On the mechanism of Cu-catalyzed enantioselective extended conjugate additions: A structure-based approach

Abstract

The enantioselective 1,6-addition to unsaturated carbonyl compounds offers unique opportunities to study the range of selectivities one can obtain using Cu catalysis. Here, a substrate-reagent approach to obtain structural information on the mechanism of extended conjugate additions is reported. By studying the influence of several halides in the Grignard reagent and in the Cu source on the enantioselective 1,6-addition, it was shown that it is advantageous to use a combination of EtMgBr as Grignard reagent and CuI as Cu source. Furthermore, exploring substrates bearing several alkyl esters revealed that tBu-ester substrates enhance the enantiodiscrimination in the 1,6-addition and allow the addition of BnCH 2 MgBr. Substrates with a variety of electron-withdrawing groups were investigated as well, identifying that ester substrates are optimal for the 1,6-addition. Two other investigations feature Me-substituted olefin substrates and substrates with all possible olefin geometries. These studies show unprecedented high enantioselectivity in the 1,6-addition when α-Me substrates are used and give relevant insight into the 1,6-addition mechanism. Finally, substrates with three or four olefins in conjugation with the electron-withdrawing groups were studied. Here, a 1,8-addition is reported that gives the corresponding products in reasonable yield, regio- and stereoselectivity. With the combined results of these studies, elucidating key substrate and reagent parameters, an adapted mechanism for the enantioselective 1,6-addition is proposed. This mechanism features the activation of a dimeric precatalyst by an equivalent of Grignard reagent, active catalyst coordination to the internal olefin of the substrate in a Cu I -π-complex, followed by coordination of the catalyst to the remote olefin forming another Cu I -π-complex. From the latter Cu I -complex, an oxidative addition gives a Cu III -σ-complex at the δ-carbon, followed by transfer of the alkyl moiety to the δ-position. This reductive elimination yields the product and reforms the active Cu I catalyst via transmetalation with another molecule of Grignard reagent.