Enones cuprate complex

The poor diasteroselectivity at the yS-carbon of cyclic enones arises from poor facial selectivity during cuprate addition. Acyclic enones may also give poor dia-stereoselectivity at the y8-carbon center because of E Z isomerization arising from an equilibrium between an enone-cuprate d-re complex and starting materials. Much work remains to be done in the development of asymmetric variations in a-aminoalkylcuprate chemistry. 

In many cases a Lewis acid has been added to a cuprate to enhance its reactivity with an enone, but there are also examples for which the Lewis acid-organocopper reagents do not work well, (Scheme 10). Reaction of the bicyclic enonate (24) with Me2CuLi led to smooth conjugate addition,71 but the use of either Me2CuLiBF3 or MeCuBFj resulted in formation of a dark resinous material. It is often difficult to predict when the reaction will go astray, but it should be recognized that a Lewis acid-cuprate complex is not always an effective solution to a reactivity problem. 

The reversal of the stereoselectivity is attributed to the ability of chlorotrimethylsilane to trap the initially formed cuprate-enone complex, thereby suppressing equilibration of the diastereomeric complexes. The copper-catalyzed 1,4-addition of Grignard reagents to 5-substituted 2-cyclo-hexenone also proceeded with very high trans diastereoselectivity22. 

The mechanism of conjugate addition reactions probably involves an initial complex between the cuprate and enone.51 The key intermediate for formation of the new carbon-carbon bond is an adduct formed between the enone and the organocopper reagent. The adduct is formulated as a Cu(III) species, which then undergoes reductive elimination. The lithium ion also plays a key role, presumably by Lewis acid coordination at the carbonyl oxygen.52 Solvent molecules also affect the reactivity of the complex.53 The mechanism can be outlined as occurring in three steps. 

Tanaka et al. (152) demonstrated that a chiral copper alkoxide could be used substoichiometrically to deliver MeLi to an enone in conjugate fashion. The precatalyst is formed from amino alcohol 221, MeLi and Cul, Eq. 123a. Under stoichiometric conditions, this catalyst mediates the conjugate addition of MeLi to the macrocyclic enone, affording muscone in 91% ee. Lower enantioselectivity is observed using a substoichiometric amount of 222 (0.5 equiv), affording a 79% yield of muscone in 76% ee, Eq. 123b. These selectivities are attained by portion-wise addition of the substrate and MeLi to the alkoxy-cuprate. This catalyst also exhibits a complex nonlinear effect (78, 153). 

An interesting chromium system example is represented by complex 145. Addition of cyano-Gilman cuprates occurred with complete diastereoselectivity to give conjugate adducts 146 (Scheme 6.28). Interestingly, the opposite diastereomer was accessible by treatment of enone 145 with a titanium tetrachloride/Grignard reagent combination [71c]. 

Ar= Ph, p-MePh, o-MePh R = allyl, Me, Ph, cyclopropyl, n-butyl Scheme 6.28. Diastereoselective cuprate addition to a planar chiral a lchromium enone complex 145. 

Scheme 6.29. Diastereoselective cuprate addition to chiral molybdenum Ti-allyl enone complex 147.

This rate expression is consistent with the reaction scheme shown in Eq. 10.6, formulated on the basis of the Krauss-Smith paper. Thus, the initially formed cuprate dimer/enone complex with lithium/carbonyl and copper/olefin coordinations [71, 72] transforms into the product via an intermediate or intermediates. A lithium/ carbonyl complex also forms, but this is a dead-end intermediate. Though detailed... 

Experimental evidence indicates that cuprates in solution exist largely as dimer (RiCuLi) (25), which is found as the reactive species in conjugate addition. The kinetic results were consistent with the participation of the dimer (R2CuLi)2/enone complex 26 (Figure 24) in the C—C bond-forming process of the conjugate addition. Relatively unreactive a, -unsaturated ketones, esters and nitriles were also found to form complexes represented by 26 in Figure 24. 

Since NMR studies suggest a Ca—Cf, double bond in 26 to be significantly weak, a better representation of the cuprate/enone complex is as a cupriocyclopropene 27, which is represented in the reaction shown in Figure 25. However, the indispensability of the dimeric cluster in the crucial C—C bond-forming step is not clearly understood. 

Interesting and useful variations in R involve more complex alkyllithium reagents. For example, the treatment of (3-iodoenone (10) with lithium phenylthio(2-vinylcyclopropyl)cuprate gave the conjugate addition product (11) as an intermediate en route to the bicyclic dienone (12 82% equation 9).35 The ability of a cuprate to deliver a functionalized group to the enone was a definite advantage in this synthetic scheme. 

Phosphine-complexed cuprates, formed from copper(I) iodide, 1 mol equiv. of RtLi, and 2-5 mol equiv. of tri-n-butylphosphine, show good reactivity in conjugate addition reactions with enones (Table l).39 The hazards surrounding the use of excess Bun3P, and the availability of other methodologies lower the popularity of this method, but efficiency can be realized with this methodology. 

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