Enantioselective Synthesis of Quaternary Carbon Stereogenic Centers through Copper‐Catalyzed Conjugate Additions of Aryl‐ and Alkylaluminum Reagents to Acyclic Trisubstituted Enones

Development of methods for efficient catalytic enantioselective conjugate addition (ECA) of readily accessible carbon-based nucleophiles to α,β-unsaturated carbonyls is a major objective of research in chemical synthesis.[1] Progress has been made in designing effective chiral complexes that promote a variety of catalytic ECA reactions. One especially challenging area corresponds to transformations that furnish all-carbon quaternary stereogenic centers;[2] recent years have witnessed a number of important advances in this regard,[3, 4, 5, 6] including applications to synthesis of complex natural products.[7] Nonetheless, several important limitations remain. One shortcoming is that the majority of processes relate to reactions with cyclic systems.[4-7] The paucity of ECA processes that involve acyclic trisubstituted substrates might be because their transformations, unlike those of cyclic enones, are not facilitated by ring strain; catalysts shown to be effective in differentiating the enantiotopic faces of a Z cyclic olefin might not provide optimal enantioselectivity with commonly used linear E alkenes. The limited number of cases involving acyclic substrates[3] correspond to incorporation of alkyl groups or highly activated Meldrum acid derivatives.[3b-d] There is one report of enantioselective Rh-catalyzed ECA of acyclic enoates with sodium tetraarylborates (one aryl unit transferred);[8] in a recent disclosure, three related examples of Pd-catalyzed ECA with PhB(OH)2 are shown to proceed in up to 80:20 enantiomeric ratio (e.r.).[6c] Another study relates to Cu-catalyzed ECA of methyl units to acyclic α,β-unsaturated aryl- or heteroaryl-substituted ketones; in all but one case (with Et3Al), Me3Al was used.[9]