Enolates stereochemistry

Many enolates can exist as both E- and Z-isomers.11 The synthetic importance of LDA and HMDS deprotonation has led to studies of enolate stereochemistry under various conditions. In particular, the stereochemistry of some enolate reactions depends on whether the E- or Z-isomer is involved. Deprotonation of 2-pentanone was examined with LDA in THF, with and without HMPA. C(l) deprotonation is favored under both conditions, but the Z.E ratio for C(3) deprotonation is sensitive to the presence of HMPA.12 More Z-enolate is formed when HMPA is present. 

The requirement that an enolate have at least one bulky substituent restricts the types of compounds that give highly stereoselective aldol additions via the lithium enolate method. Furthermore, only the enolate formed by kinetic deprotonation is directly available. Whereas ketones with one tertiary alkyl substituent give mainly the Z-enolate, less highly substituted ketones usually give mixtures of E- and Z-enolates.7 (Review the data in Scheme 1.1.) Therefore efforts aimed at increasing the stereoselectivity of aldol additions have been directed at two facets of the problem (1) better control of enolate stereochemistry, and (2) enhancement of the degree of stereoselectivity in the addition step, which is discussed in Section 2.1.2.2. 

If HMPA is included in the solvent, the Z-enolate predominates.236,238 DMPU also favors the Z-enolate. The switch to the Z-enolate with HMPA or DMPU is attributed to a looser, perhaps acyclic TS being favored as the result of strong solvation of the lithium ion. The steric factors favoring the -TS are therefore diminished.239 These general principles of solvent control of enolate stereochemistry are applicable to other systems.240 For example, by changing the conditions for silyl ketene acetal formation, the diastereomeric compounds 17a and 17b can be converted to the same product with high diastereoselectivity.241... 

Scheme 8), which also control the enolate stereochemistry in amide systems. The influence of metal ion structure on the stereochemical outcome of the aldol process again underscores the importance of metal ligand effects in the enhancement of aldol stereoselection. 

Whereas deprotonation of cyclic ketones (4-7-member rings) can only lead to the (E)-(0)-enolate geometry, control of enolate stereochemistry of acyclic ketones with lithium amides is rather complicated and depends on the structure of the carbonyl compound, steric requirements of the base, and reaction conditions. 

In addition to regiochemistry, acyclic carbonyl compounds can produce two possible stereoisomeric enolates, E or Z, as shown above. Steric interactions determine the favored enolate stereochemistry. Under reversible conditions, Z enolates are more stable than E as they minimize steric interactions, especially if R is large. Z enolates are also usually favored under irreversible conditions in polar aprotic solvents like HMPA that complex cations well and break up ion pairing, effectively reducing the bulk around the oxygen anion. Under irreversible conditions in ether solvents, the E enolate is often favored because the steric size of the base/cation aggregate around the oxygen dominates, especially if R is smaller, as with esters. 

Figure 5. Stereoselection in cyclopropane formation as a function of enolate stereochemistry...

The stereoselection in the cyclization of each diastereomer was examined independently. The stereochemical outcome of the cyclization should be predictable based on our assumption regarding the relationship between enolate stereochemistry and cyclopropane stereochemistry, the principles of asymmetric, intermolecular alkylation of optically active amides (9-13) and the assumption that the mechanism of cyclopropane formation involves a straightforward back-side, %2 reaction. In the case of the major diastereomer, the natural tendency of the enolate to produce the cis-cyclopropane will oppose the facial preference for the alkylation of the chiral enolate. Consequently, poorer stereochemical control would be ejected in the ring closure. In the minor diastereomer these two farces are working in tandem, and high degrees of stereocontrol should result. 

The kinetic stereoselectivity of the aldol is a function of the enolate stereochemistry and its structure. One often reads the over-generalization that (Z)-enolates gives syn aldols and (E)-enolates give anti al-dols. However, the situation is much more complex than this in addition to enolate geometry, several variables are involved. The following generalizations may be made at this time (refer to equation 37 for definition of R , R- and R ). 

Another important version of the aldol reaction involves the use of boron enolates.A cyclic TS similar to that for lithium enolates is involved and the same relationship exists between enolate geometry and product stereochemistry. In general, the stereoselectivity is higher than for lithium enolates. The O—B bond distances are shorter than those in lithium enolates, and this leads to a more compact TS and magnifies the steric interactions that control facial stereoselectivity. As with lithium enolates, the enolate stereochemistry controls diastereoselectivity. 

These general principles of solvent control of enolate stereochemistry are applicable to other systems. ... 

Aldol Product Stereochemistry Depends on Enolate Stereochemistry FORMATION OF ( ) AND (Z) ENOLATES... 

However, less highly substituted ketones usually give mixtures of E- and Z-enolates. Therefore, efforts aimed at expanding the scope of stereoselective aldol condensations have been directed at two facets of the problem (1) control of enolate stereochemistry and (2) enhancement of the degree of stereoselectivity in the addition step. 

Enolate Stereochemistry. Stereochemical control of an ester enolate Claisen rearrangement was accomplished through stereoselective enolate formation. The enolization of 3-pentanone with LDA afforded predominantly the ( )-enolate in THF and the (Z)-enolate in THF-HMPA, as shown by chlorotrialkylsilane trapping experiments (eq 8). Similar stereoselectivity (Z = 94 6) was obtained with the dipolar aprotic cosolvent DMPU. ... 

Control of Regioselectivity and Stereoselectivity. The recognition by Ireland and co-workers that Hexamethylphosphoric Triamide has a profound effect on the stereochemistry of lithium enolates has led to the examination of the effects of other additives, as the ability to control enolate stereochemistry is of utmost importance for the stereochemical outcome of aldol reactions. Kinetic deprotonation of 3-pentanone with Lithium 2,2,6,6-Tetramethylpiperidide at 0 C in THF containing varying amounts of HMPA or TMEDA was found to give predominantly the (Z)-enolate at a base ketone additive ratio of ca. 1 1 1, whereas with a base.ketone.additive ratio 1 0.25 1, formation of the ( )-enolate was favored (Table I). This remarkable result contrasts with those cases where HMPA base ratios were varied towards larger amounts of HMPA, which favored formation of the (Z)-enolate. ... 

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