Conjugate addition reactions catalyst

Quite a number of asymmetric thiol conjugate addition reactions are known [84], but previous examples of enantioselective thiol conjugate additions were based on the activation of thiol nucleophiles by use of chiral base catalysts such as amino alcohols [85], the lithium thiolate complex of amino bisether [86], and a lanthanide tris(binaphthoxide) [87]. No examples have been reported for the enantioselective thiol conjugate additions through the activation of acceptors by the aid of chiral Lewis acid catalysts. We therefore focussed on the potential of J ,J -DBFOX/ Ph aqua complex catalysts as highly tolerant chiral Lewis acid catalyst in thiol conjugate addition reactions. 

With the success in Lewis acid-catalyzed thiol conjugate addition reactions mentioned above, we further tried to apply the J ,J -DBFOX/Ph-nickel(II) aqua complex catalyst to the catalyzed asymmetric conjugate addition reactions of hydroxyl-amines [88, 89]. However, after some preliminary examinations, we found that... 

The l ,J -DBFOX/Ph-transition metal aqua complex catalysts should be suitable for the further applications to conjugate addition reactions of carbon nucleophiles [90-92]. What we challenged is the double activation method as a new methodology of catalyzed asymmetric reactions. Therein donor and acceptor molecules are both activated by achiral Lewis amines and chiral Lewis acids, respectively the chiral Lewis acid catalysts used in this reaction are J ,J -DBFOX/Ph-transition metal aqua complexes. 

The mechanism of the cyanide- and thioazolium ion-catalyzed conjugate addition reactions is considered to be analogous to the Lapworth mechanism for the cyanide-catalyzed benzoin condensation. Thus the cyano-stabilized carbanion resulting from deprotonation of the cyanohydrin of the aldehyde is presumed to be the actual Michael donor. After conjugate addition to the activated olefin, cyanide is eliminated to form the product and regenerate the catalyst. 

Nickel catalysts can be used instead of copper catalysts to promote the conjugate addition reaction, providing, in some cases, better results than the corresponding copper catalysts. In 2000, Yang et al. discovered a series of (li ,25, 3i )-3-mercaptocamphan-2-ol derivatives, which proved to be efficient ligands in the conjugate addition of ZnEt2 to chalcone upon catalysis with Ni(acac)2 (Scheme 2.29). 

As is the case for aldol addition, chiral auxiliaries and catalysts can be used to control stereoselectivity in conjugate addition reactions. Oxazolidinone chiral auxiliaries have been used in both the nucleophilic and electrophilic components under Lewis acid-catalyzed conditions. (V-Acyloxazolidinones can be converted to nucleophilic titanium enolates with TiCl3(0-/-Pr).320... 

Several modifications have been made to organoaluminum-based catalysts. Methylaluminum bis(2,6-di-tert-butyl-4-alkylphenoxide) (MAD) shows high diastereofacial selectivity in carbonyl alkylation (Scheme 72).31 11 Aluminum tris(2,6-diphenylphenoxide) (ATPH) has been developed as a catalyst for conjugate addition reactions. Since a carbonyl group is stabilized by steric effect of ATPH, the 1,4-adduct is obtained selectively.312... 

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. 

Zhou and Pfaltz (149) note that complex 215 mirrors the behavior of van Koten s complex 210. The catalyst is trimeric in solution and solid state and displays an intricate nonlinear effect (78, 146) in the conjugate addition reaction, Fig. 19 (149). It seems likely that these ligand-metal complexes are structurally related. 

To investigate the effect of the substituents in the arenethiolate structure, four differently substituted copper arenethiolates, 25-28, were tested as catalysts, but very low ees were obtained in all cases [34]. The oxazolidine complex 26, developed by Pfaltz et al. [36] and used successfully in asymmetric conjugate addition reactions to cyclic enones, gave a completely racemic product with allylic substrate 20a. 

Type B enamine catalysts have been developed more recently. They include the diarylprolinol ethers (developed by the Hayashi and Jprgensen groups, e.g. 47 and its derivatives) [71-75] as well as the MacMillan imidazolidinone catalysts (e.g. 46) [76-78]. They excel in reactions where hydrogen bonding assistance is either not required or is not essential, such as a-halogenation reactions as well as some conjugate addition reactions (Scheme 12). 

Formation of C-C bonds remains the ultimate challenge to the synthetic chemist. The employment of new synthetic methods in complex target synthesis can be frustrated by a lack of functional group tolerance and substrate specificity. These problems can be somewhat alleviated within conjugate addition reactions by the use of secondary amine catalysts where a number of important and highly selective methods have been developed. Two principle classes of nucleophile have been shown to be effective in the iminium ion activated conjugate addition of carbon nucleophiles to a,P-unsaturated carbonyl systems aryl, heteroaromatic and vinyl... 

The first application of NMR diffusion measurements to determine the aggregation state of a transition metal catalyst concerned the chiral, tetranuclear Cu(i) catalysts 130-132, used in the conjugate addition reactions of anions to a,p-unsatu-rated cyclic ketones. Compounds 130-132 react wdth isonitriles to form 133-135, and do not degrade to lower molecular weight species (see Eq. (20)) [109]. 

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