Grignard-based enolate formation

Figure 9.34 Merck production plant for Grignard-based enolate formation (by courtesy of Springer) [68].

Another feature of target 58 will complicate any chemical reaction chosen in a disconnection. If the disconnection requires an acyl addition reaction of a Grignard reagent (Chapter 18, Section 18.4) or formation of an enolate anion (Chapter 22, Sections 22.2, 22.4), there is a problem. Both Grignard reagents and enolate anions will react with an alcohol in an acid-base reaction that will interfere with the desired carbon-carbon bond-forming reaction (see Chapter 22, Section 22.2). Further, there are two sites for reaction. An aldehyde will undergo acyl addition or reaction with an enolate anion, but so will the ketone unit. Both the a-carbon of the aldehyde and the a-carbon of the ketone are candidates for enolate formation, which further complicates any reaction. 

The use of other mixed reagents to promote acylation and subsequent enolization of the ketone during its formation have been reported by Fehr. The success of the method depends on the ease of ketone deprotonation and thus was limited to substituted allylic nucleophiles. The final product was obtained entirely in the form of the a. -unsaturated ketone. A combination of the nucleophilic Grignard reagent and the nonnucleophilic base lithium diisopropylamide converts sterically hinder ester (50) into a-damas-cone (52) via (51) (Scheme 16). The ratio of ketone to tertiary alcohol was 98 2 (many cases gave selectivity greater than 9 1) however, a few examples showed a substantial amount of tertiary alcohol formation. 

A recent example by McGarvey demonstrates the formation of chiral derivatives (73)-(76) which are useful for elaboration into the ubiquitous propionate unit through stereoselective enolate-based alkylation (equation 56)." The thiol ester substrates were derived from aspartic acid in seven steps. The acylation of either dimethylcuprate or the Grignard-derived organocopper reagent was extremely clean when these organometallics were used in excess. No epimerization of the adjacent center was observed during the addition. 

Use of a Grignard Reagent as a Base (Formation of Magnesium Enolates)... 

As bases. Formation of magnesium enolates from a-chloro-a-arenesulfinylcar-boxylic acid derivatives involves desulfinylation with a Grignard reagent. f-Butyl Grignard reagents are preferred in certain circumstances for the deprotonation of carbon acids. This method has been applied to a synthesis of chiral jS-hydroxy esters from arenesulfinylacetic esters. ... 

The reaction of carbon nucleophiles with ketones or aldehydes proceeds by acyl addition, as described in Chapter 18. The reaction of carbon nucleophiles with acid derivatives proceeds by acyl substitution, as described in Chapter 20. Carbon nucleophiles included cyanide, alkyne anions, Grignard reagents, organolithium reagents, and organocuprates. Alkyne anions are formed by an acid-base reaction with terminal alkynes (RC=C-H RCsCr). In this latter transformation, it is clear that formation of the alkyne anion relies on the fact that a terminal alkyne is a weak carbon acid. Other carbon acids specifically involve the proton on an a-carbon in aldehydes, ketones, or esters. With a siiitable base, these carbonyl compounds generate a new type of carbon nucleophile called an enolate anion. 

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