Ester enolates, bromo

Carboxylic Ester Enolates with a-Bromo Boronic Esters... 

Ester enolates replace bromide from a-bromo boronic esters with remarkable diastereoselcctiv-ity. (Dibromomethyl)lithium is generated by addition of lithium diisopropylamide to dibro-momethane in the presence of a boronic ester at — 78 "C to produce an a-bromo boronic ester. Reaction of the a-bromo boronic ester with lithium 1-tert-butoxy-Tpropen-l-olate yields a product that is almost exclusively the threo-isomer (d.r. = 15 1 to 60 1), as shown by conversion to the / -hydroxy carboxylic ester24. It is worth noting the facility with which a-bromo boronic esters racemize in the presence of halide ions72. 

Early attempts to utilize acetaldehyde and monosubstituted acetaldehyde derivatives in the Darzens reaction were unsuccessful, presumably due to competitive base-catalyzed self-condensations of the aldehydes. It was subsequently reported Aat generation of the requisite bromo ester enolates with LHMDS at -78 °C provides a species which reacts with a variety of aldehydes and ketones to afford glycidic esters in good to excellent isolated yields (equation 25). ... 

Reductive deconjugation of 2-bromo-2-alkenoates. The process probably involves Michael addition, debromination, and phosphite elimination prior to the kinetic protonation of the ester enolates. Triethylamine is required as base to promote the reaction. 

As an example, ferf-butyl (45)-l-methyl-2-oxoimidazolidine-4-carboxylate was used by Nunami and colleagues as a chiral auxiliary for DKR of a-bromo-carboxylic acids. In this case, the nucleophile was a malonic ester enolate and the role of the polarity of the solvent (hexamethylphosphoramide, HMPA) was demonstrated (Scheme 1.2). The alkylated products were further easily converted to chiral a-alkylsuccinic acid derivatives and chiral jS-amino acid derivatives. Moreover, these authors showed that this methodology could be extended to other nucleophiles such as amines." Therefore, the reaction of a diastereomeric mixture of tert-bvAy (45)-l-methyl-2-oxoimidazolidine-4-carb-oxylate with potassium phthalimide predominantly afforded fcrf-butyl (45)-1-methyl-3-((25)-2-(phthaloylamino)propionyl)-2-oxoimidazolidine-4-carboxylate in 90% yield and 94% diastereomeric excess (de). The successive removal of the chiral auxiliary afforded A-phthaloyl-L-alanine. 

It is also possible to introduce additional functionality into the cK-silyl ester. Thus f-butyl (trimethylsilyl)chloroacetate reacts with carbonyl compounds after ester enolate formation with LDA to form f-butyl Q -chloro-a, 8-unsaturated esters, although the elimination of the silyl moiety may have to be encouraged by the use of thionyl chloride, as it also is with the a-bromo analog. A second silyl group, with its additional bulk, can allow for high stereoselection, although the outcome does depend on the metal counterion used in the enolate. ... 

Deoxy-D-erythro-pentose (2 1) has been elaborated from 2,3-0-isopropylldene-D-glyceraldehyde (25) either by a stereoselective dipolar cycloaddition reaction (Scheme 6, route a)" or by a stereoselective aldol condensation involving a boronated ester enolate reagent (route b). The DL-analogue of (24) has been synthesized from 1,3 2,4-di- -benzylidene-erythrltol by mono-bromination (Hanessian s procedure with NBS) to give a l-bromo-3- -benzoate,... 

Lithium alkoxyacetylides 233 represent synthetic equivalents of ester enolates. They can also be generated by the treatment of trichloroethene with n-butyllithium in the presence of the appropriate potassium alkoxide or directly from l-bromo-2-... 

The palladium-catalysed -arylation of ester enolates with aryl bromides has been studied both experimentally and computationally. The effect of the ligand on the selectivity of the a/j9-arylation reactions of ortho- and mcta-bromofluorobenzenes has been described. While / -arylation was predominantly observed with 1-bromo-2-fluorobenzene for a range of biarylphosphine ligands, a-arylation was primarily observed with l-bromo-3-fluorobenzene. It has been shown that electronic factors play a major role in the a// -arylation selectivity, with electron-withdrawing substituents favouring 0-arylation. 

In recent years, several modifications of the Darzens condensation have been reported. Similar to the aldol reaction, the majority of the work reported has been directed toward diastereo- and enantioselective processes. In fact, when the aldol reaction is highly stereoselective, or when the aldol product can be isolated, useful quantities of the required glycidic ester can be obtained. Recent reports have demonstrated that diastereomeric enolate components can provide stereoselectivity in the reaction examples include the camphor-derived substrate 26, in situ generated a-bromo-A -... 

Various diastereoselective Michael reactions are based on y-bromo-, y-alkyl-, or y-alkoxy-2(5//)-furanones following the trans-face selectivity shown in Section 1.5.2.3.1.2. Thus the lithium enolates of esters such as ethyl propanoate, ethyl a-methoxyacetate and ethyl a-phenylacetate add to methoxy-2(5/f)-furanone with complete face selectivity269-273 (see Section 1.5.2.4.4.2.). 

The mechanism of these alkylations involves a tetracoordinate boron intermediate formed by addition of the enolate of the a-bromo ester to the organoborane. The migration then occurs with displacement of bromide ion. In agreement with this mechanism, retention of configuration of the migrating group is observed.23... 

Methyl 2-bromo-2-cyclopropylideneacetate (11a) has never been tested in these reactions, but has been used as a starting material for the stepwise construction of 1,6-heptadienes with methylenecyclopropane units for intramolecular Heck reactions. Thus, bromo ester 11a, after reduction, subsequent conversion of the resulting alcohol to the bromide and coupling with enolates of substituted malonates, was transformed into dienes of the type 254 (Scheme 73) - versatile synthetic blocks for the preparation of functionally substituted spirocyclopropanated bicyclo[4.3.0]nonenes 255a-d by a domino Heck-Diels-Alder reaction [122a]. 

A typical example is alkylation of the steroid ester 11. Treatment of 1 with LDA in tetrahydrofuran at —78 °C for 1 hour followed by addition of 4-bromo-2-methyl-2-butene in the presence of HMPA at —78 °C to —20 °C furnished an 87 13 mixture of the monoalkylated esters 3a and 3b. The potassium enolate 2 (KHMDS, THF, —78 °C, 1 h) has been hydroxylated with an oxaziridine reagent in 70% yield to give a 3 1 mixture of a-hydroxy derivatives. 

The most advanced synthetic methods involve chiral directors that have C2 symmetry. These are discussed first for x-chloro boronic esters (Section 1.1.2.1.2.1.) and then for the bromo analogs, which are better in reactions involving enolates (Section 1.1.2.1.2.2.). The first syntheses of secondary alcohols utilized pinanediol as chiral director (Section 1.1.2.1.2.3.). The method is marginally successful for some tertiary alcohols (Section 1.1.2.1.2.4.). 

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