Lithium zinc enolates

Darzens reactions between the chiral imine 52 and a-halo enolates 53 for the preparation of nonracemic aziridine-2-carboxylic esters 54 (Scheme 3.17) were studied by Fujisawa and co-workers [61], It is interesting to note that the lithium enolate afforded (2K,3S)-aziridirie (2i ,3S)-54 as the sole product, whereas the zinc enolate give rise to the isomer (2S,3i )-54. The a-halogen did not seem to affect the stereoselectivity. 

Tin(Il) shows considerable affinity towards nitrogen, therefore is expected to activate the imino group. The diastereoselective addition of tin(II) enolates derived from thioesters 1 to x-imino-esters 2 is reported12. This reaction proceeds smoothly to afford. vi w-/j-amino acid derivatives 3 (d.r. 95 5) in good yields. Lithium, magnesium, and zinc enolates do not react while titanium enolates give the adducts in low yield with preferential formation of the anti-isomer. 

The diastereoselectivity of the zinc iodide catalyzed reaction of the azetidinone I with the trimethylsilyl enolate derivatives of the chiral 3-(l-oxopropyI)oxazolidinones 6 was considerably lower (about 60 40), although independent generation of the zinc enolate, via exchange of the lithium enolate with zinc bromide, afforded the /9-Iactam carboximide derivatives in a ratio (RIS) 80 20177. 

Other organometallic compounds that are hydrolyzed by water are those of sodium, potassium, lithium, zinc, and so on, the ones high in the electromotive series. Enantioselective protonation of lithium enolates and cyclopropyllithium compounds have been reported. When the metal is less active, stronger acids are required. For example, R2Zn compounds react explosively with water, R2Cd slowly, and R2Hg not at all, though the latter can be cleaved with concentrated HCl. How-... 

The addition of carbonyl compounds towards lithiated 1-siloxy-substituted allenes does not proceed in the manner described above for alkoxyallenes. Tius and co-work-ers found that treatment of 1-siloxy-substituted allene 67 with tert-butyllithium and subsequent addition of aldehydes or ketones led to the formation of ,/i-unsaturated acyl silanes 70 (Scheme 8.19) [66]. This simple and convenient method starts with the usual lithiation of allene 67 at C-l but is followed by a migration of the silyl group from oxygen to C-l, thus forming the lithium enolate 69, which finally adds to the carbonyl species. Transmetalation of the lithiated intermediate 69 to the corresponding zinc enolate provided better access to acylsilanes derived from enolizable aldehydes. For reactions of 69 with ketones, transmetalation to a magnesium species seems to afford optimal results. 

So far, numerous efforts by Erdik and coworkers for amination of lithium and zinc enolates with 6f were found to be unsuccessful. ... 

In step D, a chiral auxiliary, also derived from cysteine, is used to achieve double stereodifferentiation in an aldol condensation. A tin enolate was used. The stereoselectivity of this reaction parallels that of aldol condensations carried out with lithium or zinc enolates. Once the configuration of all the centers has been established, the synthesis proceeds to P-D-lactone by functional group modifications. 

Zinc enolates obviously give a better induction than the corresponding lithium enolates. This condensation also occurs with good yields with various enolates generated from ketones, esters and lactones, however, the enantiomeric excesses are poor27. 

Chiral P-formyl-p-hydroxycarboxylic esters were also obtained by the employment of either lithium or zinc enolate of ethyl acetate in place of Grignard reagents in the above-mentioned reaction in moderate to excellent optical purity (62 to 92 % e.e.)122). 

This reaction sequence has been extended to lithium enolates. The deprotonation of the aminoester 54 with LDA followed by a transmetalation with zinc bromide in ether furnishes a zinc enolate, which readily adds to the double bond providing the proline derivative 55 in high diastereoselectivity (Scheme 23) . ... 

An interesting variation of this methodology was developed whereby zinc enolates 127 were employed giving 2-ester-substituted pyrrolidines 128-13060c. The enolates 127 were obtained via transmetallation of lithium ester enolates 126 with ZnBr2 (equation 59). 

On the other hand, the O-metallated structure E is also observed, for example when a zinc enolate is prepared by transmetallation of a lithium enolate with a Zn(II) salt5. 

Three approaches to zinc enolates are commonly adopted the process associated to the classical Reformatsky reaction is based on the insertion of Zn(0) into the carbon—halogen bond of an a-haloester. Two additional routes involve (i) transmetallation of a lithium enolate with a Zn(II) salt (Section V.A) and (ii) the transition-metal-catalysed conjugate addition of diethylzinc to Michael acceptors (Section V.B). 

The most general route to transition metal enolates involves lithiation of an enolisable substrate followed by transmetallation with a proper metal halide several reports are available in the literature where zinc enolates are prepared via lithium/zinc exchange, and selected examples are discussed henceforth. 

In the reaction of a simple ketone enolate with a chiral aldehyde, the use of a zinc enolate may offer advantages in terms of facial selectivity with respect to the use of a lithium enolate. This is exactly the result recorded in the condensation of the kinetic enolate of 2-undecanone 140 with 141, the key step in a total synthesis of (-l-)-preussin 142, a fermentation product with antifungal and antibacterial activity (equation 77)169. While 2-undecanone Li enolate did not display stereocontrol when added to 141, an acceptable syn diastereoselectivity was displayed by the Zn enolate 140. 

The zinc-enolate cyclizations are not restricted to a-aminoesters as /3-aminoesters have also been successfully involved in such reactions275. The preformed lithium enolate generated by treatment of the /J-arninoester 423 with LDA had to be added dropwise to an ethereal solution of ZnBr2 in order to avoid a competing /3-elimination reaction induced by the zinc enolate. this reverse addition protocol was respected, a smooth carbocyclization reaction occurred and provided, after hydrolysis, the substituted 3-carbomethoxypyrrolidine 424 as a 87/13 mixture of diastereomers (equation 183). 

The Eschenmoser reaction is extremely useful for the conversion of amides into enaminoesters via the thioamide reaction with a-haloesters, and triphenylphosphine mediated sulfide contraction, and we are fortunate that Shiosaki has published a thorough review on this topic [180]. The accompanying scheme shows a typical example for which an organometallic route with a lithium or a zinc enolate was not successful [181]. 

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. 

P-Hydroxy esters. 4 The lithium enolate of ethyl-N-methoxyacetimidate (2) reacts with (S)-( — )-l to provide (R)-(4-methylphenylsulfinyl)-ethyI-N-methoxyacetimidate (3). The enolate of 3 reacts with an aldehyde to give the adducts 4, which are converted by desulfuration and hydrolysis into P-hydroxy acids (5). The stereochemical outcome depends on the experimental conditions. The reaction of the lithium enolate of 3 with benzaldehyde under thermodynamic control gives (S)-5 in 75% ee. Use of the zinc enolate also gives (S)-5, in 86% ee, but use of zirconium enolate, obtained by addition of Cp2ZrCl2 to the lithium enolate, results in (R)-5 in 88% ee. 

---