Enol acyl, formation

The enolates of ketones can be acylated by esters and other acylating agents. The products of these reactions are [Tdicarbonyl compounds, which are rather acidic and can be alkylated by the procedures described in Section 1.2. Reaction of ketone enolates with formate esters gives a P-ketoaldehyde. As these compounds exist in the enol form, they are referred to as hydroxymethylene derivatives. Entries 1 and 2 in Scheme 2.16 are examples. Product formation is under thermodynamic control so the structure of the product can be predicted on the basis of the stability of the various possible product anions. 

The formation of the acyl chloride with SOCl2 and the conversion of the a-bromoacyl chloride into the bromoester with MeOH are simple nucleophilic substitutions at the carbonyl group, just like the synthesis of esters from acyl chlorides in Chapter 12. The intermediate stage, the bromination of the very easily enolized acyl chloride, is a typical enol bromination. 

S)-Proline was homologated to the pyrrolidinylacetic ester 864, after which N-acylation with p-methoxyphenylacetyl chloride, intramolecular condensation and enol ether formation created the indolizidinone system of 865. Standard transformations completed the synthesis of the alkaloid ( + )-(842), which was isolated as the hydrobromide salt ([a]o +54.1°, c 1, EtOH). 

In the next example, there are three possible sites for enolate anion formation, but only one product is formed and in good yield too. If we consider all three possible enolate anions, the choice is more easily made. First, the reaction that does happen. An enolate anion is formed from the ketone at the green site and acylation at carbon follows. The product is a fused rather than a bridged bicyclic structure and can easily form a stable enolate anion. 

The acylation of enolates derived from ketones with esters is an important tool for enhancing reactivity and selectivity in synthetic modification of ketones. Some representative examples are given in Scheme 2.7. The most common example of this is the formylation of ketone enolates by formate esters ... 

Enolate ion formation allows coenzyme A-bound acyl groups to serve as nucleophiles and to react at electrophilic centres. This permits thioesters to participate in the formation or degradation of carbon—carbon linkages by mechanisms analogous to the aldol condensation or more specifically the Qaisen type ester condensation. There are few available mechanisms for carbon—carbon bond formation or deavage which can be employed under biological reaction conditions, and pathways which depend on coenzyme A thioesters for this purpose are widespread. 

Moving forward from 59, six steps were required to convert this compound to 60. Vicinal dihydroxylation of the olefin was followed by oxidative cleavage of the intermediate diol using lead tetraacetate. Reductive amina-tion of the resulting aldehyde with methylamine, followed by acylation of the intermediate secondary amine gave the desired carbamate. Swern oxidation of the secondary alcohol, followed by enol ether formation gave 60. Elimination of -toluenesulfinic acid from 60 provided 61. Oxidation of this dienol ether to dienone 62 was followed by release of the secondary amine, followed by a conjugate addition reaction to establish the critical C-N bond. The remainder of the synthesis followed known chemistry. The mixture of enones 63 was converted to codeinone (35), codeine (3) and then morphine (1). 

Acyl Formation Compared with hydrolysis reactions, esterification and transesterification reactions are much slower and require the use of activated esters to facilitate the reaction and to make it kinetically irreversible. These include trichloroethyl esters, trifluoroethyl esters, enol esters, thioesters and vinylcarbamates. Lipases isolated from Pseudomonas species are highly selective for the hydrolysis of esters of secondary alcohols, and therefore also for the corresponding reverse reactions. 

Mixed Claisen condensations (Section 21.3) Diethyl carbonate, diethyl oxalate, ethyl formate, and benzoate esters cannot form ester enolates but can act as acylating agents toward other ester enolates. 

Flavone formation is believed to proceed through a similar mechanism as the synthesis of chromones, albeit aromatic acid anhydrides and their corresponding salts are used. The first step is benzoylation of 12 to give the ester 14. Enolization and o-alkylation then affords the enolbenzoate 15. Enolbenzoate 15 then undergoes an acyl transfer to yield... 

Only in 1961 did Woodward and Olofson succeed in elucidating the true mechanism of this interesting reaction by making an extensive use of spectroscopic methods. The difficulty was that the reaction proceeds in many stages. The isomeric compounds formed thereby are extremely labile, readily interconvertible, and can be identified only spectroscopically. The authors found that the attack by the anion eliminates the proton at C-3 (147) subsequent cleavage of the N—0 bond yields a -oxoketene imine (148) whose formation was established for the first time. The oxoketene imine spontaneously adds acetic acid and is converted via two intermediates (149, 150) to an enol acetate (151) whose structure was determined by UV spectra. Finally the enol acetate readily yields the W-acyl derivative (152). 

In the following the reaction is outlined for an a-bromination. The reaction mechanism involves formation of the corresponding acyl bromide 3 by reaction of carboxylic acid 1 with phosphorus tribromide PBr3. The acyl bromide 3 is in equilibrium with the enol derivative 4, which further reacts with bromine to give the a -bromoacyl bromide 5 ... 

Step 1 of Figure 27.7 Claisen Condensation The first step in mevalonate biosynthesis is a Claisen condensation (Section 23.7) to yield acetoacetyl CoA, a reaction catalyzed by acetoacetyl-CoA acetyltransferase. An acetyl group is first bound to the enzyme by a nucleophilic acyl substitution reaction with a cysteine —SH group. Formation of an enolate ion from a second molecule of acetyl CoA, followed by Claisen condensation, then yields the product. 

Diels-Alder reaction, 493 El reaction, 391-392 ElcB reaction, 393 E2 reaction, 386 Edman degradation, 1032 electrophilic addition reaction, 147-148. 188-189 electrophilic aromatic substitution, 548-549 enamine formation, 713 enol formation, 843-844 ester hydrolysis, 809-811 ester reduction, 812 FAD reactions. 1134-1135 fat catabolism, 1133-1136 fat hydrolysis, 1130-1132 Fischer esterification reaction, 796 Friedel-Crafts acylation reaction, 557-558... 

When 2-lithio-2-(trimethylsilyl)-l,3-dithiane,9 formed by deprotonation of 9 with an alkyllithium base, is combined with iodide 8, the desired carbon-carbon bond forming reaction takes place smoothly and gives intermediate 7 in 70-80% yield (Scheme 2). Treatment of 7 with lithium diisopropylamide (LDA) results in the formation of a lactam enolate which is subsequently employed in an intermolecular aldol condensation with acetaldehyde (6). The union of intermediates 6 and 7 in this manner provides a 1 1 mixture of diastereomeric trans aldol adducts 16 and 17, epimeric at C-8, in 97 % total yield. Although stereochemical assignments could be made for both aldol isomers, the development of an alternative, more stereoselective route for the synthesis of the desired aldol adduct (16) was pursued. Thus, enolization of /Mactam 7 with LDA, as before, followed by acylation of the lactam enolate carbon atom with A-acetylimidazole, provides intermediate 18 in 82% yield. Alternatively, intermediate 18 could be prepared in 88% yield, through oxidation of the 1 1 mixture of diastereomeric aldol adducts 16 and 17 with trifluoroacetic anhydride (TFAA) in... 

---