Esters electrophilicity

Merck s thienamycin synthesis commences with mono (V-silylation of dibenzyl aspartate (13, Scheme 2), the bis(benzyl) ester of aspartic acid (12). Thus, treatment of a cooled (0°C) solution of 13 in ether with trimethylsilyl chloride and triethylamine, followed by filtration to remove the triethylamine hydrochloride by-product, provides 11. When 11 is exposed to the action of one equivalent of tm-butylmagnesium chloride, the active hydrogen attached to nitrogen is removed, and the resultant anion spontaneously condenses with the electrophilic ester carbonyl four atoms away. After hydrolysis of the reaction mixture with 2 n HC1 saturated with ammonium chloride, enantiomerically pure azetidinone ester 10 is formed in 65-70% yield from 13. Although it is conceivable that... 

Mixed condensations of esters are subject to the same general restrictions as outlined for mixed aldol reactions (Section 2.1.2). One reactant must act preferentially as the acceptor and another as the nucleophile for good yields to be obtained. Combinations that work best involve one ester that cannot form an enolate but is relatively reactive as an electrophile. Esters of aromatic acids, formic acid, and oxalic acid are especially useful. Some examples of mixed ester condensations are shown in Section C of Scheme 2.14. Entries 9 and 10 show diethyl oxalate as the acceptor, and aromatic esters function as acceptors in Entries 11 and 12. 

As indicated above, the traditional base-catalysed hydrolysis of 0,5-dialkyl thio-carbonates for the synthesis of thiols is generally unsatisfactory, as oxidation leads to the formation of disulphides. Under phase-transfer conditions, the procedure produces thioethers to the virtual exclusion of the thiols, as a result of the slow release of the thiolate anions in the presence of the electrophilic ester. However, a simple modification of the reaction conditions provides an efficient one-pot reaction [50] from haloalkanes (Table 4.15) via the intermediate formation of the thermally labile (9-/ert-butyl-5-alkyl dithiocarbonates (Scheme 4.8). 

The following reactions demonstrate that the electrophilic ester carbonyl groups of (16) predominantly determine the reactivity Heating (16b) for several hours in ethanol saturated with HC1 affords (16a) by transes-terfication. Ester hydrolysis and decarboxylation occur at room temperature in the presence of dilute alkaline hydroxide. Hydrolysis of (16a R = R2 = R3 = Me) to 3-carboxy-2-pyrrolone 21 succeeds in the presence of aqueous methanolic KOH at 60°C. Subsequent HC1 work-up at 0°C furnishes 21 with 82% yield (86UP1). (See Fig. 11.)... 

Esters are far less reactive as electrophiles when compared to aldehydes and ketones. Successful tandem vicinal dialkylations are possible using alkyl formates,67 but most esters lack the needed reactivity. More reactive thioesters can serve as electrophiles in these sequences.208 Presence of a potentially electrophilic ester group as a substituent in the conjugate enolate permits very efficient Dieckmann cycliza-tion to take place as the second step of a MIRC sequence (e.g. equations 5118 and 52).24 Ortho esters are far more reactive, giving p-keto esters as adducts when used in sequences that employ enones as substrates.230... 

Vinyl ethers have also been prepared by addition of alkoxides to acetylene,6 7 6 elimination from halo ethers and related precursors,6 8 and vinyl exchange reactions.6 Reaction of an electrophilic tungsten carbenoid with methylene phosphorane or diazomethane also produces vinyl ethers.9 Enol ethers have resulted from the reaction of some tantalum and niobium carbenoids with esters,10 and the reaction of phosphoranes with electrophilic esters.4... 

Making alcohol 3 by reducing the less electrophilic ester is not so easy but protection of the ketone as an acetal 4—a functional group that does not react with nucleophiles—allows reduction of the ester with the more nucleophilic L1AIH4. 

These compounds are largely eno-lized under normal conditions. So, you might ask, why don t they immediately react with themselves by the aldol reaction There are two aspects to the answer. First, the enols are very stable (see Chapter 21 for a full discussion) and, secondly, the carbonyl groups in the unenolized fraction of the sample are poorly electrophilic ester and ketone groups. The second carbonyl group of the enol is not electrophilic because of conjugation. 

The amino acid ester forms the hydantoin 33 with the isocyanate 41. The free amine 32 attacks the isocyanate carbon and the nucleophilic isocyanate nitrogen in 42 then reacts with the electrophilic ester moiety. The carbonate base prevents protonation of the amine. 

T-r, ise we want the aldehyde to form an enolate and we want the enolate to attack the ester. The Idi 4 all right the aldehyde will form an enolate more readily than the ester. But under these conditions, only a small amount of enolate will be formed and it will react fester with the lan with the less electrophilic ester. The aldehyde will self-condense in an aldol reaction. 

The Claisen condensation is regioselective because the most stable enolate 28 of the product 26 is formed under the reaction conditions and it is more stable than the alternative 29. Reaction with hydrazine occurs at the two keto groups rather than at the less electrophilic ester. 

Activation-substitution. To promote coupling of biomonomers via a nucleophilic substitution, which has to be performed under mild conditions, the electrophilic (esteric/carboxylic/acetal) site is activated to increase its electrophilicity. This is achieved by an introduction of electron-withdrawing moieties (decrease the electron density at the electrophilic site), thereby favoring the subsequent nucleophilic attack. Some of the common activated structures are illustrated in Table 8.6. 

The metal-insertion ROP owes its name to the propagation mechanism [Fig. 21.2]. After coordination of the metal-alkoxide with the carbonyl group of the lactone, the addition of the nucleophilic alkoxides takes place onto the electrophilic ester bond. Subsequently, an elimination reaction occurs via acyl-oxygen scission. The novel alkoxide will act as the newly generated propagating species. 

The electrophilic ester carbonyl is susceptible to nucleophilic addition, the most nucleophilic site now available is the oxygen of the oxime. Alcohols and esters react to give esters, and here there is lactone (i.e. a cyclic ester) formation by standard addition-elimination mechanism at an ester. 

Acid catalysis of ester hydrolysis is also very effective. Oxygen exchange from water is observed under most cases, supporting addition-elimination. Specific-acid catalysis is the most common mode of hydrolysis, although general-acid catalysis is observed with more electrophilic esters. 

Interestingly, solid-state structure investigations on methyl thiosalicylate dialkylaluminum compounds uncovered close intermolecular S - C(ti) contacts (with an average S - C distance of 3.382 A significantly below the sum of the corresponding van der Waals radii [76, 77]) between the Al-S thiolate units and the ester component (28, Fig. 9) that can effectively compete with the putative sulfur-aluminum hypercoordinate bond (27, Fig. 9) [141]. The latter results provide the first evidence for the competition of intermolecular n Ti interactions, involving the thiolate sulfur atom and the electrophilic ester carbon atom, with the hypercoordinate bond in metal complexes it opens up an interesting area for further studies. 

Several recent review articles provide excellent summaries of the stoichiometric and catalytic reactivity of synthetic metal aqua and hydroxide complexes with carbon-centered electrophiles (esters, amides, peptides, CO2, nitriles) [8, 10-13, 82-90] and phosphate derivatives (activated phosphate esters, DNA, RNA) [6, 11-13, 17-20, 82, 83, 85, 91-99]. In particular, these reviews provide insight into how various metal/ligand assemblies influence catalytic hydrolytic reactions. 

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