Ester enolates conjugate additions

Thus, the dianion derived from a-amino acid substitutes the /1-chloride to give the ester of 2-(phenylsulfonyl)ethenyl amino acid and subsequent desulfonylation provides N-(benzoyl)vinylalanine methyl ester (62) (equation 61). The conjugate addition of enolates to methyl styryl sulfone (63) and subsequent intramolecular addition to the carbonyl moiety provide a synthetically valuable method for the construction of bicyclic and tricyclic skeletons52. Desulfonylation of the cyclization product 64 with sodium in ethanol-THF gives the diene 65 in good yield (equation 62). 

OL, -Bifunctionalization of cyclopentenone.1 Although simple ester enolates do not undergo conjugate additions, the enolate of 1 undergoes conjugate addition to cyclopentenone in THF/HMPT (3.3 1) at -20°. This reaction coupled with in situ enolate alkylation provides a notably short synthesis of methyl jasmonate (3). 

Conjugate additions of enolates to alkynyl-ketones or to alkynyl-esters are further variations on the synthetic theme. 

Stabilized anions exhibit a pronounced tendency to undergo conjugate addition to a p unsaturated carbonyl compounds This reaction called the Michael reaction has been described for anions derived from p diketones m Section 18 13 The enolates of ethyl acetoacetate and diethyl malonate also undergo Michael addition to the p carbon atom of a p unsaturated aldehydes ketones and esters For example... 

The mechanism of the Fiesselmann reaction between methylthioglycolate and a,P-acetylenic esters proceeds via consecutive base-catalyzed 1,4-conjugate addition reactions to form thioacetal Enolate formation, as a result of treatment with a stronger base, causes a Dieckmann condensation to occur providing ketone 8. Elimination of methylthioglycolate and tautomerization driven by aromaticity provides the 3-hydroxy thiophene dicarboxylate 9. 

The best Michael reactions are those that take place when a particularly stable enolate ion such as that derived from a /i-keto ester or other 1,3-dicarbonyl compound adds to an unhindered a,/3-unsaturated ketone. Tor example, ethyl acetoacetate reacts with 3-buten-2-one in the presence of sodium ethoxide to yield the conjugate addition product. 

A Michael reaction involves the conjugate addition of a stable enolate ion donor to an o,/3-unsaturated carbonyl acceptor, yielding a 1,5-dicarbonyl product. Usually, the stable enolate ion is derived from a /3-diketone, jS-keto ester, malonic ester, or similar compound. The C—C bond made in the conjugate addition step is the one between the a carbon of the acidic donor and the (3 carbon of the unsaturated acceptor. 

The first step of the Robinson annulation is simply a Michael reaction. An enamine or an enolate ion from a jS-keto ester or /3-diketone effects a conjugate addition to an a-,/3-unsaturated ketone, yielding a 1,5-diketone. But as we saw in Section 23.6,1,5-diketones undergo intramolecular aldol condensation to yield cyclohexenones when treated with base. Thus, the final product contains a six-membered ring, and an annulation has been accomplished. An example occurs during the commercial synthesis of the steroid hormone estrone (figure 23.9). 

Several examples of conjugate addition of carbanions carried out under aprotic conditions are given in Scheme 2.24. The reactions are typically quenched by addition of a proton source to neutralize the enolate. It is also possible to trap the adduct by silylation or, as we will see in Section 2.6.2, to carry out a tandem alkylation. Lithium enolates preformed by reaction with LDA in THF react with enones to give 1,4-diketones (Entries 1 and 2). Entries 3 and 4 involve addition of ester enolates to enones. The reaction in Entry 3 gives the 1,2-addition product at —78°C but isomerizes to the 1,4-product at 25° C. Esters of 1,5-dicarboxylic acids are obtained by addition of ester enolates to a,(3-unsaturated esters (Entry 5). Entries 6 to 8 show cases of... 

Conjugate addition.1 This base undergoes efficient 1,4-addition to a,(i-un-saturated esters to give the enolate of a (3-amino ester, which can be trapped by an alkyl halide to give a-alkyl-(3-amino esters (2) as a mixture of syn- and antiisomers (about 1 1). These esters can be converted into 3-lactams (3) by hydrolysis and dehydration (11, 449) or into a-alkyl-a,3-unsaturated esters (4) by N-quater-nization and 3-elimination on silica gel ( 75% yield). 

Scheme 3.7. Diastereoselective formation of /S-silyl ( )- or (Z)-ester enolates by silylcuprate conjugate addition followed by alkylation with aldehydes [49]. Stereoselective synthesis of ( )-and (Z)-allyl silanes [50].

Diastereoselectivity in the aldol and the conjugate additions of 2 -hydroxy-1,T-binaphthyl ester enolates with a variety of carbonyl electrophiles has also been explored the tendency of the ester enolates, generated by BuLi, to react with aldehydes to give threo products preferentially with high diastereoselectivity has been interpreted in terms of an acyclic transition state of chelated lithium enolate involving the aldehyde carbonyl and the 2 -hydroxy group. 

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