Ester enolates, alkylation

Entries 3 to 6 are examples of ester enolate alkylations. These reactions show stereoselectivity consistent with cyclic TSs in which the hydrogen is eclipsed with the enolate and the larger substituent is pseudoequatorial. Entries 4 and 5 involve SN2 substitutions of allylic halides. The formation of the six- and five-membered rings, respectively, is the result of ring size preferences with 5 > 7 and 6 > 8. In Entry 4, reaction occurs through a chairlike TS with the tertiary C(5) substituent controlling the conformation. The cyclic TS results in a trans relationship between the ester and vinylic substituents. 

The intramolecular variant of ester enolate alkylations is a very useful ring-forming reaction. It can often be carried out under milder conditions than the corresponding intermolecular alkylation. Yields and diastereoselectivities are usually high. 

Scheme 1.1.6 Tandem aza-Michael addition/a-ester enolate alkylation or aldol reaction.

In addition, we were able to extend the tandem hetero Michael addition/a-ester-enolate alkylation protocol by an intramolecular variant via a Michael-initiated ring closure (MIRC) reaction leading to diastereo- and enantiomerically pure trans-configured 2-amino-cycloalkanoic acids 30 (Scheme 1.1.7) [14c,d]. 

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... 

When competing Claisen condensation of the ester is a problem, the use of the sterically hindered t-butyl esters is recommended. Unlike with ketone enolates, the 0-alkylation of ester enolates generally is not a problem. Consequently, HMPA may be added to ester enolate alkylations to improve yields. Many S 2 reactions proceed more readily in HMPA than in THF, DME, or DMSO. A solvent for replacing the carcinogenic HMPA in a variety of alkylation reactions is l,3-dimethyl-3,4,5,6-tetrahy-dro-2(lH)pyrimidinone (A,A -dimethylpropyleneurea, DMPU), which also has a strong dipole to facilitate metal counterion coordination. ... 

Step 2. Chemoselective reduction of the a-alkoxy ester Step 4. Ester enolate alkylation (5-exo-tet cyclization)... 

Kim, D., Shin, K.J., Kim, I.Y., and Park, S.W., A total synthesis of (-)-reiswigin A via sequential Claisen rearrangement-intramolecular ester enolate alkylation. Tetrahedron Lett., 35, 7957, 1994. 

Scheme 3.14. Helmchen s asymmetric ester enolate alkylation [73,74].

The mechanistic rationale for the selectivity of these ester enolate alkylations may be summarized as follows (Scheme 3.14 and 3.13 [74]) ... 

In the same way, glycolic acid can be ste-reoselectively transformed into the Dispoke derivative 10 (61 %) with enantiomerically pure 3b. [8] Formation of the ester enolate, alkylation with methyl iodide, renewed enolate formation and treatment with benzyl bro-... 

Ether synthesis by alkylation of alcohol using an inorganic base is sometimes troublesome. In such cases, soluble organic superbases are often effective. Knapp et al. performed the alkylation of 145 with isopropyl bromoacetate using the strong soluble base BEMP, achieving 95% yield [46]. Intramolecular ester enolate alkylation of 147 with EDA took place to give 148, which was effectively led to the natural product octosyl acid A (149) (Scheme 7.33). 

Chem. Soc., Chem. Commun. 1984,28. McGarvey, G. J. Williams, J. M. "Stereoelectronic Controlling Features of Allylic Asymmetry. Application to Ester Enolate Alkylations" J. Am. Chem. Soc. 1985,107, 1435. 

For lead references see Yamamoto, Y. Maruyama, K. The Opposite Diastereoselectivity in Alkylation and Protonation of Enolates J. Chem. Soc., Chem. Commun. 1984, 904-905. Fleming, I. Lewis, J. J. A Paradigm for Diastereoselectivity in Electrophilic Attack on Trigonal Carbon Adjacent to a Chiral Center The Methylation and Protonation of Some Open-Chain Enolates J. Chem. Soc., Chem. Commun. 1985, 149-151. McGarvey, G. J. Williams, J. M. Stereoelectronic Controlling Features of Allylic Asymmetry. Application to Ester Enolate Alkylations J. Am. Chem. Soc. 1985, 107, 1435-1437. Hart, D. J. Krishnamurthy, R. Investigation of a Model for 1,2-Asymmetric Induction in Reactions of a-Carbalkoxy Radicals A Stereochemical Comparison of Reactions of a-Carbalkoxy Radicals and Ester Enolates J. Ors. Chem. 1993, 57, 4457-4470. 

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