Zinc enolates synthesis

They have developed direct asymmetric synthesis of quaternary carbon centers via addition-elimination process. The reactions of chiral nitroenamines with zinc enolates of a-substituted-8-lactones afford a,a-disubstituted-6-lactones with a high ee through addition-elimination process, in which (5)-(+)-2-(methoxy methy l)pyrrolidine (SMP) is used as a chiral leaving group (Eq. 4.96).119 Application of this method to other substrates such as a-substituted ketones, esters, and amides has failed to yield high ee. 

Tandem 1,4-addition to cycloalkenones constitutes an extremely versatile and elegant methodology for the synthesis of 2,3-disubstituted cycloalkanones, as is evident from its application in areas such as prostaglandin synthesis. Noyori et al. have reported the use of organozinc reagents in copper-catalyzed tandem additions [64]. The zinc enolate resulting from the catalytic enantioselective 1,4-addition of Et2Zn to cyclohexenone reacts readily with an aldehyde in a subsequent aldol condensation. 

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. 

In the course of examining the CAI effect of conformational restriction of the C3-side-chain, intermediate 24 was prepared. Shankar and co-workers (Shankar et al., 1996) demonstrated that 10, a key intermediate in the research synthesis could be accessed by Wacker oxidation of olefin 24 (Scheme 13.7). Additionally, an alternative chiral variant of the well-precedented addition of zinc enolates to imines was demonstrated. Treatment of the bromoacetate 25, derived from 8-phenylmenthol with zinc and sonication followed by imine addition afforded 26 in 55% yield with greater than 99% de. Ethyl magnesium promoted ring-closure followed by C3 alkylation with 28, intercepts the previously demonstrated route through formation of olefin 24 (Shankar et al., 1996). 

Because zinc enolates are intrinsically reactive species, especially towards carbonyl compounds, the attempted synthesis of such species often results in the formation of selfcondensation products which are often polymeric materials. Only in a few cases could pure organozinc enolates be isolated and structurally characterized. 

In this chapter attention will be focused on the different protocols recently developed to prepare zinc enolates, and on the most significant applications of these reactive intermediates in the field of organic synthesis. 

The electron-poor aromatic ring of 1-acylpyridinium ions is known to easily undergo nucleophilic addition by carbon nucleophiles an example was proposed by Comins and coworkers, who exploited the addition of zinc enolate 68 to enantiopure 67 (R = trans-2-(a-cumyl)cyclohexyl) in a total synthesis of (-F)-cannabisativine (equation 42)125. 

An efficient asymmetric synthesis of / -lactams, reported by van Koten and coworkers128, was based on a-aminoesters as chiral auxiliaries and on the preformed imine-ZnCl2 complex (e.g. structure 72 in equation 45), which was then added to the glycine zinc enolate 73. The presence of ZnCl2 as Lewis acid was essential to ensure complete lactamization. 

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 carbocyclization reaction was applied to the synthesis of diverse 3-substituted proline chimeras. To this end, the stable cyclic organozinc intermediate... 

Aldol condensation of the zinc enolate of resin-bound alkyl ester 29 with aromatic aldehyde or ketone forms a P-hydroxy ester, which upon treatment with DIBAL-H leads to simultaneous reduction and cleavage of the ester moiety from the resin to give a soluble 1,3-diol 31 [31], Parallel synthesis utilizing three ester and nine carbonyl building blocks afforded a library of 27 analogs which was screened for antioxidative efficiency using a ferric thiocyanate assay. 

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