Enolate anions, esters, Dieckmann

Modem synthetic practice frequently requires the use of methods mote specific than those outlined above. Much attention has been focused on the mixed Claisen or Dieckmann reaction, i.e. the acylation of one ester by another, or its intramolecular equivalent, the regioselective cyclization of an unsymmetri-cal diester. A similar problem arises with the acylation of unsymmetrical ketones. This chapter thus describes the inter- and intra-molecular carbon-carbon bond-forming reactions in which a delocalized enolate anion (or close equivalent) reacts at an sp carbon atom in an addition-elimination sequence, as well as the acid-catalyzed equivalent employing an enol. In Table 1 we list the potential nucleophiles and the electrophiles that have been employed in these reactions, although not every possible combination has been reduced to synthetic practice. Table 2 gives details of acid-catalyzed acylations (see Section 3.6.4.3). 

The classical Dieckmann reaction occurs under equilibrium conditions, the initial step involving the base-catalyzed formation of the ester enolate anion. The rate-determining step is ring closure, the subsequent loss of the alkoxide being rapid (Scheme 14). ... 

This type of enolate anion reaction occurs among esters in the Claisen (Section 15.3A) and Dieckmann condensations (Section 15.3B). 

Identify the a-carbon for each ester group. Convert one of the a-carbons to an enolate anion and show it adding to the other carbonyl carbon. Because Dieckmann condensations occur with nucleophilic acyl substitution, the —OR group of the carbonyl being attacked Is eliminated from the final product. It often helps to number the atoms in the enolate anion and the ester being attacked. 

Addition of enolate anions derived from aldehydes or ketones (aldol reactions) and esters (Claisen and Dieckmann condensations) to the carbonyl groups of other aldehydes, ketones, or esters. 

The intra-molecular Claisen condensation is called a Dieckmann condensation, and it generates a cyclic compound 58,99,101,118. Malonic esters can be converted to the enolate anion and condensed with aldehydes, ketones, or add derivatives. The reaction of malonic acid with an aldehyde using pyridine as a base is called the Knoevenagel condensation 59, 60, 61, 62, 69, 99,108,110,112, 113,119,124. 

We have described what is commonly known as the acetoacetic ester synthesis and have illustrated the use of ethyl acetoacetate as the starting reagent. This same synthetic strategy is applicable to any j8-ketoester, as, for example, those that are available by the Claisen (Section 19.3A) and Dieckmann (Section 19.3B) condensations. For example, following are structural formulas for two jS-ketoesters available from Dieckmann and Claisen condensations that can be made to tmdergo (1) formation of an enolate anion, (2) alkylation or acylation, (3) hydrolysis followed by (4) acidification, and finally (5) decarboxylation just as we have shown for ethyl acetoacetate. 

Domino transformations combining two consecutive anionic steps exist in several variants, but the majority of these reactions is initiated by a Michael addition [1]. Due to the attack of a nucleophile at the 4-position of usually an enone, a reactive enolate is formed which can easily be trapped in a second anionic reaction by, for example, another n,(5-urisalurated carbonyl compound, an aldehyde, a ketone, an inline, an ester, or an alkyl halide (Scheme 2.1). Accordingly, numerous examples of Michael/Michael, Michael/aldol, Michael/Dieckmann, as well as Michael/SN-type sequences have been found in the literature. These reactions can be considered as very reliable domino processes, and are undoubtedly of great value to today s synthetic chemist... 

Dieckmann cyclization of diethyl adipate can be described by the two successive equilibria shown below. Use SpartanView to obtain the energies of diethyl adipate, the keto ester, the keto ester enolate ion, ethanol, and ethoxide anion, and calculate AH° for both steps. Which step is more favorable ... 

The synthesis of the 10-methoxytetracyclic ketone 353 (Scheme 26) started from the readily available 3-methyl-5-methoxyindole 355, which after Boc protection, was brominated, and then condensed with the anion of the Schollkopf auxiliary 356 (from l-valine). Removal of the Boc-protecting group, followed in succession by A -methylation and hydrolysis, gave the required A -methyl-5-methoxy-D-tryptophan ethyl ester 357, which was then transformed into the key 10-methoxytetracyclic ketone 353, via N-benzylation, Pictet-Spengler condensation, and Dieckmann cyclization. Subsequent N-alkylation by the vinyl iodide 358 followed by Pd-catalyzed (enolate-driven)... 

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