Dianions lithium enolates

The lithium enolate of AUV-dimethylacetamide underwent addition to 2-aryl-1-nitroethenes to give /faryl-y-nitroamides. The lithium dianions and the trianions of /l-oxo esters and /i,y-dioxo esters undergo addition to 2-aryl-1-nitroethenes to give bicyclic compounds as a single dia-stereomer8. 

Three tactical approaches were surveyed in the evolution of our program. As outlined in Scheme 2.7, initially the aldol reaction (Path A) was performed direcdy between aldehyde 63 and the dianion derived from tricarbonyl 58. In this way, it was indeed possible to generate the Z-lithium enolate of 58 as shown in Scheme 2.7 which underwent successful aldol condensation. However, the resultant C7 P-hydroxyl functionality tended to cyclize to the C3 carbonyl group, thereby affording a rather unmanageable mixture of hydroxy ketone 59a and lactol 59b products. Lac-tol formation could be reversed following treatment of the crude aldol product under the conditions shown (Scheme 2.7) however, under these conditions an inseparable 4 1 mixture of diastereomeric products, 60 (a or b) 61 (a or b) [30], was obtained. This avenue was further impeded when it became apparent that neither the acetate nor TES groups were compatible with the remainder of the synthesis. 

A new method of kinetically controlled generation of the more substituted enolate from an unsymmetrical ketone involves precomplexation of the ketone with aluminium tris(2,6-diphenylphenoxide) (ATPH) at —78°C in toluene, followed by deprotonation with diisopropylamide (LDA) highly regioselective alkylations can then be performed.22 ATPH has also been used, through complexation, as a carbonyl protector of y./)-unsaturated carbonyl substrates during regioselective Michael addition of lithium enolates (including dianions of /i-di carbonyl compounds).23... 

Ketone dilithio a,ft-dianion species (74) have been generated by the tin-lithium exchange reaction of the lithium enolate of /3-tributyltin-substituted ketones.291 Reaction with carbon electrophiles gives substituted ketones. 

Ketone dilithio a,f - and a -dianions have been generated by a tin-lithium exchange reaction of the lithium enolate of /3-tributyltin-substituted ketones.30 A chelation-aided approach, which employs /S-dichlorobutyltin-substituted ketones and n-BuLi, has been used for the generation of ketone a, f) -dianions having the Z-geometry at the alkene. The generated dianions have been transformed into ketones... 

The lithium enolates of carboxylic acids can be formed if two equivalents of base are used. Carboxylic acids are very acidic so it is not necessary to use a strong base to remove the first proton but, since the second deprotonation requires a strong base such as LDA, it is often convenient to use two equivalents of LDA to form the dianion. With carboxylic acids, even BuLi can be used on occasion because the intermediate lithium carboxylate is much less electrophilic than an aldehyde or a ketone. 

Kowalski and coworkers reported that lithium enolates of a-bromo ketones can be converted to the corresponding ketone dilithio a,a-dianions by Li—Br exchange with r-BuLi (Scheme if. To generate lithium enolates of a-bromo ketones, either method A or B can be used deprotonation of a-bromo ketones by one equivalent of lithium hexamethyldisilazide (LHMDS) (method A) or deacetylation of enol acetates of a-bromo... 

Cohen and coworkers reported on dilithio species of ketone ,/ -dianions, in which cyclopropyllithium constitutes the / -carbanion portion10. In the examples given in Scheme 9, the first lithium enolate was produced by proton-abstraction with lithium 2,2,5,5-tetramethylpiperidide (LTMP), and the second involved the reductive cleavage of the carbon-sulfur bond by lithium 4,4 -di-tczt-butylbiphenylide (LDBB). 

Table 2 lists examples of monoalkylation reactions of ketone a,p-dianions. The dianions always react with alkylating agents at the /3-carbon atom to generate the corresponding lithium enolates, which can be quenched by water or electrophiles such as TMSC1 and PhSSPh. The last two examples demonstrate the results of the single alkylation reaction of a ketone a,5-dianion with hexyl and allyl bromides, which occurs at the 5-position to give lithium Z-enolates. 

The more reactive ft -carbon atom of ketone a,/ -dianions can be regiospecifically coupled with alkyl halides to give first lithium enolates, which are then trapped by more reactive carbon electrophiles such as allylic halides. The first example shown in Table 8 deals with the sequential /1-alkylation and ce-allylation of a ketone a,/1-dianion1 13. Thus, the dianion underwent regioselective alkylation at the ft carbon with //-pentyl bromide and then allylation with allyl bromide at the a carbon. When an excess of allyl bromide is reacted with the a, ft -dianion, the diallylated product is obtained in a good yield, whereas a threefold excess of pentyl bromide only resulted in the formation of the ft-alkylation product. Similar consecutive alkyl/allyl-type reactions are also possible for ketone a,5-dianions14. 

Single acylation reactions of dianionic cuprates have already been shown in Table 4. After the acylation reactions of these cuprates with one equivalent of an acyl chloride, the resulting lithium enolates can be subjected to a second acylation or alkylation28. The first example shown in Scheme 18 demonstrates such a case, in which the second acylation using benzoyl chloride gave a triketone (Scheme 18). The second example deals with the treatment of the enolate with iodomethane, which resulted in the corresponding 2-methyl-1,4-diketone. 

While this process is not directly observable, Hess Law says that the endothermicity of this reaction is the sum of the next three reactions, equations 15-17. The sum is 566 kJmoC, some 215 kJmol more endothermic than the aforementioned ketene cleavage. We can conclude that lithiation and dianion formation significantly weaken the CC bond in the dilithium enolate as the lithium enolate has a considerably stronger CC bond than ketene. 

The asymmetric hydroxylation of ester enolates with N-sulfonyloxaziridines has been less fully studied. Stereoselectivities are generally modest and less is known about the factors influencing the molecular recognition. For example, (/J)-methyl 2-hydroxy-3-phenylpropionate (10) is prepared in 85.5% ee by oxidizing the lithium enolate of methyl 3-phenylpropionate with (+)-( ) in the presence of HMPA (eq 13). Like esters, the hydroxylation of prochiral amide enolates with N-sulfonyloxaziridines affords the corresponding enantiomerically enriched a-hydroxy amides. Thus treatment of amide (11) with LDA followed by addition of (+)-( ) produces a-hydroxy amide (12) in 60% ee (eq 14). Improved stereoselectivities were achieved using double stereodifferentiation, e.g., the asymmetric oxidation of a chiral enolate. For example, oxidation of the lithium enolate of (13) with (—)-(1) (the matched pair) affords the a-hydroxy amide in 88-91% de (eq 15). (+)-(Camphorsulfonyl)oxaziridine (1) mediated hydroxylation of the enolate dianion of (/J)-(14) at —100 to —78 °C in the presence of 1.6 equiv of LiCl gave an 86 14 mixture of syn/anti-(15) (eq 16). The syn product is an intermediate for the C-13 side chain of taxol. 

Generally, ester enolates of structure (202 R = M, R = Oalkyl) rearrange via a 3,3-shift, whereas the corresponding amide enolates (202 R = M, R = N(alkyl)2) and acid dianions (202 R = M, R = OM) prefer the 2,3-pathway (equation 20). Both pathways have been observed with ketone enolates (202 R = M, R = alkyl). With substrate (179), Koreeda and Luengo observed only traces of Wittig rearrangement product (205), except for the lithium enolate, where (205) accounted for up to 20% of the reaction mixture (equation 21). ° Thomas and Dubini, however, reported predominant formation of 2,3 Wittig products (207) and (209) under base treatment of ketones (206) and (208) (equation 22). ... 

Several ketone lithium enolates and dianions of jS-dicarbonyl substrates similarly undergo highly selective 1,4-addition to a variety of a-enones. Thus, tandem inter- and intramolecular Michael addition using the enolates of a,/l-unsaturated ketones as Michael donors was achieved successfully (Scheme 6.88) [111] treatment of 111-ATPH complex in toluene with a THF solution of the benzalacetone lithium enolate at -78 °C, then heating under reflux for 13 h gave the stereo-chemically homogeneous annulation product in 50% yield almost exclusively. 

Dicarbonyl compounds may be converted into dianions, which react with electrophiles at the more basic site. Huckin and Weiler found that 3-keto ester dianions undergo aldol addition reactions at the more basic methyl position (equation 32). The lithium/sodium dianion shows surprisingly weak reactivity, giving the aldol in only 11% yield after 1 h at -78 °C In contrast, the lithium enolates of simple ketones and esters, which should be much less basic than the 3-keto ester dianion, react with aldehydes to give nearly quantitative yields of aldols in THF in seconds at -78 °C. ° Seebach and Meyer also studied this reaction, and obtained the oxolactone (equation 33). Simple diastereoselection in the reaction of 3-keto ester dianions has also been studied (vide infra). 

The dianion of the hydroxybutyrolactone (87) reacts with aldehydes with high diastereofacial selectivity to give mixtures of dihydroxy lactones (88) and (89) (equation 76 Table 5). ° The lithium enolate shows little simple stereoselection with the sterically undemanding aldehydes phenylacetaldehyde and tetradecanal. Significant stereoselectivity is seen in the reaction with benzaldehyde, and pivalaldehyde gives only a single product. Because the aldol relative stereochemistry in the reactions with benzalde-... 

For lithium enolate anions, the tendency is for the enolate to occupy the concave face of the transition structure cf. Figure 6.4d and 6.5c) and therefore to prefer transition structures such as those illustrated in Figure 6.6b and c. Table 6.2 lists several examples of simple acyclic diastereoselection, which show a tendency for E -> syn and Z —> anti selectivity, in contrast to the tendency observed for hydrocarbon substituted carbanions (Table 6.1). Entries 1 and 2 involve dianions of crotyloxy acetates, and show E -> syn and Z —> anti selectivity. A more complex example involving extension of a steroid side chain (similar to Scheme 6.6a), is 100% anti selective from an -alkene, however [53]. 

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