Enolate anions, acylation

Acetylenedimagnesium bromide, 66, 84, 137 Acyl-alkyl diradical disproportionations, 299 Acyl-alkyl diradical recombination, 296 Alkaline hydrogen peroxide, 10, 12, 20 Alkylation of formyl ketones, 93 Alkylation via enolate anions, 86 17a-Alkynyl steroids from 17-ketones, 67 2a-Al]yl-17jS-hydroxy-5a-androstan-3 -one, 9 5 Allylic acetoxylation, 242 Allylmagnesium bromide, 64 17 -Aminoandrost-5-en-3 -ol, 145 17 a-Aminomethy 1-5 a-androstane-3, 1718-diol, 387... 

THF) at room temperature (Scheme 18) (95T8605). The proposed mechanism for this conversion involves the abstraction of H3 by basic attack of NaH to give an enolate anion, which, via ring opening, affords the 2(5//)-furanone 61 by a straightforward intramolecular nucleophilic acyl substitution (Scheme 18) (95T8605). 

Now this is exactly the same situation we encountered when we compared the reactivity of aldehydes and ketones with that of carboxylic acid derivatives (see Section 7.8). The net result here is acylation of the nucleophile, and in the case of acylation of enolate anions, the reaction is termed a Claisen reaction. It is important not to consider aldol and Claisen reactions separately, but to appreciate that the initial addition is the same, and differences in products merely result from the absence or presence... 

The leaving group is the enolate anion of acetyl-CoA, and the reaction thus cleaves off a two-carbon fragment from the original fatty acyl-CoA. Since the nucleophile is coenzyme A, the other product is also a coenzyme A ester. In fact, the reaction generates a new fatty acyl-CoA, shorter by two carbons, which can re-enter the P-oxidation cycle. Most natural fatty acids have an even number of carbons, so the process continues until the original fatty acid chain is cleaved completely to acetyl-CoA fragments. 

Coenzyme A is another adenine nucleotide derivative, with its primary functional group, a thiol, some distance away from the nucleotide end of the molecule. This thiol plays an important role in biochemistry via its ability to form thioesters with suitable acyl compounds (see Box 7.18). We have seen how thioesters are considerably more reactive than oxygen esters, with particular attention being paid to their improved ability to form enolate anions, coupled with thiolates being excellent leaving groups (see Box 10.8). 

There follows cleavage of acetyl-CoA from the end of the chain via a reverse Claisen reaction (see Box 10.15). This requires use of a molecule of coenzyme A as nucleophile, with the loss of the enolate anion of acetyl-CoA as leaving group. The net result is production of a new fatty acyl-CoA that is two carbons shorter than the original, and a molecule of acetyl-CoA that can be metabolized via the Krebs cycle. 

Undesirable intermolecular reactions can be avoided during certain synthetic conversions. Thus it is often useful to carry out C-alkylation and C-acylation of compounds that form enolate anions, for example, esters with a-hydrogens. Such reactions are often complicated by self-condensation since the enolate anion can attack the carbonyl group of a second ester molecule. Attachment of the enolizable ester to a polymer support at low loading levels allows the alkylation and acylation reactions (Eq. 9-79) to be performed under... 

The enolate anion attacks the carbonyl carbon of a second molecule of ester and gives a P-ketoester. Thus, the Claisen condensation is a nucleophilic acyl substitution reaction. Eor example, two molecules of ethyl acetate condense together to form the enolate of ethyl acetoacetate, which upon addition of an acid produces ethyl acetoacetate (P-ketoester). 

A novel base-catalyzed Fries-like rearrangement of a 3-acetoxythiophene has been reported (Scheme 149) (79JOC3292). This has been explained as the result of iodide-induced deacylation and subsequent C-acylation of the intermediate enolate anion. Some transformations of 4-hydroxy-2-methylthiophene-3-carboxylic ester are shown in Scheme 150 (69KGS567,75KGS914,71KGS759). 

These enzymes do not catalyze any proton exchange at C-3 of pyruvate or at C-2 of an acyl-CoA unless the biotin is first carboxylated. This suggested that removal of the proton to the biotin oxygen and carboxylation might be synchronous. However, 13C and 2H kinetic isotope effects and studies of 3H exchange66 support the existence of a discrete enolate anion intermediate as shown in Eq. 14-11.165/67 This mechanism is also consistent with the observation that propionyl-CoA... 

However, these experiments may not have established a mechanism for natural flavoprotein catalysis because the properties of 5-deazaflavins resemble those of NAD+ more than of flavins.239 Their oxidation-reduction potentials are low, they do not form stable free radicals, and their reduced forms don t react readily with 02. Nevertheless, for an acyl-CoA dehydrogenase the rate of reaction of the deazaflavin is almost as fast as that of natural FAD.238 For these enzymes a hydride ion transfer from the (3 CH (reaction type D of Table 15-1) is made easy by removal of the a-H of the acyl-CoA to form an enolate anion intermediate. 

The Perkin synthesis of cinnamic acids is considered to involve reaction of the enolate anion derived from the acid anhydride with the aldehyde, giving rise to the alkoxide (391). Intramolecular acylation follows and the resulting /3-acyloxy derivative undergoes elimination to the unsaturated acid (Scheme 125). 

Enolate anions of esters, such as ethyl 3-oxobutanoate or diethyl propanedioate, react with aeyl halides or anhydrides to give acylation products. These reactions are carried out best using sodium hydride instead of sodium ethoxide for production of the enol salt, because then no alcohol is liberated to react with the acyl halide or anhydride ... 

Several important reactions of arenols involve aromatic substitution of arenolate ions with carbon electrophiles. In a sense, these reactions are alkylation and acylation reactions as discussed for arenes (Sections 22-4E and 22-4F). In another sense, they are alkylation and acylation reactions of enolate anions and therefore could give rise to products by C- and O-alkyla-tion, or C- and O-acylation (Section 17-4). Thus ... 

The second stage of the condensation is the reaction of the enolate anion with the acyl group of a second molecule of acetyl-CoA ... 

Nucleophilic addition to the neutral activated acyl group is a favored process, and coenzyme A is a good leaving group from the tetrahedral intermediate. The occurrence of this process with the acetate anion, that is, acetate reacting with an enolate anion, again provides a sharp contrast with the... 

Enolate anions 54, which can be generated from peri-acyl-oxy-substituted naphthyl benzyl ketones 52 or from their enolacylates 53, undergo rearrangement into 5-methoxynaphtholactone 48 or 2-benzyl-... 

Anodic oxidation of cyclic enol esters with /1-hydrogens leads to allyl radicals, which then lose acyl radical to form a, /1-unsaturated ketones. When the electrolysis is performed in an undivided cell, these are converted by the cathode into enolate anion radicals, which then couple to form /1-dimers (Scheme 66)164. 

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