. Moreover, titanium euolates have been used in oxidation reactions with remarkable diastereoselectivity. 

Enantioselective Aldol Reactions. The use of 1 for generating two contiguous stereocenters via an asymmetric aldol condensation has also been investigated,but only with marginal success. For example, reaction of the lithium enolate derived from tert-butyl propionate with the /Y-lithio derivative of 1, followed by condensation with benzaldehyde, provided a mixture of anti and syn aldol products in poor-to-modest % ee (eq 8). 

The aldol reactions of titanium enolates have been the best studied of all the transition metal enol-ates."- In many cases they show higher stereoselectivity and chemoselectivity in their reactions than lithium enolates and are easily prepared using inexpensive reagents. They also promote high levels of diastereofacial selectivity in reactions of chiral reactants. The Lewis acidity of the titanium metal center can be easily manipulated by variation of the ligands (chloro, alkoxy, amino, cyclopentadienyl, etc.) attached to titanium, which leads to enhanced selectivity in appropriate cases. Moreover, the incorporation of chiral ligands on titanium makes possible efficient enantioselective aldol reactions. 

An important development is the use of D-glucose-derived alkoxy ligands on titanium in cyciopentadi-enyldi(alkoxy)titanium enolates, which undergo efficient enantioselective aldol reactions with aldehydes. The chiral titanium reagent (30), prepared from reaction of cyclopentadienyltitanium trichloride with two equivalents of (l,2 5,6)-di-0-isopropylidene-a-D-glucofuranose, can be used to transmetal late the lithium enolate of t-butyl acetate in ether solution (equation 10). The titanium enolate generated is then... 

Enantioselective additions of lithium enolates to aldehydes forming aldols ( 3-hydroxyaldehydes) are synthetically well established and have been reviewed elsewhere [20]. A catalytic variant, the Mukaiyma aldol reaction, i.e., the addition of silyl enol ethers to aldehydes, is usually mediated by chiral Lewis acids [21,22]. 

Scheme 2.8 Enantioselective aldol reaction of aldehydes with trimethoxysilyl enol ethers with the use of chiral lithium(i) binaphtholate.

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). 

Evans type aldolizations using boron or lithium enolates are mechanistically different. Although both reactions lead predominantly to 2,3-syrc-aldols, the enantioselectivities are inverted i.e. whereas in our original strategy (5)-oxazolidinones lead to the desired 2(5), 3(5) aldols, the same result via lithium enolates requires switching to (R)-oxazolidinones. This change of selectivity has been explained by differing... 

A particularly attractive version of this reaction relies on the action of a catalytic chiral lithium binaphtholate and an excess of water on trimethoxysilylenol ether119. The tetralone enolate thus generated was directly employed in an aldol reaction, which turned out to be poorly diastereoselective but highly enantioselective for both diastereomers (Scheme 27). 

In contrast, reaction of diethyl propionylphosphonate with lithium bis-(trimethylsilyl)amide (LiHMDS) at -78 °C gave the expected enolate as evidenced by its highly diastereoselective condensation with benzaldehyde, leading to the formation of 3-hydroxy-2-methyl-3-phenylpropionic acid (equation 91) " . An attempt was made to develop this concept to enantioselective aldol condensation. However, condensation of a cyclic chiral propionylphosphonamidate (31), synthesized from ( S)-A-isopropyl-4-aminobutan-2-ol, with benzaldehyde yielded 3-hydroxy-2-methyl-3-phenylpropionic acid in disappointingly low 47% e.e. (equation 92)... 

Enolates Revisited-Solution Structure. Although proven to be a ubiquitous base in organic s)mthesis, little was known about the structure of LDA until recently.With increased importance in the enantioselectivity and stereoselectivity of aldol reactions, much of the research within the past decade has surrounded a more complete understanding of how lithium amide bases coordinate to enolate ions in solution, and what role does this play in determining the reactivity. 

A variety of other chiral lithium amides, for example 106 and 108, have been applied more recently to bring about enantioselective aldol additions. As sho vn in Eqs. (48) [179] and (49) [180], both simple diastereoselectivity and induced stereroselectivity can be induced by these reagents. In the latter reaction, the enolate itself becomes chiral, because of desymmetrization of ketone 107 on deprotonation. 

Shortly thereafter, acetate aldol reactions using camphor-derived imidazo-lidinone 27 vere reported by Palomo and co vorkers [15]. They reported moderate yields and enantioselectivity for a variety of unsaturated and aliphatic aldehydes (Table 2.4, entries 8-12). Interestingly, enantioselectivity for unsaturated aldehydes vas opposite that for aliphatic aldehydes. Also, enantioselectivity reported for titanium vas completely opposite that of the corresponding lithium enolate reactions. 

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