Zinc enolates electrophiles

Scheme 2.23 provides some examples of conjugate addition reactions. Entry 1 illustrates the tendency for reaction to proceed through the more stable enolate. Entries 2 to 5 are typical examples of addition of doubly stabilized enolates to electrophilic alkenes. Entries 6 to 8 are cases of addition of nitroalkanes. Nitroalkanes are comparable in acidity to (i-ketocslcrs (see Table 1.1) and are often excellent nucleophiles for conjugate addition. Note that in Entry 8 fluoride ion is used as the base. Entry 9 is a case of adding a zinc enolate (Reformatsky reagent) to a nitroalkene. Entry 10 shows an enamine as the carbon nucleophile. All of these reactions were done under equilibrating conditions. 

This approach to C (1) nucleophiles has been recently extended. The Lichten-thaler zinc enolate reacts efficiently with more demanding aldehyde electrophiles to provide C-disaccharides [108,109], and activation of the C(l) bromide 276 can also be carried out using CeCl3/NaI (Scheme 72). The latter method is based on the earlier work of Ftdcuzawa [110] and others [111], although the mechanism of this cerium-mediated reaction has yet to be fully understood. 

Zinc enolates are exploited in a variety of synthetic applications where they are trapped by suitable electrophiles, particularly by carbonyl compounds. 

The addition of zinc enolates to alkenes in the intramolecular version finds several examples in recent literature. Thus, hydrazone 155, subjected to the same treatment reported for 151 (equation 80), undergoes diastereoselective 5-exo-trig (n = 1) or 6-exo-trig (n = 2) carbocyclization to yield -156, which on reaction with the electrophile E+ gives 157 (equation 81)174. 

The copper-catalysed asymmetric conjugate addition of dialkylzinc leads to homo-chiral zinc enolates.28 These intermediates have been trapped in situ with activated allylic electrophiles, without the need for additional palladium catalysis (Scheme 3). 

Transmetallation of 12 with a catalytic amount of the higher order cyanocuprate Me2Cu(CN)Li2, in the presence of Me3ZnLi and with slow addition of enone 7 led first to the initial conjugate addition product 14, then to zinc enolate 15 after Cu-to-Zn transmetallation. The third component, the electrophile, either an aide-... 

High anti-diastereoselectivity is observed for several aromatic imines for ortho-substituted aromatic imines the two newly formed stereocenters are created with almost absolute stereocontrol. Aliphatic imines can also be used as substrates and the reaction is readily performed on the gram scale with as little as 0.25 mol% catalyst loading. Furthermore, the Mannich adducts are readily transformed to protected a-hydroxy-/8-amino acids in high yield. The absolute stereochemistry of the Mannich adducts revealed that Et2Zn-linked complex 3 affords Mannich and aldol adducts with the same absolute configuration (2 R). However, the diastereoselectiv-ity of the amino alcohol derivatives is anti, which is opposite to the syn-l,2-diol aldol products. Hence, the electrophiles approach the re face of the zinc enolate in the Mannich reactions and the si face in the aldol reactions. The anti selectivity is... 

The oxidative insertion of zinc into a-halo carbonyl compounds and the subsequent reaction of the zinc enolates formed with various electrophiles can either be carried out in a one-pot Barbier-type fashion or in two consecutive steps.1-3 Zinc enolates exhibit a reasonably high stability over a wide temperature range (from -78°C to above 80°C for short periods of time) compared to other metal enolates. Although it has been reported that solutions of BrZnCH2COOtBu can be stored for several days without loss in activity,5 it is generally advisable to use freshly prepared reagents in order to avoid... 

Once again, the zinc enolates generated in the conjugate addition can be trapped with various electrophiles besides protons. For example, reaction of the enolate 270 obtained by treating cyclohex-2-enone with dimethylzinc in the presence of Cu(OTf)2 and phosphoramidite 269 with trimethylsilyl triflate and diiodomethane provided the cyclopropanation product 271 with good diastereoselectivity and high enantiomeric excess and chemical yield... 

The pyrrolidinylmethylzinc reagents derived from the carbocyclization of zinc enolates were further functionalized with various electrophiles such as iodine or allyl bromide. In this last case, three carbon-carbon bonds, and one ring were formed in a single operation. 

On the basis of this concept the same group has developed a similar strategy using a copper-catalyzed addition of organozinc reagents to enones, followed by trapping of the resulting zinc-enolate by ketones, esters or nitriles as terminal electrophiles (Scheme 35) [83]. 

Electrophile) used, zinc enolate intermediates obtained in organozmc addition to enones can be either O-trapped or C-trapped (Scheme 28). 

If the reaction between an a-halo ketone and zinc is carried out in an qirotic solvent in the presence of an electrophilic reagent, the zinc enolate (6) can be trapped. Products corresponding to reaction at carbon are observed with carbon electrophiles (alkyl halides or aldehydes equation 8), but reaction occurs at oxygen with halosilanes and acid anhydrides (equation 9). " ... 

Traditionally, aldol reactions were carried out under protic conditions, such that the enolate was formed reversibly (see Volume 2, Chapter 1.5). An added measure of control is possible if one uses a sufficiently strong base that the enolate may be quantitatively formed prior to addition of the electrophile. The renaissance that has occurred in the aldol reaction in the last two decades has been mainly due to the development of methods for the formation and use of preformed enolates. The simplest enolates to prepare are those associated with lithium and magnesium, and there now exists a considerable literature documenting certain aspects of lithium and magnesium enolate aldol chemistry. This chapter summarizes the aldol chemistry of preformed enolates of these Group I and Group II metals. Other chapters in this volume deal with boron enolates, zinc enolates, transition metal enolates and the related chemistry of silyl and stannyl enol ethers. 

Highly diastereo- and enantio-selective catalytic capture of chiral zinc enolates using nitroolefins as electrophiles has been described. The tandem y-nitro ketone products were obtained in the presence of a monodentate phosphoramidite ligand, in good yields with high diastereo- and enantio-selectivities (up to 96% ee). 

The zinc enolate formed as an intermediate in these conjugate addition reactions can be trapped by an electrophile in situ to provide further functionalization of the substrate. This is demonstrated by the synthesis of the anticancer agent clavularin B (eq 103). Sequential conjugate addition to cycloheptenone of Me2Zn in the presence of catalytic CuOTf-chiral peptide ligand complex, and enolate alkylation with 4-iodo-1-butene provide the key compound with 97% ee. 

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