Ketone lithium enolates regioselective deprotonation

A new method of kinetically controlled generation of the more substituted enolate from an unsymmetrical ketone involves precomplexation of the ketone with aluminium tris(2,6-diphenylphenoxide) (ATPH) at —78°C in toluene, followed by deprotonation with diisopropylamide (LDA) highly regioselective alkylations can then be performed.22 ATPH has also been used, through complexation, as a carbonyl protector of y./)-unsaturated carbonyl substrates during regioselective Michael addition of lithium enolates (including dianions of /i-di carbonyl compounds).23... 

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. 

With ketones we come to the problem of regioselectivity, and the situation from chapter 3 is that methyl ketones 98 and ketones with one primary and one secondary alkyl group, particularly cyclic ketones such as 103 give the less substituted lithium enolate 97 or 102 by kinetically controlled deprotonation with LDA, and the more substituted silyl enol ether 99 or 104 on silylation under equilibrium conditions. Either derivative (lithium enolate or silyl enol ether) may be used to make the other, e.g. 96 and 100. 

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 triphenylmethyllithium 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. Protic solvents promote enolate equilibration by allowing protonation-deprotonation pathways to operate on the isomeric enolates. Excess ketone seems to catalyze equilibration in much the same way by acting as a proton source. 

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. 

Kinetic control can be achieved by slow addition of the ketone to an excess of strong base in an aprotic solvent. Kinetic control requires a rapid, quantitative and irreversible deprotonation reaction 2-6. The use of a very strong, sterically hindered base, such as lithium diisopropylamide or triphenylmethyllithium (trityllithium), at low temperature (— 78 °C) in an aprotic solvent in the absence of excess ketone has become a general tool for kinetic control in selective enolate formation. It is important to note that the nature of the counterion is sometimes important for the regioselectivity. Thus, lithium is usually better than sodium and potassium for the selective generation of enolates by kinetic control. 

A number of bases may be used for deprotonation, but the most important ones are lithium amide bases such as those illustrated in Figure 3.3. Although other alkali metals may be used with these amides, lithium is the most common. Amide bases efficiently deprotonate virtually all ctirbonyl compounds, and do so regioselectively with cyclic ketones such as 2-methylcyclohexanone i.e., C2 vs. C6 deprotonation) and stereoselectively with acyclic carbonyls (i.e., E(O)- vs. Z(O)- enolates. If the carbonyl is added to a solution of the lithium amide, deprotonations are irreversible and kinetically controlled [36-38]. Under such conditions, the con-... 

Regioselective enolate formation using kinetic deprotonation of an unsymmetri-cal ketone has been discussed in Section 1.1.1. The specihc enolate can react with aldehydes to give the aldol product, initially formed as the metal chelate in aprotic solvents such as THF or EtiO. Thus, 2-pentanone, on deprotonation with lithium diisopropylamide (LDA) and reaction of the enolate with butanal, gave the aldol product 44 in reasonable yield (1.56). 

Modified Amine Base. The regioselectivity of ketone deprotonation was improved by the use of lithium t-butyldimethylsilyl-amide as base. The base was prepared by deprotonation of isopropylamine with n-BuLi in THF (eq 22). The resulting anion was quenched with TBDMSCl to give the amine in 70% yield after distillation. Deprotonation of various ketones using this amide base was found to be equally or more selective than LDA. For example, the TBDMS-modified base gave a 62 38 ratio of kinetic to thermodynamic enolate, whereas LDA gave a 34 66 ratio with phenyl acetone. 

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