Halides, alkyl, reaction with lactone enolates

The reaction of these lithium enolates with alkyl halides is one of the most important C-C bondforming reactions in chemistry. Alkylation of lithium enolates Works with both acyclic and cyclic ketones as well as with acyclic and cyclic esters (lactones). The general mechanism is shown below, alkylation of an ester enolate alkylation of a ketone enolate... 

Diketene similarly reacts readily with tributyltin oxide in THF at room temperature47 to give the stannyl 3-stannyloxybut-3-enoate which rearranges to the 2-enolate this enolate will then give an ene reaction with an aldehyde,48 or react with an alkyl halide,49 followed by decarboxylation, providing a route to ketones, enones, and ketoaldehydes. Similar reactions with bromomethyl P- or y-lactones result in the formation of P-hydroxy-y-lactones or y-hydroxy-5-lactones. 

In the conversion of 66 to 67, we saw that HMPA was used as an additive. Another useful ingredient in many alkylation reactions is hexamethylphosphorus triamide [HMPT, (Me2N)3P], which coordinates with the enolate anion, diminishing the aggregate state and increasing reactivity. This additive also enhances the polarity of the solvent and thereby enhances the facility of the Sn2 alkylation step (sec. 2.7.A.i). The use of an additive such as HMPA or HMPT is very common when the enolate anion reacts slowly and/or the halide is relatively unreactive. Other acid derivatives such as lactones can react with LDA to give an enolate anion, which then reacts with alkyl halides in the usual manner. 

In the presence of a Lewis acid, silyl enol ethers can be alkylated with reactive secondary halides, such as substituted benzyl halides, and with chloromethylphenyl sulfide (ClCH2SPh), an activated primary halide. Thus, reaction of the benzyl chloride 10 in the presence of zinc bromide with the trimethylsilyl enol ether derived from mesityl oxide allowed a short and efficient route to the sesquiterpene ( )-ar-turmerone (1.22). Reaction of ClCH2SPh with the trimethylsilyl enol ethers of lactones in the presence of zinc bromide, followed by 5-oxidation and pyrolytic ehmination of the resulting sulfoxide (see Section 2.2), provides a good route to the a-methylene lactone unit common in many cytotoxic sesquiterpenes (1.23). Desulfurization with Raney nickel, instead of oxidation and elimination, affords the a-methyl (or a-alkyl starting with RCH(Cl)SPh) derivatives. ... 

Activation of C-X Bonds. Even more important than carbonyl activation, ZnBr promotes substitution reactions with suitably active organic halides with a variety of nucleophiles. Alkylation of silyl enol ethers and silyl ketene acetals using benzyl and allyl halides proceeds smoothly (eq 13). Especially useful electrophiles are a-thio halides which afford products that may be desulfurized or oxidatively eliminated to result in a,p-unsaturated ketones, esters, and lactones (eq 14). Other electrophiles that have been used with these alkenic nucleophiles include Chloromethyl Methyl Ether, HC(OMe)3, and Acetyl Chloride... 

All of these reactions may be repeated starting with methyl (2/ ,3f )-3-hydroxy-2-methylbutanoate (9a) which is obtained, as shown in Scheme 2, by the double deprotonation of methyl 3-hydroxybutanoate (2b) using lithium di-isopropylamide (LDA) to give the alkoxide-enolate (8) and alkylation with a methyl halide in THF at —After reduction with lithium aluminium hydride, tosyla-tion of the alcohol group and nucleophilic attack by lithium chloride, the (2f ,3f )-l-chloro-2-methyl-3-butanol (10) is available for the sequential metallation reactions and conversion to 1,4-diols or lactones. 

---