Alkylations amide enolates

By contrast, lithium enolates derived from tertiary amides do react with oxiranes The diastereoselectivity in the reaction of simple amide enolates with terminal oxiranes has been addressed and found to be low (Scheme 45). The chiral bicyclic amide enolate 99 reacts with a good diastereoselectivity with ethylene oxide . The reaction of the chiral amide enolate 100 with the chiral oxiranes 101 and 102 occurs with a good diastereoselectivity (in the matched case ) interestingly, the stereochemical course is opposite to the one observed with alkyl iodides. The same reversal is found in the reaction of the amide enolate 103. By contrast, this reversal in diastereoselectivity compared to alkyl iodides was not found in the reaction of the hthium enolate 104 with the chiral oxiranes 105 and 106 °. It should be noted that a strong matched/mismatched effect occurs for enolates 100 and 103 with chiral oxiranes, and excellent diastereoselec-tivities can be achieved. 

Birch reduction of enantiomcrieally pure benzamides followed by alkylation of the amide enolate was used with remarkable success to obtain chiral cyclohexadiene derivatives22. In this case the chiral auxiliary was located in the benzamide moiety. 

This section deals with the alkylation reactions of such enolates. In the presence of strong bases, amides carrying at least one a-hydrogen 1 can be deprotonated to form enolate ions which, on subsequent alkylation, give alkylated amides. Further reaction, e g., hydrolysis or reduction, furnishes the corresponding acids or primary alcohols, respectively. The pKa values for deprotonation are typically around 35 (extrapolated value DMSO3 7) unless electron-withdrawing substituents are present in the a-position. Thus, deprotonation usually requires non-nucleophilic bases such as lithium diisopropylamide (extrapolated 8 pKa for the amine in DMSO is around 44) or sodium hexamethyldisilazanide. 

Rotation is hindered in the enolate. Thus, if the a-substituent R1 4= R2, the enolate can exist in two forms, the syn- and anti-forms (enolates 2 and 3, respectively, if R2 has higher priority than R1). Attack of an electrophile on either face of the enolates, 2 or 3, leads to a mixture of the alkylated amides, 4 and 5. If R1 and R2 and the A-substituents R3 and R4 are all achiral, the two alkylated amides will be mirror images and thus a racemate results. If, however, any of the R substituents are chiral, enolate 2 will give a certain ratio of alkylated amide 4/5, whereas enolate 3 will give a different, usually inverted, ratio. Thus, for the successful design of stereoselective alkylation reactions of chiral amide enolates it is of prime importance to control the formation of the enolate so that one of the possible syn- or anti-isomers is produced in large excess over the other,... 

This section mainly deals with the practical applications of amide enolate alkylations, although a short discussion of some mechanistic aspects is necessary in order to understand the steric course of these reactions. 

One of the most important factors for successful diastereoselection in chiral amide enolate alkylation reactions is the presence of strongly chelated ionic intermediates1 3. The chelation serves the purpose of locking the chiral auxiliary in a fixed position relative to the enolate. The metal counterion is chelated between the enolate oxygen and an additional polar group, anionic, carbonyl or ether oxygen attached to the chiral auxiliary. 

Alkylation of Amide Enolates Steric Hindrance vs. Electronic Control... 

In contrast to the many examples dealing with esters (see Section 1.1.1.3.2.), there are few examples in the literature of alkylations of amide enolates where the steric course is governed by the configuration of chiral units on the carbon side of the starting amide, i.e., substrate control by C-chirality. It is likely, however, that amide alkylations of this type will emerge as a very useful procedure since amide enolates are easy to prepare and usually, in contrast to some esters, provide very high ratios of syn- to a / -enolate. 

The chiral irans-2,5-disubstituted 1-acylpyrrolidines have been used in many diastereoselective reactions, in particular alkylation reactions. Thus, the amide enolates have been used in the preparation of a wide variety of chiral acid derivatives, e.g., 2-alkylalkanoic acids7,8 and other 2-substituted acids, such as 2-hydroxy-9, 2-cyano-2-methyl10, and 2-aminoalkanoic acids112 and their derivatives (see Tables 7 and 8), in high chemical yield. The induced diastereoselectivity is usually very high (mostly d.r. >97.5 2.5). 

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