Homoenolate, copper

The zinc homoenolates from cyclopropanes 15. react in the presence of MejSiCl/HMPA with a,[3-unsaturated ketones to give good yields of 1,6-D systems, by a copper-mediated (CuBr-Me2S) Michael-type addition (Table 5.4). 

COPPER-CATALYZED CONJUGATE ADDITION OF A ZINC HOMOENOLATE ETHYL 3-[3-(TRIHETHYLSILYL0XY)CYCL0HEX-... 

Among the characterized metal homoenolates, only zinc homoenolate of alkyl propionate undergoes substitution reactions with electrophiles under suitable conditions. Two types of metal catalysts, copper(I) and metals of the nickel triad (e.g. Pd), have successfully been used to effect allylation, arylation, and vinylation reactions. 

Zinc homoenolate reacts with allylic halides and diene monoepoxides under copper catalysis [29]. Treatment of the zinc nomoenolate with a catalytic amount of Cu(II) in a polar solvent (e.g. hexamethylphosphoramide, HMPA, N,N-dimethylacetamide, DMA) generates a copper species which undergoes clean Sn2 allylation reactions Eq. (40). Polar solvents not only accelerate the reaction but greatly improve the SN2 selectivity. A variety of allylating reagents can be employed in this reaction (Table 9). The SN2 /SN2 ratio is particularly high (close to 100%) when the alkylated carbon bears no substituents. The reaction of... 

Copper catalyzed reaction of the homoenolate 9 with an acetal of an unsaturated aldehyde proceeds in an SN2 manner, Eq. (41), the net reaction representing a 1,2-addition of the homoenolate. The presence of Me3SiCl or BF3 Et20 is mandatory in this reaction [29]. 

The reaction of zinc homoenolate 9 with acid chlorides in ethereal solvents containing 2 equiv of HMPA rapidly produces 4-ketoesters in high yield Eq. (44) [33]. A palladium catalyst [40] (or less effectively a copper catalist) [28] accelerates the reaction. This is in contrast to the cyclopropane formation in a nonpolar solvent see (Eq. 22 above). 

A very practical route to zinc homoenolate involves reduction of 3-iodoesters with zinc/copper couple in the presence of a polar solvent, e.g. DMF, DMA [49] Eq. (51). The nature of the species obtained in this approach is not well-defined, but appears to be essentially the same as the one obtained along the siloxycyclo-propane route. Acylation, arylation, and vinylation reactions have been reported. 

DeCamp et al.t19l synthesized the lactone intermediate of the 1-hydroxyethylene isostere with high yields and stereoselectivity. As summarized in Scheme 10 (Section 10.6.2), the titanium homoenolate is prepared from ethyl 3-iodopropionate. The iodide is metalated with zinc/copper couple to give the iodozinc homoenolate species. The alkyltitanium homoenolate is then generated by transmetalation of the iodozinc precursor with one of the several chlorotitanium isopropoxide species. The resulting titanium homoenolate reacts with a N-protected a-amino aldehyde, leading to a mixture of 45-diastereomers. In the last step, the product is lactonized. 

Reformatsky reagent which then adds to carbonyl derivatives according to Scheme 20. These authors also observed conjugate addition of the homoenolate anion to a,)5-unsaturated ketones in the presence of copper ion as shown ... 

Conjugate addition of catalytically generated zinc homoenolate (cf. Eq. 39) has been used for the stereoselective synth b of a key inl mediate to ( )-cortisone (38). Precedents of the cuprate addition onto a tronr-fused hydrindane such as 35 was expected to give 36 but attack of the nucleophilic copper reagent from the desirable, le hindered oc-side. Although treatm t of the enone 35 with the zinc homoenolate under standard condition (Eq. 39, MCjSiCI/HMPA/ cat. CuBr - MejS) afforded the adduct in quantitative yield, the product was a 1 1 mixture of 36 and 37. In contrast, use of BFj EtjO instead of M iO gave the desired isomer 36 with better than 9S% selectivity with some additional steps... 

Treatment with zinc/copper couple activated by ultrasound in dimethylacetamide gave the zinc homoenolate 57 stabilised by chelation to either the ester or the carbamate. Acylation with acid chlorides and Pd(0) catalysis gave the enantiomerically pure y-oxo-amino acids 58 in good yield. 

Reaction of a silyloxycyclopropane and Cu(Bp4)2 in ether results in symmetrical coupling of two homoenolate moieties (Scheme 10). This reaction provides a convenient route to 1,6-diketones. Intermediacy of a copper(II) homoenolate has been suggested. AgBp4 and Cup2 effect the same reaction,... 

Copper(I) and metals of the nickel triad have been used to effect allylation, aryladon, vinylation and acylation reactions of zinc homoenolates. Transient homoenolates generated under Pd catalysis and Ag catalysis have also been used for direct arylation and acylation of silyloxycyclopropanes. 

Zinc homoenolates (9) react rapidly with acid chlorides in ethereal solvents containing a dipolar aprotic solvent to give 1,4-keto esters in high yield (Scheme 23). 9 palladium catalyst (or, less effective, a copper catalyst) ° accelerates the reaction, in contrast to cyclopropane formation in halometh-ane solvents (see Section 1.14.3.1). 

Reduction of 3-iodocarbonyl compounds with a zinc/copper couple in polar solvents (e.g. DMF, DMA) > generates homoenolates of esters, nitriles and ketones - (Scheme 24). These species are not well defined, but they appear to be very similar to those obtained by the silyloxycyclopropane route. 

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