Regioselectivity enolate formation

Step a. Regioselective enolate formation, directed toward the sterically less encumbered a -position. 

Matsuda, I., Okada, H., Sato, S., Izumi, Y. A regioselective enolate formation of trimethylsilylmethyl ketones. Application to the (E)-selective synthesis of a,P-unsaturated ketones. Tetrahedron Lett. 1984, 25, 3879-3882. 

Lithium 2,2,6,6-tetramethylpiperidide (LITMP) was introduced by Olofson and Dougherty in 1973. This base appears to be significantly more hindered than LDA, and is useful for regioselective enolate formation in cases where a very bulky base is desirable. " Another very hindered base is lithium t-butyl-t-octylamide, introduced by Corey and Gross."... 

A particular advantage of the Reformatsky reaction stems from the fact that the site of reaction is strictly determined by the halogen moiety. This feature can be advantageously used for regioselective enolate formations in polycarbonyl compounds which are difficult to achieve by proton abstraction methods. As a consequence, this transformation has seen a renaissance over recent decades and has found many elegant uses, particularly in intramolecular variants [23]. 

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). 

This means that the charge accelerated rearrangement does not only stereos-electively give rise to two sp3-centers, but additionally amounts to regioselective enolate formation. In other words, there is no need to take any precautions as far as selectivity is concerned the process directs itself... 

Scheme 3.63 Regioselective enolate formation via an efficient electrophile-initiated homoconjugate addition of acetate to cyclopropyl ketones.

In later applications of this concept, Birchs conditions were frequently replaced by the hydride donor L-selectride that also generates lithium enolates from enones. That, even in the case of cross-conjugated dienones, a regioselective enolate formation occurs based upon the different steric encumbrance at the termini of the carbon-carbon double bonds, has been demonstrated by formation and subsequent diastereoselective allylic alkylation of the lithium enolate 112 (Scheme 2.34) [128]. 

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

Scheme 1.1 shows data for the regioselectivity of enolate formation for several ketones under various reaction conditions. A consistent relationship is found in these and related data. Conditions of kinetic control usually favor formation of the less-substituted enolate, especially for methyl ketones. The main reason for this result is that removal of a less hindered hydrogen is faster, for steric reasons, than removal of a more hindered hydrogen. Steric factors in ketone deprotonation are accentuated by using bulky bases. The most widely used bases are LDA, LiHMDS, and NaHMDS. Still more hindered disilylamides such as hexaethyldisilylamide9 and bis-(dimethylphenylsilyl)amide10 may be useful for specific cases. 

Ketone imine anions can also be alkylated. The prediction of the regioselectivity of lithioenamine formation is somewhat more complex than for the case of kinetic ketone enolate formation. One of the complicating factors is that there are two imine stereoisomers, each of which can give rise to two regioisomeric imine anions. The isomers in which the nitrogen substituent R is syn to the double bond are the more stable.114... 

There are also procedures in which the enolate is generated quantitatively and allowed to react with a halogenating agent. Regioselectivity can then be controlled by the direction of enolate formation. Among the sources of halogen that have been used under these conditions are bromine,125 (V-chlorosuccinimide,126 trifluoromethanesul-fonyl chloride,127 and hexachloroethane.128... 

By means of in situ NMR spectroscopy combined with deuterium incorporation experiments, van Leeuwen has elucidated the mechanism of termination by protonolysis, showing that the fl-chelates are in equilibrium with their enolate form by a p-H elimination/hydride migration process (Scheme 7.19). The enolate intermediates are regioselectively protonated at the C2 carbon atom by either MeOH or H2O to give Pd-OMe or Pd-OH and keto terminated copolymer. The enolate formation has been reported to be rate determining in the chain transfer [19]. 

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. 

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. 

Another important contribution is to the regioselectivity of enolate formation from unsym-metrical ketones. As we established in chapter 13, ketones, particularly methyl ketones, form lithium enolates on the less substituted side. These compounds are excellent at aldol reactions even with enolisable aldehydes.15 An application of both thermodynamic and kinetic control is in the synthesis of the-gingerols, the flavouring principles of ginger, by Whiting.16... 

For example, 2-phenylcyclohexanone can be deprotonated regioselectively with LDA (Figure 13.11). This reaction is most successful at -78 °C in THF because the reaction is irreversible under these conditions as long as a small excess of LDA is employed. Hence, the reaction is kinetically controlled and proceeds via the most stable transition state. The standard transition state of all enolate formations from C,H acids with LDA is thought to be cyclic, six-membered, and preferentially in the chair conformation (A and B in Figure 13.11). To be as... 

Fig. 13.24. O-Phosphoryla-tion of a ketone enolate to afford an enol phosphonamide (see Figure 13.13, bottom row, regarding the regioselectivity of the enolate formation) ...

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