Aldol reaction of lithium enolates

Table 4. Directed Aldol Reaction of Lithium Enolate of l-Fluoro-3,3-dimethylbutanone [7]...

The diastereoselectivity of this reaction contrasts dramatically with the generally low selectiv-ities observed for aldol reactions of lithium enolates of iron acyls. It has been suggested thal this enolate exists as a chelated species48 the major diastereomer produced is consistent with the transition state E which embodies the usual antiperiplanar enolate geometry. 

Aldol Reactions of Lithium Enolates. Entries 1 to 4 in Scheme 2.1 represent cases in which the nucleophilic component is a lithium enolate formed by kinetically controlled deprotonation, as discussed in Section 1.1. Lithium enolates are usually highly reactive toward aldehydes and addition occurs rapidly when the aldehyde is added, even at low temperature. The low temperature ensures kinetic control and enhances selectivity. When the addition step is complete, the reaction is stopped by neutralization and the product is isolated. 

The mechanism obviously involves attack by the enol (or boron enolate ) of the ketone on the anhydride, catalysed hy the Lewis acid. Prohahly the boron atom holds the reagents together, much as the lithium atom does in aldol reactions of lithium enolates (p. 625). 

The coupling of 96 with 77 was followed by the epoxidation to give 98. Aldol reaction of lithium enolate of ethyl acetate was conducted by the remote chelation effect with the C7-oxygen atom as well as by a steric bulkiness of the Cg-methyl group at the transition state. As a result of this unexpected bonus, the product 99 was stereochemically pure at the C3 position. The operation to... 

From these and many related examples the following generalizations can be made about kinetic stereoselection in aldol additions of lithium enolates. (1) The chair TS model provides a basis for analyzing the stereoselectivity observed in aldol reactions of ketone enolates having one bulky substituent. The preference is Z-enolate syn aldol /(-enolate anti aldol. (2) When the enolate has no bulky substituent, stereoselectivity is low. (3) Z-Enolates are more stereoselective than /(-enolates. Table 2.1 gives some illustrative data. 

Aldol Reactions of Boron Enolates. The matter of increasing stereoselectivity in the addition step can be addressed by using other reactants. One important version of the aldol reaction involves the use of boron enolates.15 A cyclic TS similar to that for lithium enolates is involved, and the same relationship exists between enolate configuration and product stereochemistry. In general, the stereoselectivity is higher than for lithium enolates. The O-B bond distances are shorter than for lithium enolates, and this leads to a more compact structure for the TS and magnifies the steric interactions that control stereoselectivity. 

Zirconium enolates can also prepared by reaction of lithium enolates with (Cp)2ZrCl2, and they act as nucleophiles in aldol addition reactions.34... 

Murai and coworkers reported on operationally simple aldol reactions with lithium enolates generated from carbonylation of silylmethyl lithium species [57]. Upon 1,2-silicon shift, a-silyl acyllithium species can be stereo-selectively converted to (E) lithium enolates that undergo addition to aldehydes to give /3-hydroxy acylsilanes (Scheme 14). 

Aldol reactions of magnesium enolates are frequently more diastereoselective than the corresponding reactions of lithium enolates. The aldol condensation proceeds via a cyclic transition state in agreement with the Zimmerman-Traxler chelated model . 

Highly stereoselective aldol reactions of lithium ester enolates (LiCR1 R2CC>2R3) with (/0-2-(/ -tolylsulfiny I (cyclohexanone have been attributed to intermediacy of tricoordinate lithium species which involve the enolate and the sulfinyl and carbonyl oxygens of the substrates.43 The O-metallated /<-hydroxyalkanoatcs formed by aldol-type reaction of carbonyl compounds with enolates derived from esters of alkanoic acids undergo spontaneous intramolecular cyclization to /1-lactones if phenyl rather than alkyl esters are used the reaction has also been found to occur with other activated derivatives of carboxylic acids.44... 

This procedure illustrates a general method for the preparation of crossed aldols. The aldol reaction between various silyl enol ethers and carbonyl compounds proceeds smoothly according to the same procedure (see Table I). Sllyl enol ethers react with aldehydes at -78°C, and with ketones near 0°C. Note that the aldol reaction of sllyl enol ethers with ketones affords good yields of crossed aldols which are generally difficult to prepare using lithium or boron enolates. Lewis acids such as tin tetrachloride and boron trifluoride etherate also promote the reaction however, titanium tetrachloride is generally the most effective catalyst. 

Aldol-type reactions.1 Reaction of lithium enolates with SEM chloride results in a-hydroxymethyl ketones protected as the P-trimethylsilylethyl ethers, which can undergo deprotection with Bu4NF or TFA. Yields are in the range of 55-80%. 

Aldol reactions of boron enolates are frequently more diastereoselective than aldol reactions of, for example, lithium or aluminium enolates. This is partly ascribed to the relatively short boron-oxygen bond length (B-O = 1.36-1.47 A, Li-0 = 1.92-2.00 A, Al-0 = 1.92 A) which exacerbates the unfavourable 1,3-diaxial interactions that occur between the boron substituent... 

Zirconium enolates are prepared by the reaction of lithium enolates with Cp2ZrCl2. Aldol reactions mediated by zirconium enolates are characterized by high syn selectivity and good yields as a result of stereo control of the ligands on the metal (Eq. 1) [2]. Even at -78 °C zirconium enolates are reactive in addition to aldehydes because of the high Lewis acidity of the metal. The reaction of (Z)-enolates with aldehydes proceeds via chair-like conformation the conformation is boat-like for (E)-eno-lates [2a]. Thus both ( )- and (Z)-enolates (2) prepared from ketone 1 give predominantly syn aldols syn- i. 

Other examples The addition reaction of lithium enolates of ketones to 1,2-epoxides to afford the a-alkyl-y-hydroxyketones. (a) P. Crotti, V. D. Bussolo, L. Favero, M. Pineschi, M. Pasero, J. Org. Chem. 1996, 61, 9548-9552. The cross-aldol reactions between ketones and aldehydes, (b) S. Fuku-zawa, T. Tsuchimoto, T. Kanai, Bull. Chem. Soc. Jpn. 1994, 67, 2227-2232. 

Although boron enolates are usually more stereoselective in aldol reactions than lithium enolates, the latter are more readily prepared (e.g., using LDA). To obtain synthetically useful levels of aldol stereoselectivities with lithium enolates, the (E)-(O)- and (Z)-(0)-enolates must be available with high selectivity (> 95 5), and the non-enolized carbonyl group Rmust be large (Table 6.3). ... 

Aldol reactions of lithium (Z)-((9)-enolates derived from a-trimethylsilyloxy ketones with aldehydes provide, depending on the workup conditions, either (3-hydroxy aldehydes, 3-hydroxy acids or (3-hydroxy ketones with high levels of 2,3-syn selectivity. 

Bodnar, P. M., Shaw, J. T., Woerpel, K. A. Tandem Aldol-Tishchenko Reactions of Lithium Enolates A Highly Stereoselective Method for Diol and Triol Synthesis. J. Org. them. 1997, 62, 5674-5675. 

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... 

Now the two parts, 184 and 199, must be linked in a controlled aldol reaction. The lithium enolate 200 reacts with the aldehyde in 199 in the presence of excess Lewis acid Me2AICI to give one diastereoisomer of 201 as the only product. Presumably the aluminium coordinates the tertiary amide and aldehyde oxygen atoms to hold the aldehyde in one Felkin conformation while it is attacked by the lithium enolate from one face only as sketched in 202. 

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