Copper zinc enolate addition

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. 

Chlorodifluoromethylketones underwent aldol reactions (Eq. 124) via zinc enolates, to afford good yields of a,a-difluoro-/ -hydroxy ketones, in a study by the Kyoto group [327]. Copper(I) or silver salt catalysis was essential and boron-trifluoride additive appeared to exert a key role in the conversion to the enolate. Earlier [328], chlorodifluoromethyl ketones had been converted to the di-fluoroenoxy silanes by the action of zinc in the presence of chlorotrimethyl silane. A difluoroenoxy silane was used by McCarthy and co-workers [329] to synthesise a kynureninase inhibitor (Eq. 125) Lewis acid-mediated reaction with a chloroglycinate installed the key carbon-carbon bond. 

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). 

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]. 

The preparation of silyl enol ethers from carbonyl compounds represents one of the major uses of TMSOTf. Recently, the stereochemistry and regiospeciflcity of such transformation has been addressed for aldehydes and Q -(lV-alkoxycarbonylamino) ketones, respectively. On the other hand, enantiopure silyl enol ethers can be formed by addition of TMSOTf to zinc enolates, which are obtained from the copper-catalyzed enantioselective conjugate addition of dialkyIzinc reagents to cyclic (eq 36) and acyclic enones. ... 

Another example of a domino allylation reaction was published by Cook and Jarugumili [169]. Fe2(CO)g in combination with PPhj has been identified as a low-cost and environmentally benign catalyst system for the allylation of zinc enolates 158 generated in situ from copper-catalyzed asymmetric conjugate addition reactions. This catalyst system provides the allylated products 159 in modest to good yields at room temperature with unprecedented diastereoselectivity in cyclic enone systems (Scheme 12.74). 

For instance, it is reported that a chiral copper catalyst (R,R)-L promotes asymmetric conjugate addition of dialkyl zinc to a,p-unsaturated ketone 19 to form homochiral zinc enolate 20. This intermediate is then trapped in situ with NPP as electrophile, without the need of additional palladium catalysis. Good yield, high trans/cis (95/5) ratio, and excellent enantioselectivity (99%) are obtained. Moreover, the multi-functionalized nature of 21 makes it a versatile intermediate for further elaboration. 

A derivatization of zinc enolates like 418, formed in a copper-catalyzed conjugate addition, by trapping as silyl enol ethers 419 was reported by Alexakis group [209]. The addition occurred in very high enantioselectivity when mediated by phosphoramidite 417 or related ligands. Remarkably, the selectivity was distinctly lower when chlorotrimethylsilane was present from the beginning. Therefore,... 

The challenge of three-component synthesis of prostaglandines has been met by Ryoji Noyori et /. with extraordinary success. The assembly of the "lower" ((d) and the "upper" (a) side chain is accomplished in a "one-pot" protocol. The (D-side chain is attached by addition of (5)-/raiw-3-terr-butyldimethylsiIyIoxy-l-octenyllithium complexed with one equivalent of dimethylzinc or, alternatively, with copper iodide and tributylphosphine. To install the a-chain, the zinc enolate formed in the preceding step is directly condensed with the functionalized cts-allylic or propargylic part, whereas the copper enolate has to be added in the presence of triphenyltin chloride and hexamethylphosphoric acid triamide (HMPA). ... 

The allylic or benzylic alkylation of chiral zinc enolates, resulting from an asynunetric copper-catalysed conjugate addition reaction of dialkylzinc, has been performed with allylic or benzylic halides in reasonable yields and high diastereoselectivities (up to 20 1 dr). ... 

The key step to this first reported case of the highly diastereoselective addition of a fluorinated enolate in an aldol process is the selective formation of the enolate a,a-Difluonnated enolates prepared by a metallation process employing either a zinc-copper couple [S] or reduced titanium species [9] undergo aldol condensation smoothly (equation 9) (Table 5)... 

Asymmetric conjugate addition of dialkyl or diaryl zincs for the formation of all carbon quaternary chiral centres was demonstrated by the combination of the chiral 123 and Cu(OTf)2-C H (2.5 mol% each component). Yields of 94-98% and ee of up to 93% were observed in some cases. Interestingly, the reactions with dialkyl zincs proceed in the opposite enantioselective sense to the ones with diaryl zincs, which has been rationalised by coordination of the opposite enantiofaces of the prochiral enone in the alkyl- and aryl-cuprate intermediates, which precedes the C-C bond formation, and determines the configuration of the product. The copper enolate intermediates can also be trapped by TMS triflate or triflic anhydride giving directly the versatile chiral enolsilanes or enoltriflates that can be used in further transformations (Scheme 2.30) [110],... 

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