Regioselectivity and Stereoselectivity in Enolate Formation

An unsymmetrical dialkyl ketone can form two regioisomeric enolates on deprotonation  

In order to exploit fully the synthetic potential of enolate ions, control over the regioselectivity of their formation is required. While it may not be possible to direct deprotonation so as to form one enolate to the exclusion of the other, experimental conditions can often be chosen which will provide a substantial preference for the desired regioisomer. To understand the reason a particular set of experimental conditions leads to the preferential formation of one enolate whereas other conditions leads to the regioisomer, we need to examine the process of enolate generation in more detail. 

The composition of an enolate mixture may be governed by kinetic or thermodynamic factors. The enolate ratio is governed by kinetic control when the product composition is governed by the relative rates of the two competing proton abstraction reactions. 

One the other hand, if enolates A and B can be interconverted rapidly, equilibrium will be established and the product composition will reflect the relative thermodynamic stability of the enolates. The enolate ratio is then governed by thermodynamic control 

By adjusting the conditions under which an enolate mixture is formed from a ketone, it is possible to establish either kinetic or thermodynamic control. Ideal conditions for kinetic control of enolate formation are those in which deprotonation is rapid, quantitative, and irreversible, This ideal is approached experimentally by using a very strong base such as lithium diisopropylamide or hexamethyldisilylamide in an aprotic solvent in the absence of excess ketone. Lithium as the counterion is better than sodium or potassium for regioselective generation of the kinetic enolate. Aprotic solvents are required because protic solvents permit enolate equilibration by allowing reversible protonation-deprotonation, which gives rise to the thermodynamically controlled enolate composition. Excess ketone also catalyzes the equilibration. 

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Regioselectivity and Stereoselectivity in Enolate Formation from Ketones and Esters... 

The regio- and stereoselectivity of enolate formation are essential for the control of alkylation reactions. The regioselectivity of ketone deprotonation has been extensively investigated and this important step in alkylation reactions has been discussed in many reviews (e.g., refs 1-4, 71) and textbooks (e.g., refs 5, 6). Therefore, this topic will be discussed here only in general terms. 

The regio- and stereoselectivity of enolate formation has been discussed in many reviews . In general, the stereo- and regioselectivity of ketone deprotonation can be thermodynamically or kinetically controlled. Conditions for the kinetic control of enolate formation are achieved by slow addition of the ketone to an excess of strong base in an aprotic solvent at low temperature. In this case the deprotonation occurs directly, irreversibly and with high regioselectivity (equation 1). By using a proton donor (solvent or excess of ketone) or a weaker base, an equilibration between the enolates formed may... 

Scheme 7.26 Regioselective and stereoselective formation of oxetanes in the PB reactions of silyl enol ethers.

The reaction, if not controlled, can give a very complicated mixture of products due to reactivity, chemoselectivity, regioselectivity, and stereoselectivity issues. The synthesis of aldols with defined stereocenters in an efficient diastereo- and enantio-controlled fashion can be achieved with nature s aldolaze enzymes [2]. Their ability to control the enantioselectivity of the direct aldol reaction led chemists to the development of one of the most important C-C bond formation reactions. In the modem aldol reaction, a preformed enolate is added to a carbonyl compound even though the direct cross-aldol reaction is a more attractive approach [3]. 

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. ... 

A further improvement utilizes the compatibility of hindered lithium dialkylamides with TMSC1 at —78 °C. Deprotonation of ketones and esters with lithium dialkylamides in the presence of TMSC1 leads to enhanced selectivity (3) for the kinetically generated enolate. Lithium t-octyl-t-butyl-amide (4) appears to be superior to LDA for the regioselective generation of enolates and in the stereoselective formation of (E) enolates. 

On the other hand, lithium enolates derived from substituted endocyclic ketones have largely been exploited in the synthesis of steroids since the regioselectivity of their deprotonation can be controlled and high levels of 1,2- and 1,3-stereoselection occur9,418. The control is steric rather than electronic, with the attack directed to the less substituted ji-face of the enolate for conformationally rigid cyclopentanones, whereas stereoelectronic control becomes significant for the more flexible cyclohexanones. Finally, an asymmetric variant of the formation of a-branched ketones by hydration of camphor-derived alkynes followed by sequential alkylation with reactive alkyl halides of the resulting ketones was recently reported (Scheme 87)419. 

Kinetic enolates.2 The kinetic enolate of a ketone or ester is generated with enhanced selectivity by a lithium dialkylamide in the presence of chlorotrimethylsilane. In addition, LOBA is superior to LDA for regioselective generation of enolates and for stereoselective formation of (E)-enolates. 

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