Enolates of esters

Four different orientations are possible when the enantiofaces of (E)- and (Z)-enolates and an ( )-enone combine via a closed transition state, in which the olefinic moieties of the donor and the acceptor are in a syn arrangement. It should be emphasized that, a further four enan-tiomorphous orientations of A-D are possible leading to the enantiomers 2 and 3. On the basis of extensive studies of Michael additions of the lithium enolates of esters (X = OR) and ketones (X = R) to enones (Y = R) it has been concluded ... 

Closely related to enolate additions to enones is the diastereoselective 1,4-addition of lithium enolates of esters, thioesters and amides to a,/ -unsaturated esters. These reactions provide syn-or ar /-2,3-disubstituted glutarates (pentanedioates). 

Tabic 4. Pentanedioatcs from Addition of the Lithium Enolates of Esters to x./MJnsaturated Esters LiO... 

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.). 

Aldol Addition Reactions of Enolates of Esters and Other Carbonyl Derivatives... 

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

Arylations have also been extended to zinc enolates of esters (Reformatsky reagents).178... 

More traditional carbon nucleophiles can also be used for an alkylative ring-opening strategy, as exemplified by the titanium tetrachloride promoted reaction of trimethylsilyl enol ethers (82) with ethylene oxide, a protocol which provides aldol products (84) in moderate to good yields <00TL763>. While typical lithium enolates of esters and ketones do not react directly with epoxides, aluminum ester enolates (e.g., 86) can be used quite effectively. This methodology is the subject of a recent review <00T1149>. 

The kinetic enolization of esters with amide bases such as lithium diisopropylamide (LDA) and the resultant aldol condensations with representative aldehydes have been investigated by several groups (2,32,33). The enolate stereochemical assignments were determined by silylation in direct analogy to studies reported by Ireland (34). The preponderance of (E )-enolate observed with LDA (THF) in these... 

The enolates of other carbonyl compounds can be used in mixed aldol condensations. Extensive use has been made of the enolates of esters, thioesters, amides, nitriles, and nitroalkanes. Scheme 2.4 gives a selection of such reactions. 

Figure 2.7 Reaction of enolates of esters derived from monofluoroacetic acid. ...

Silylation.1 l.ithium enolates of esters and lactones undergo ot-silylation with this reagent rather than the more usilal O-silylation encountered with other reagents. Addition of HMPT results in considerable O-silylation. The reagent effects only O-silylation of ketones. 

Asymmetric hydraxylation of lithium enolates of esters and amides.2 Hydroxylation of typical enolates of esters with ( + )- and (-)-l is effected in 75-90% yield and with 55-85% ee. The reaction with amide enolates with ( + )- and ( — )-l results in the opposite configuration to that obtained with ester enolates and with less enantioselectivity. Steric factors appear to predominate over metal chelation. 

The enolates of esters or ketones again are envisioned to add to ir-allylpalladium intermediates in the second step of the proposed mechanism (Scheme 3X96... 

ASYMMETRIC OXIDATION OF LITHIUM ENOLATES OF ESTERS AND AMIDES USING (+)-(2R.8aS)-10-(CAMPHORYLSULFONYL)OXAZIRIDINE... 

Scheme 36 (3-lactam ring opening with Li-enolates of esters. An access to the hydroxy (keto) ethylene dipeptide isostere... 

Lithium enolates of esters 72 can be made direct from the ester itself with the strong hindered bases LDA or LiHMDS [(Me3Si)2NLi] and react cleanly with even enolisable aldehydes and ketones, e.g. 74, to give aldols 75 in high yield.13... 

Reaction of ester enolates with epoxides.1 Lithium enolates of esters do not open epoxides, but the aluminum enolates do. Li to A1 exchange can be effected with diethylaluminum chloride. The less substituted O-C bond is cleaved and the syn-diastereomer predominates. Reactions of optically active epoxides proceed with high... 

Complete details for synthesis of ( + )- or ( —)-l from (IS)- or (1R)-10-camphor-sulfonic acid in 77% yield are now available. In general, this oxaziridine is less active than other N-sulfonyloxaziridines, but it is the preferred reagent for hydrox-ylation of lithium enolates of esters, amides, and ketones in 30-95% ee.1... 

The Reformatsky reagents, i.e. zinc enolates of esters, undergo Ni catalysed cross-coupling with aryl halides.53 The Ni catalysed reaction of arylzincs with a-bromoacetates also permits a-arylation of esters54 (Scheme 11.13). However, a-alkenylation of enolates of ketones, aldehydes, and esters has been less satisfactory. Its further development is clearly desirable. Alternatively, a-alkenylation of a-iodoenones in conjunction with conjugate reduction discussed earlier should be considered. 

Ghosh also took advantage of the C—2 hydroxyl moiety of aminoindanols as a handle in the aldol reaction. Chiral sulfonamide 41 was O-acylated to give ester 42. The titanium enolate of ester 42 was formed as a single isomer and added to a solution of aldehyde, precomplexed with titanium tetrachloride, to yield the anft -aldol product 43 in excellent diastereoselectivities.63 One additional advantage of the ester-derived chiral auxiliaries was their ease of removal under mild conditions. Thus, hydrolysis of 43 afforded a ft -a-methyl- 3-hydroxy acid 44 as a pure enantiomer and cis-1-/ -1 o I y I s u I f on a m i do- 2 - i n da n ol was recovered without loss of optical purity (Scheme 24.7).63... 

The addition of an alkaline earth metal enolate A to a carbonyl compound is always an exer-gonic process irrespective of whether the enolate is derived from a ketone, an ester, or an amide and whether the carbonyl compound is an aldehyde or a ketone (Figure 13.44, top). One of the reasons for this exergonicity hes in the fact that the alkaline earth metal ion is part of a chelate in the alkoxide B of the aldol addition product. The driving forces for the additions of alkaline earth metal enolates of esters and amides to carbonyl compounds are further increased because the aldol adducts B are resonance-stabilized, whereas the enolates are not. 

Zinc enolates, made from the bromoesters, are a good alternative to lithium enolates of esters. The mechanism for zinc enoiate formation should remind you of the formation of a Grignard reagent. 

Disconnection on either side of the alkyne leads us back to a bromo-alcohol alkylating agent. In the synthesis of the pheromone, it turned out to be best if the hydroxyl group was protected as its THP ether. You should be able to think of other alkylation-type reactions that you have met that proceed reliably and therefore provide a good basis for a disconnection—the alkylation of enolates of esters or ketones, for example (Chapter 26). 

Nucleophilic dithioacetalisation can be used to introduce acyclic dithioacetals adjacent to carbonyls too. For example the lithium enolate of ester 96.1 was converted to the dithioacetal 96.2 in good yield using methyl methanethiosulfo-nate [Scheme 2.96].191 After elaboration of the chain, the carbonyl group was deprotected by silver(I)-assisted oxidative hydrolysis. 

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