Organozinc compounds conjugate additions

Feringa and co-workers described the tandem addition-aldol cyclization protocol leading to the formation of 6,6-, 6,7-, and 6,8-annulated bicyclic systems (Scheme 68).39 Using Cu(n)-29 as catalyst and functionalized organozinc reagents as nucleophiles, the conjugate addition reaction followed by aldol cyclization can offer highly enantioselec-tive annulation products (up to 98% ee). This method can be used in the synthesis of carbocyclic compounds, such as steroids, terpenes, and other natural products. 

There are a large number of reports on copper(I)-catalyzed conjugate additions, yet there is only scant information available about their reaction mechanisms. Recently, the conjugate addition of organozinc compounds to enones was found by Kitamura, Noyori, et al. to be catalyzed by N-benzylbenzenesulfonamide and CuCN, and the mechanism was scrutinized (Fig. 10.1). The kinetic rate was found to be first order in the concentrations of the catalyst that exist in equilibrium with R2Zn and enone [77]. 

The Pd-catalyzed acylation of organozincs was reported in 1983144, and it has since been widely employed as one of the most satisfactory methods of acylation of organometals20. Even in cases where ,/J-unsaturated carbonyl compounds are the products, their subsequent conjugate addition reactions do not appear to be competitive. Among recent examples of its application to the synthesis of natural products, the synthesis of amphidi-nolides Tl, , T4 and T5 by Fiirstner and coworkers213 is particularly noteworthy (Scheme 81). 

An indirect addition converts alkynes to an organozinc compound using a palladium catalyst, which then reacts with allylic halides. " Similarly, the reaction of an alkyne with Ti(0/Pr)4/2 /PrMgCl followed by addition of an alkyne leads to a conjugated diene. 

Organozinc compounds add to conjugated systems. The use of chiral ligands is effective for conjugate addition of diaUcylzinc compounds to a,p-unsaturated ketones, esters, and so on, including conjugated lactones." Many dialkyl-zinc compounds can be used, including vinylzinc compounds.Dialkylzinc... 

Keywords Ligand, Ether, Amine, Nucleophilic addition, Organolithium, Grignard reagent, Organozinc, Copper, Phosphorus, Conjugate addition. Alkylation, Phosphine, Activated olefin, P-Substituted carbonyl compound... 

Various other examples of nickel-catalyzed asymmetric addition of organozinc compounds to enones have been reported using different chiral auxiliaries111-117. Complexes of other transition metals, such as rhodium118-119, lanthanum120, and titanium121, have also been found to promote asymmetric conjugate addition of enolates to a,/i-unsaturated ketones. 

To extend the scope of the carbometallative aldol cycloreduction, the feasibility of Cu-catalyzed conjugate addition-aldol cyclization process was examined. Cu-catalyzed addition of organozinc compounds to o ,jS-unsaturated carbonyl compounds has been well established (169-171,187-189). Trapping of the Zn-enolates using aldehydes (169,188,190) and acetals/ketals (191) has been reported however, the use of ketones as electrophiles to trap Zn-enolates failed in the absence of strong Lewis acids (191). Rrische and co-workers reported the first successful example of Cu-catalyzed tandem conjugate addition-aldol cyclization with ketones, esters, and nitriles as electrophiles (Scheme 107) (192). In this cyclization process, enone-ketones 237 and 239 afforded products in good to excellent... 

---