Lithium enolates tandem reactions

Several examples of conjugate addition of carbanions carried out under aprotic conditions are given in Scheme 2.24. The reactions are typically quenched by addition of a proton source to neutralize the enolate. It is also possible to trap the adduct by silylation or, as we will see in Section 2.6.2, to carry out a tandem alkylation. Lithium enolates preformed by reaction with LDA in THF react with enones to give 1,4-diketones (Entries 1 and 2). Entries 3 and 4 involve addition of ester enolates to enones. The reaction in Entry 3 gives the 1,2-addition product at —78°C but isomerizes to the 1,4-product at 25° C. Esters of 1,5-dicarboxylic acids are obtained by addition of ester enolates to a,(3-unsaturated esters (Entry 5). Entries 6 to 8 show cases of... 

The tandem Michael and cyclopropanation reaction of lithium enolates with nitroalkenes gives tricyclic ketones in one pot, as shown in Eq. 7.42.43... 

The ability of lithium amides to add on enoates to provide lithium enolates has been known for some while161. This reaction has found many useful synthetic applications, one of the most spectacular being the tandem, stereocontrolled, conjugate additions (Scheme 38)162. 

A remarkable example of tandem conjugate addition-aldol reaction has been recently reported by Tomioka and coworkers. The transient lithium enolate, generated by 1,4-addition of benzyl lithium thiolate onto the corresponding a,-unsaturated ester182,595, is followed by an intramolecular aldol tandem cyclization, resulting in a five-membered... 

This volume, which complements the earlier one, contains 9 chapters written by experts from 7 countries. These include a chapter on the dynamic behavior of organolithium compounds, written by one of the pioneers in the field, and a specific chapter on the structure and dynamics of chiral lithium amides in particular. The use of such amides in asymmetric synthesis is covered in another chapter, and other synthetic aspects are covered in chapters on acyllithium derivatives, on the carbolithiation reaction and on organolithi-ums as synthetic intermediates for tandem reactions. Other topics include the chemistry of ketone dilithio compounds, the chemistry of lithium enolates and homoenolates, and polycyclic and fullerene lithium carbanions. 

The y-lactam 110 is prepared by the reaction of the lithium silyl-substituted ynolate 105 with the aziridine 108 activated by a p-toluenesulfonyl group. The initial product is the enolate 109, which can be acidified to yield the a-silyl-y-lactam 110. Intermediate 109 can be trapped by aldehydes to afford the a-alkylidene-y-lactams 111 via a Peterson reaction (equation 45) . These reactions may be considered to be formal [3 + 2] cycloadditions as well as tandem reactions involving nucleophilic ring opening and cyclization. 

Bodnar, P. M., Shaw, J. T., Woerpel, K. A. Tandem Aldol-Tishchenko Reactions of Lithium Enolates A Highly Stereoselective Method for Diol and Triol Synthesis. J. Org. them. 1997, 62, 5674-5675. 

Woerpel has recently reported a tandem double asymmetric aldol/C=0 reduction sequence that diastereoselectively affords propionate stereo-triads and -pentads commonly found in polyketide-derived natural products (Scheme 8-2) [14], When the lithium enolate of propiophenone is treated with excess aldehyde, the expected aldolates 30/31 are formed however, following warming to ambient temperature a mono-protected diol 34 can be isolated. In a powerful demonstration of the method, treatment of 3-pentanone with 1.3 equiv of LDA and excess benzaldehyde yielded product in corporating five new stereocenters in 81% as an 86 5 5 3 mixture of diastereomers (Eq. (8.8)). A series of elegant experiments have shown that under the condition that the reaction is conducted, the aldol addition reaction is rapidly reversible with an irreversible intramolecular Tischenko reduction serving as the stereochemically determining step (32 34, Scheme 8-2). 

Both these silyl enol ethers 50 and 52 could of course be hydrolysed to the saturated aldehydes, but that would be to sacrifice the useful reactivity of these intermediates in aldol and other reactions explored in chapters 2-6. A more productive development is to react the silyl enol ether with an electrophile and hence develop a synthesis from three components in two consecutive reactions.23 This approach has formed the basis of many modern syntheses as it develops the target molecule so quickly and is discussed in chapter 37 under tandem reactions . It is not necessary to trap the enolate with Me3SiCl when lithium cuprates are used with ketones as the lithium enolate is the product of 1,4-addition. You may choose the lithium enolate or the silyl enol ether, whichever is more appropriate for the next step. 

Simple stereoselective aldol reactions (chapter 3) can also be controlled by tandem conjugate addition. Addition of Me2CuLi to the simple unsaturated ketone 27 gives the lithium enolate 28. It would be very difficult to produce this enolate from the parent ketone MhiCO.Me with regio- or stereoselectivity. The cyclic transition state 29 with zinc replacing lithium then shows the way to the anti-aldol7 30. 

The tandem Michael-Michael reaction gave a very different result. This time the lithium enolate 44 reacted with the unsaturated ester 46 at -78 to -40 °C and gave an 86% yield of a single adduct, endo-49. The most obvious conclusion is that the reaction does indeed go by a two-step mechanism, especially as the stereochemistry can be convincingly explained by lithium coordination to the two reagents 50. There is just a possibility that it is a Diels-Alder reaction showing greater stereoselectivity because of the lower temperature. 

The stereochemistry is controlled by the first conjugate addition represented mechanistically as 50a that gives the new lithium enolate in the right conformation for the second conjugate addition 51 giving the enolate 52 of endo-49. We shall assume that these reactions are tandem Michael-Michael additions for the rest of this section. 

The tandem aldol reaction simply involves adding an aldehyde to the lithium enolate before work-up. Since it is a Z-enolate we can expect a syn aldol. The Z -enolate 90 is indeed formed (we are drawing the molecules in a different way to make the aldol stereochemistry clearer) and it does give a syn-aldol with the added advantage that only one of the two possible. vyn-aldols 90 predominates. The two benzylic groups can be removed, the first with CAN , ceric ammonium nitrate, Ce(IV)(NH4)2(N03)6 and the second by reduction, to give one enantiomer of 95. 

An aldol-Claisen tandem sequence is illustrated by the reaction of the cinnamaldehyde (211) with the chiral acetate (212) to give (88) followed by treatment with the lithium enolate (89) to give (90 equation 46 see equation 25, Section 3.6.3.4.2). ° ... 

Lithium enolate 329 and a nitrile-furnished enamino ester 330, which on condensation with isocyanates/isothiocyanates gave N-3 substituted 331 (X = O, S) through a tandem nucleophilic addition-intramolecular aza-Michael reaction (Scheme 126) (09JFC1145). 

Conjugate Addition. Conjugate addition-aldol tandem reaction of Q , S-unsaturated esters in the presence of catalytic amount of lithium phenylthiolate proceeds stereoselectively with the formation of aleohol (after protodesilylation). The aldol reaction of the lithium enolate with aldehyde takes place from the hottom face, anti to the phenylsulfenyl group in the thermodynamic enolate conformation (eq 30). ... 

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