Ester enolate precursor

Enders [273] reported a solid-phase ester-enolate imine condensation for the preparation of [i-lactams. The easy access to a number of imines and imine precursors is the advantage of this procedure. Ester enolate precursors were attached to a triazene linker, notably stable under the basic conditions required in order to generate the enolate species. The main limitation concerning this linker is the ability to immobihze only aromatic diazonium salts, due to the intrinsic instability of the aliphatic ones. 

As enolate precursors can be used CH-acidic carbonyl compounds such as malonic esters, cyanoacetic esters, acetoacetic esters and other /3-ketoesters, as well as aldehydes and ketones. Even CH-acidic hydrocarbons such as indene and fluorene can be converted into suitable carbon nucleophiles. 

The reaction of a citronellic ester enolate with electrophilic agents gives open-chain fluorinated products 32 and 33 only.11 The absence of rearranged fluorinated products in this system, a potential precursor to a 5-hexenyl-type radical clock, indicates that free radicals are not intermediates in the path to fluorinated products.12... 

Dimethylalkenes.1 The readily available a-silyl esters, obtained by C-silylation of lithium ester enolates with 1, are useful precursors to trisubstituted alkenes, including 1,1-dimethylalkenes. 

Enantio-enriched enol esters - potential precursors of enantiopure a-arylalkanoic acids - have been prepared by asymmetric coupling of ketenes with aldehydes, using a chiral ferrocene bearing a dimethylaminopyridine function.20... 

Various imines and imine precursors reacted with immobilized ester-enolate-derived triazene esters 481 to give polymer-bounded azetidin-2-ones 482 (Scheme 68). The esters were bound to a benzylamine resin by a triazene linker employing diazonium salts. Traceless cleavage from the triazene linker yielded the desired azetidin-2-ones 483 <2002JOC8034>. 

Not surprisingly, carbonyl compounds are excellent reaction partners for the ester enolates 104. Since the primary adducts are only isolable in singular cases and the subsequent ring opened products (y-lactols) are very versatile precursors for synthesis of heterocycles, these addition reactions as well as those of electrophiles with a S = C unit will be discussed in a separate paragraph (see section 4.6). 

In the first step the base (usually an alkoxide, LDA, or NaH) deprotonates the a-proton of the ester to generate an ester enolate that will serve as the nucleophile in the reaction. Next, the enolate attacks the carbonyl group of the other ester (or acyl halide or anhydride) to form a tetrahedral intermediate, which breaks down in the third step by ejecting a leaving group (alkoxide or halide). Since it is adjacent to two carbonyls, the a-proton in the product p-keto ester is more acidic than in the precursor ester. Linder the basic reaction conditions this proton is removed to give rise to a resonance stabilized anion, which is much less reactive than the ester enolate generated in the first step. Therefore, the p-keto ester product does not react further. 

M. ihara and co-workers utilized an intramolecular double Michael addition for the efficient and completely stereoselective construction of the tricyclo[6.3.0.0 ]undecan-10-one framework during the total synthesis of (+)-longiborneol. The substituted cyciopentenone precursor was exposed to several different reaction conditions, and the highest yield was obtained when LHMDS was used as the base. The first deprotonation took place at C11 the resulting enolate added to C9, and the ester enolate (negative charge located at CIO) in turn added to the cyciopentenone at C3. 

Enantioselective reduction of acetylenic ketones is a route frequently used to prepare the starting materials. The synthesis of a dihydrocompactin precursor 10 involves such a reaction sequence via Ireland rearrangement of 8477. Problems arising with considerable C-silylation of the ester enolate in the rearrangement of 8 can be overcome by adding hexamethylphosphoric triamide to the enolate (1.2 mL/mmol), followed by four equivalents of /ert-butylchlorodimethyl-silane in tetrahydrofuran. The product ester 9 is obtained as a 12 1 mixture of diastereomers in 81 % yield ... 

A 1,3-disubstituted system is shown by ester 489. Treatment with LDA generates the equilibrating enolates 490A and 490B, favoring 490B. Using the acid as the enolate precursor (R = H in 489), alkylation with iodo-... 

The first report on the synthesis of P-lactams through an ester enolate-imine condensation was reported by Gilman and Specter close to 45 years ago [68]. The method involved reaction between an a-bromoester and an imine in the presence of zinc and iodine as catalyst to give P-aminoesters or P-lactams, depending on the reaction conditions employed. The mechanistic and stereochemical features of this reaction have been widely studied [69], however its utility in the preparation of valuable P-lactams for carbapenem synthesis has received very little attention. Recently we [70a] demonstrated the utility of this reaction for the preparation of 3-alkyl-4-acetoxyazetidin-2-ones as precursors for the synthesis of ( ) PS-5 and ( ) PS-6 antibiotics. 

Some new methods for the formation of macrolides have also come to light. An alternative double activation method is the reaction between the usual hydroxy-acid precursors and NN-dimethylformamide dineopentylacetal, affording intermediates of type (113) which cyclize as shown.Yields for n = 10—16 are in the range 40—50%, the remainder of the substrate ending up as cyclic oligomers. Trost and Verhoeven have developed a route to macrolides in which the ring-closure step is a C—C bond formation by intramolecular attack of an ester enolate on a 7r-allyl-palladium complex (viz. 114) prepared from an allylic acetate and Pd(PPh3)4. ... 

Diastereoselective synthesis of a /3-lactam side chain precursor using a chiral imine has also been accomplished by Fujisawa and his collaborators who condensed a chiral imine with an ester enolate in a stereocontrolled way. Thus, reaction of 7.1.17 with enolate afforded the desired cislactam in 84% diastereomeric excess and 90% yield. The other enantiomer of the cis /3-lactam (diastereomeric when R is attached) was not detected (244). 

An intramolecular addition of an ester enolate to a benzyne intermediate generated from the brominated precursor 18 has been reported by Castedo et al. as the key step in the total synthesis of ( )-clavizepine (Scheme 12.7) [19]. 

A variation of the malonic ester synthetic uses a P-keto ester such as 116. In Section 22.7.1, the Claisen condensation generated P-keto esters via acyl substitution that employed ester enolate anions. When 116 is converted to the enolate anion with NaOEt in ethanol, reaction with benzyl bromide gives the alkylation product 117. When 117 is saponified, the product is P-keto acid 118, and decarboxylation via heating leads to 4-phenyl-2-butanone, 119. This reaction sequence converts a P-keto ester, available from the ester precursors, to a substituted ketone in what is known as the acetoacetic acid synthesis. Both the malonic ester synthesis and the acetoacetic acid synthesis employ enolate alkylation reactions to build larger molecules from smaller ones, and they are quite useful in synthesis. 

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