Kinetics enolate formation

Alkylation of enamines requires relatively reactive alkylating agents for good results. Methyl iodide, allyl and benzyl halides, a-halo esters, a-halo ethers, and a-halo ketones are the most successful alkylating agents. The use of enamines for selective alkylation has largely been supplanted by the methods for kinetic enolate formation described in Section 1.2. 

The conjugate addition of unstabilized enolates to various acceptors was conceptually recognized by early researchers however, complications were encountered depending on the enolates and acceptors employed. Reexamination of this strategy was made possible by the development of techniques for kinetic enolate formation. This discussion is divided into three enolate classes (a) aldehyde and ketone enolates, azaenolates or equivalents, (b) ester and amide enolates, dithioenolates and dienolates and (c) a,0-carboxylic dianions and a-nitrile anions, in order to emphasize the differential reactivity of various enolates with various acceptors."7 The a-nitrile anions are included because of their equivalence to the hypothetical a-carboxylic acid anion. 

The effect of the steric and electronic nature of lithium amide bases (71-74) on highly stereoselective kinetic enolate formation from six ketones (70a-f) in THF has been investigated. The results in general can be rationalized with respect to the cyclic... 

Further selectivity is needed if the enol component is an unsymmetrical ketone. Some selectivity can be achieved by choice of acid, favouring the more substituted enol, or base, favouring kinetic enolate formation on the less substituted side. The acid 32 was used at a very early stage of Woodward and Eschenmoser s synthesis5 of vitamin Bi2. Standard a -unsaturated carbonyl disconnection revealed unsymmetrical ketone 33 and unenolisable but very electrophilic glyoxylic acid 34 available as its hydrate. In acid solution reaction occurred very selectively indeed. 

There must never be more ketone in the mixture than base, or exchange of protons between ketone and enolate will leed to equilibration. Kinetic enolate formations with LDA muat be done by adding the ketone to the LDA so that there Is excess LDA present throughout the reaction. 

In general, this effect is sufficient to allow selective kinetic deprotonation of methyl ketones, that is, where the distinction is between Me and alkyl. In this example, unusually, MeLi is used as a base LDA was probably tried but perhaps gave poorer selectivity. The first choice for getting kinetic enolate formation should always be LDA. 

Kinetic enolate formation must occur at the methyl group of the ketohe followed by acylation with the lactone. Lactones are rather more electrophilic than noncyclic esters, but the control in this sequence is still remarkable, Notice how a stable enolate is formed by proton transfer within the first-fofmed product. 

The most important method6 for the regioselective synthesis of less substituted enolates is kinetic enolate formation with strong irreversible bases (LDA etc). Since the lithium enolate7 20 can be converted into the silyl enol ether8 21 directly without isolation, we have access to the two most valuable specific enol equivalents for the less substituted isomer. Alkylation of the lithium enolate of 23 goes more than 99% on the less substituted side.9... 

The Diels-Alder was successful20 129 but now the methyl group in the SW comer needs to be added by conjugate addition and that requires an enone. Oxidation of the silyl enol ether 130, prepared by kinetic enolate formation with LDA, with catalytic Pd(OAc)2 and benzoquinone as the stoichiometric oxidant gave the required enone 131 in 57% yield. Addition of Me2CuLi was stereoselective to give 132 and the synthesis of mevinolin completed. 

The Stork-Oanheiser alkylation of 3-alkoxy-2-cyclohexenones under conditions of kinetic enolate formation at the 6-position has enjoyed extensive application in alicyclic synthesis. Such kinetic enolates have... 

The last two ketones have two different a-positions so there is a good chance of controlling enol formation from the parent ketone. But the first ketone has two primary a-positions and the difference appears only in the two p-positions. The obvious solution is conjugate addition and trapping (described in the textbook on p. 603). The thermodynamic enol is needed from the second ketone and direct silylation is a good bet. The third requires kinetic enolate formation and LD A is a good way to do that. 

The first step requires a specific enol from an enone. Treatment with LDA achieves kinetic enolate formation by removing one of the more acidic hydrogens immediately next to the carbonyl group. The lithum enolate is trapped with McsSiCl to give the silyl enol ether. 

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