Enolates, lithium salts, aldol

Enolates, lithium salts, aldol condensation with, 54, 49 Enol esters, preparation, 52,... 

Stereoselectivities of 99% are also obtained by Mukaiyama type aldol reactions (cf. p. 58) of the titanium enolate of Masamune s chired a-silyloxy ketone with aldehydes. An excess of titanium reagent (s 2 mol) must be used to prevent interference by the lithium salt formed, when the titanium enolate is generated via the lithium enolate (C. Siegel, 1989). The mechanism and the stereochemistry are the same as with the boron enolate. 

When an enolate is forced to take the E configuration, e.g, the enolate derived from cyclohexanone, predominant formation of the anti-aldol might be expected. Surprisingly, early experiments gave more or less stereorandom results in that the reaction with benzaldehyde gave a ratio of. vvtt/ant/ -aldols of 48 521B 23, Contrarily, recent investigations24 reveal a substantial anti selectivity (16 84), which is lowered in a dramatic manner (50 50) by the presence of lithium salts. Thus, the low stereoselectivity in the early experiments may be attributed to impurities of lithium salts or lithium hydroxide. 

Other fates are possible for the enolate formed in the initial conjugate addition and an obvious possibility is an aldol reaction. With an asymmetric catalyst, the combination of three simple molecules leads to one enantiomer of one diastereoisomer of the tandem Michael-aldol product14 83. The catalyst 84 is based on a BINOL A1 complex (see chapters 25, 26). It can be drawn either as a lithium salt with an aluminium cation or, better, as a lithium aryloxide with a Lewis-acidic aluminium atom. This is better because both basic ArCT and Lewis acidity are necessary for catalysis. 

Lithium acetate (LiOAc)-catalyzed aldol reactions between trimethylsilyl enolates and aldehydes proceed smoothly in anhydrous DMF or pyridine to afford corresponding aldols in good to excellent yields under weakly basic conditions (Scheme 20) (120,121). Obviously, it was further evidence that water could accelerate the aldol reaction of ketene silyl acetals with carbonyl compounds (120). Other lithium salts, for example, lithium pyrrolidone, was also an effective catalyst in the aldol reaction between trimethylsilyl enolates and aldehydes (123). 

A total synthesis of ( )-aromatin has utilized the lithium anion of the dithiane of (E)-2-methyl-2-butenal as a functional equivalent of the thermodynamic enolate of methyl ethyl ketone in an aprotic Michael addition (Scheme 189) (81JOC825). Reaction of the lithium anion (805) with 2-methyl-2-cyclopentenone followed by alkylation of the ketone enolate as its copper salt with allyl bromide delivered (807). Ozonolysis afforded a tricarbonyl which cyclized with alkali to the aldol product (808). Additional steps utilizing conventional chemistry converted (808) into ( )-aromatin (809). 

Aldol reactions with lithium enolates are improved if zinc (II) salts are present, or, if silyl enol ethers are used, TiCl4 is also helpful. We have chosen the example of Me2CuLi addition to the enone 57 as the examples in the literature23 are overwhelmingly of cyclic enones, and we wanted an acyclic example. The aldols (mixed diastereoisomers) 59 are formed in 96% yield.25... 

It is not clear whether enolization is avoided under the lithium-free, high-concentration conditions, or whether it occurs reversibly enough to permit eventual conversion of the ketone to the alkene. However, the most successful procedures involve alkoxide bases (159, 168-170) or require the presence of excess phosphonium salt (171). Proton exchange and reversible enolate formation are likely under these conditions, and aldol condensation pathways would also be reversible when potassium or sodium bases are used. Thus, excellent yields of alkenes are possible with the most hindered substrates, provided that other pathways for irreversible enolate decomposition are not available. 

After pioneering work on the Lewis base-catalysed Mukaiyama aldol reaction, Mukaiyama-Michael reaction, and Mukaiyama-Mannich-type reaction with the use of lithium acetate, Mukaiyama also demonstrated the same reactions using simple sodium salts (Scheme 2.28). For example, a catalytic Mukaiyama aldol reaction between benzaldehyde and trimethylsilyl enolate using sodium methoxide in DMF proceeded smoothly under mild conditions. Moreover, the Mukaiyama-Michael reaction between chalcone and trimethylsilyl enolates using sodium acetate in DMF provided the desired Michael adduct as the major product in 92% yield along with the 1,2-adduct in 8% yield. ... 

In order to improve the stereoselectivity of the aldol process even further, metal salts of enolate anions other than those bearing lithium have been examined. For example, both magnesium and boron enolates have been prepared. Magnesium enolates are very much like lithium enolates in their stereoselectivity, while boron enolates, where there are relatively short metal-oxygen bonds, give improved selectivity. For the boron enolates, the (Z)-enolate is generally more stable than its E)-isomer, and erythro- or 5yn-products are developed. 

Further selected examples of diastereoselective aldol reactions between lithium enolates and chiral aldehydes are given in Eqs. (42) [171], (43) [172], and (44) [173]. In the last example, the salt-free generation of the lithium enolate was occasionally found to be crucial to stereoselectivity [174]. 

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